Maria Agnese Fabbri

Randomized Trial of Two Induction Chemotherapy Regimens in Metastatic Colorectal Cancer: An Updated Analysis

BACKGROUND In a randomized trial with a median follow-up of 18.4 months, 6 months of induction chemotherapy with a three-drug regimen comprising 5-fluorouracil (by continuous infusion)-leucovorin, irinotecan, and oxaliplatin (FOLFOXIRI) demonstrated statistically significant improvements in response rate, radical surgical resection of metastases, progression-free survival, and overall survival compared with 6 months of induction chemotherapy with fluorouracil-leucovorin and irinotecan (FOLFIRI). METHODS From November 14, 2001, to April 22, 2005, we enrolled 244 patients with metastatic colorectal cancer. To evaluate if the superiority of FOLFOXIRI is maintained in the long term, we updated the overall and progression-free survival data to include events that occurred up to February 12, 2009, with a median follow-up of 60.6 months. We performed a subgroup and a risk-stratified analysis to examine whether outcomes differed in specific patient subgroups, and we analyzed the results of treatment after progression. Survival curves were estimated by the Kaplan-Meier method. Multivariable Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS FOLFOXIRI demonstrated statistically significant improvements in median progression-free survival (9.8 vs 6.8 months, HR for progression = 0.59, 95% CI = 0.45 to 0.76, P < .001) and median overall survival (23.4 vs 16.7 months, HR for death = 0.74, 95% CI = 0.56 to 0.96, P = .026) with a 5-year survival rate of 15% (95% CI = 9% to 23%) vs 8% (95% CI = 4% to 14%). The improvements in progression-free survival and, to a lesser extent, in overall survival were evident even when the analysis excluded patients who received radical resection of metastases. With regard to the risk-stratified analysis, FOLFOXIRI results in longer progression-free survival and overall survival than FOLFIRI in all risk subgroups. CONCLUSIONS Six months of induction chemotherapy with FOLFOXIRI is associated with a clinically significant improvement in the long-term outcome compared with FOLFIRI with an absolute benefit in survival at 5 years of 7%.

Chemosensitivity profile assay of circulating cancer cells: prognostic and predictive value in epithelial tumors

The prognostic value associated with the detection of circulating tumor cells (CTCs) in metastatic breast cancer by the CellSearch™ technology raise additional issues regarding the biological value of this information. We postulated that a drug‐resistance profile of CTCs may predict response to chemotherapy in cancer patients and therefore could be used for patient selection. One hundred 5 patients with diagnosis of carcinoma were enrolled in a prospective trial. CTCs were isolated from peripheral blood, and positive samples were evaluated for the expression of a panel of genes involved in anticancer drugs resistance. The drug‐resistance profile was correlated with disease‐free survival (DFS; patients in adjuvant setting) and time to progression (TTP; metastatic patients) in a 24‐months follow‐up. Objective response correlation was a secondary end point. Fifty‐one percent of patients were found positive for CTCs while all blood samples from healthy donors were negative. The drug‐resistance profile correlates with DFS and TTP (p < 0.001 in both). Sensitivity of the test: able to predict treatment response in 98% of patients. Specificity of the test: 100%; no sample from healthy subject was positive for the presence of CTCs. Positive and negative predictive values were found to be 96.5 and 100%, respectively. We identified a drug‐resistance profile of CTCs, which is predictive of response to chemotherapy, independent of tumor type and stage of disease. This approach may represent a first step toward the individualization of chemotherapy in cancer patients.

Role of KRAS-LCS6 polymorphism in advanced NSCLC patients treated with erlotinib or docetaxel in second line treatment (TAILOR).

MicroRNAs were described to target mRNA and regulate the transcription of genes involved in processes de-regulated in tumorigenesis, such as proliferation, differentiation and survival. In particular, the miRNA let-7 has been suggested to regulate the expression of the KRAS gene, a common mutated gene in non-small cell lung cancer (NSCLC), through a let-7 complementary site (LCS) in 3′UTR of KRAS mRNA. We have reported the analysis performed on the role of the polymorphism located in the KRAS-LCS (rs61764370) which is involved in the disruption of the let-7 complementary site in NSCLC patients enrolled within the TAILOR trial, a randomised trial comparing erlotinib versus docetaxel in second line treatment. In our cohort of patients, KRAS-LCS6 polymorphism did not have any impact on both overall survival (OS) and progression free survival (PFS) and was not associated with any patient’s baseline characteristics included in the study. Overall, patients had a better prognosis when treated with docetaxel instead of erlotinib for both OS and PFS. Considering KRAS-LCS6 status, the TG/GG patients had a benefit from docetaxel treatment (HR(docetaxel vs erlotinib) = 0.35, 95% CI 0.15–0.79, p = 0.011) compared with the TT patients (HR(docetaxel vs erlotinib) = 0.72, 95% CI 0.52–1.01, p = 0.056) in terms of PFS.

Fulvestrant 500 milligrams as endocrine therapy for endocrine sensitive advanced breast cancer patients in the real world: the Ful500 prospective observational trial

The observational prospective trial herein presented aimed at evaluating the efficacy of fulvestrant 500 mg in the treatment of endocrine sensitive advanced breast cancer patients from the real world setting. The primary end point was clinical benefit rate (CBR). Secondary end points were overall survival (OS), progression free survival (PFS) and tolerability. One hundred sixty three patients were enrolled. At a median follow up of 20 months, the 61% of patients reached CBR, whose median duration was 10.8 months. Median PFS and OS were 7 and 35 months, respectively. Endocrine sensitive patients showed better PFS and OS. No relevant toxicity appeared when analyzing safety data. In multivariate analysis, visceral involvement, endocrine sensitivity and previous endocrine therapy were prognostic factor for PFS, whereas endocrine sensitivity and metastasis at diagnosis had prognostic relevance for OS. Estrogen receptor expression >50%, single metastatic site, and no prior endocrine therapy for advanced disease were predictive of CBR. In this prospective trial, fulvestrant 500 mg appeared to be a safe and active treatment and confirmed its efficacy in the daily clinical practice. A high percent expression of estrogen receptors (above 50%) was associated with higher CBR. Treatment was very well tolerated. Endocrine sensitivity had a major impact on treatment outcome. As expected, patients who had received first-line endocrine therapy for advanced disease exhibited worse outcome and a lower CBR.The observational prospective trial herein presented aimed at evaluating the efficacy of fulvestrant 500 mg in the treatment of endocrine sensitive advanced breast cancer patients from the real world setting. The primary end point was clinical benefit rate (CBR). Secondary end points were overall survival (OS), progression free survival (PFS) and tolerability. One hundred sixty three patients were enrolled. At a median follow up of 20 months, the 61% of patients reached CBR, whose median duration was 10.8 months. Median PFS and OS were 7 and 35 months, respectively. Endocrine sensitive patients showed better PFS and OS. No relevant toxicity appeared when analyzing safety data. In multivariate analysis, visceral involvement, endocrine sensitivity and previous endocrine therapy were prognostic factor for PFS, whereas endocrine sensitivity and metastasis at diagnosis had prognostic relevance for OS. Estrogen receptor expression >50%, single metastatic site, and no prior endocrine therapy for advanced disease were predictive of CBR. In this prospective trial, fulvestrant 500 mg appeared to be a safe and active treatment and confirmed its efficacy in the daily clinical practice. A high percent expression of estrogen receptors (above 50%) was associated with higher CBR. Treatment was very well tolerated. Endocrine sensitivity had a major impact on treatment outcome. As expected, patients who had received first-line endocrine therapy for advanced disease exhibited worse outcome and a lower CBR.

Abiraterone acetate in metastatic castration-resistant prostate cancer after chemotherapy: A “real life” retrospective analysis of progression-free (PFS) and overall survival (OS) according to duration of androgen deprivation therapy.

337 Background: Abiraterone acetate (AA) is a potent, selective androgen (CYP17) biosynthesis inhibitor, which showed to improve overall survival in mCRPC pts progressing after docetaxel. Few data are available concerning the clinical outcome of AA treatment in mCRPC in terms of the duration of prior androgen deprivation therapy (ADT). In this retrospective analysis we assessed the PFS and OS in patients affected with mCRPC according to the duration of ADT. Methods: We retrospectively reviewed the clinical data of pts affected by mCRCP progressive after chemotherapy who received AA (1000 mg/d) plus prednisone (5 mg/twice daily). A total of 189 pts were included in the analysis, 71 received AA with ADT duration<12 months (Group A) and 118 received AA with ADT duration ≥ 12 months (Group B). Patient characteristics’ in the two treatment groups (A VS B) were: median age: 75 vs 69 years, Gleason score ≥7: 96% vs 92%; median PSA at AA start 47 (range 36-2130) vs 32 (range 85-2100), No of metastatic sites: 1 : ...

Epirubicin and docetaxel as first-line treatment for hormonal receptor positive metastatic breast cancer: the predictive value of luminal subtype: A retrospective cohort analysis

Abstract Background: We retrospectively evaluated the efficacy of first-line epirubicin and docetaxel in patients with metastatic, hormonal receptor (HR)-positive, and human epidermal growth factor receptor-2-negative breast cancer. A subgroup analysis evaluated the predictive value of immunohistochemistry-defined luminal subtype. Methods: We included patients with at least one visceral and measurable site of metastatic disease. Patients were grouped as luminal A (HR+ and Ki67<13%) or luminal B (HR+ and Ki67>13%). Results: Forty-four patients were entered and prognostic variables were similar between the subgroups. Luminal B patients achieved higher objective response rate than luminal A (69% versus 19%; P = 0·001), longer time to progression (12·2 months versus 8·6 months; P = 0·039), and longer overall survival (24·6 months versus 19·5 months; P = 0·041). The multivariate analysis confirmed the predictive value of luminal B subtype for longer time to progression. Conclusions: Identification by Ki67 labelling index of human epidermal growth factor receptor-2-negative luminal A could predict a substantial benefit from systemic chemotherapy. Endocrine therapy would be the most appropriate therapy for luminal A tumours.

Progression-free survival (PFS) with maintenance treatment with bevacizumab (B) in patients with responding mCRC after first-line chemotherapy (CT) plus B.

612 Background: Maintenance treatment with B is considered an option for mCRC pts in responding pts after a first line CT + B, but few data are available on its real benefit on PFS. METHODS We collected data from a cohort of mCRC pts consecutively treated in five oncologic centers of Lazio. One-hundred-ninety-nine mCRC pts treated with first line CT + B achieving a response [partial (PR) or complete (CR)] or a stable disease (SD) were considered eligible, 117 pts had received B maintenance (BM) whereas 82 did not (noBM). The two groups were homogeneous for main characteristics. First-line therapy in the BM vs noBM group included FOLFIRI regimen (96 vs 59 pts), FOLFOX (18 vs 22 pts) and FUFA (3 vs 1 pts). K-ras status was analyzed in 115 pts with an higher percentage of wild-type (wt) in the BM group (65 vs 50 pts, p= 0.04). A CR or PR have been achieved in 65% of pts in the BM group and 61% of noBM group, while a SD was observed in 35% and 39% of pts respectively for the BM and noBM group. The median number of BM cycles administered was 7 (range 3-25). Effectiveness measures included the PFS duration. A multivariate Cox proportional hazard model was developed using stepwise regression (forward selection) Results: At a median follow-up of 18 months (1-109), the median PFS was 13 months (C.I.95%: 11-15) vs 8 months (C.I.95%: 7-10; p<0.0001, and the 1-year PFS 53% vs 28% for BM and noBM respectively. Pts with CR/PR had a mPFS of 15 months (CI 95% 12-19) vs 10 months (CI 95% 10-12) p=0.004 and a 1-year PFS of 62.6% vs 33.7% for the BM vs noBM group respectively. No difference in the 1-year PFS was observed in pts showing SD to chemotherapy and bevacizumab. The mPFS in these patients was 12 (CI 95% 10-13) vs 8 months (CI 95% 7-10, p=0.11) for the BM and noBM group respectively. The multivariate analysis did not show any difference in PFS comparing age, sex, number and site of metastasis, ECOG PS and k ras status. A significant difference in PFS was observed for response to first-line CT (CR/PR vs SD, p=0.002) and for BM vs noBM (p=0.003). CONCLUSIONS The maintenance strategy with B shows a longer PFS in pts responding to the first line chemotherapy + B whereas for pts who achieving an SD no difference was observed.