Henri Roché

Trastuzumab for Patients With Axillary-Node–Positive Breast Cancer: Results of the FNCLCC-PACS 04 Trial

PURPOSE To evaluate the efficacy of trastuzumab in patients with node-positive breast cancer treated with surgery, adjuvant chemotherapy, radiotherapy, and hormone therapy if applicable. PATIENTS AND METHODS Three thousand ten patients with operable node-positive breast cancer were randomly assigned to receive adjuvant anthracycline-based chemotherapy with or without docetaxel. Patients who presented human epidermal growth factor receptor 2 (HER2) -overexpressing tumors were secondary randomly assigned to either a sequential regimen of trastuzumab (6 mg/kg every 3 weeks) for 1 year or observation. The primary end point was disease-free survival (DFS). RESULTS Overall 528 patients were randomly assigned between trastuzumab (n = 260) and observation (n = 268) arm. Of the 234 patients (90%) who received at least one administration of trastuzumab, 196 (84%) received at least 6 months of treatment, and 41 (18%) discontinued treatment due to cardiac events (any grade). At the date of analysis (October 2007), 129 DFS events were recorded. Random assignment to the trastuzumab arm was associated with a nonsignificant 14% reduction in the risk of relapse (hazard ratio, 0.86; 95% CI, 0.61 to 1.22; P = .41, log-rank stratified on pathologic node involvement). Three-year DFS rates were 78% (95% CI, 72.3 to 82.5) and 81% (95% CI, 75.3 to 85.4) in the observation and trastuzumab arms, respectively. CONCLUSION After a 47-month median follow-up, 1 year of trastuzumab given sequentially after adjuvant chemotherapy was not associated with a statistically significant decrease in the risk of relapse.

Ki67 Expression and Docetaxel Efficacy in Patients With Estrogen Receptor–Positive Breast Cancer

PURPOSE The indications of adjuvant chemotherapy for patients with estrogen receptor (ER) -positive breast cancer are controversial. We analyzed the predictive value of Ki67, HER2, and progesterone receptor (PR) expression for the efficacy of docetaxel in patients with ER-positive, node-positive breast cancer. PATIENTS AND METHODS Expression of Ki67, HER2, and PR was measured by immunohistochemistry in tumor samples from 798 patients with ER-positive breast cancer who participated in PACS01, a randomized trial that evaluated the efficacy of docetaxel. Risk reduction was evaluated using a Cox model adjusted for age, tumor size, nodal involvement, treatment arm, and biomarkers. The predictive value of biomarkers was assessed by an interaction test. Disease-free survival (DFS) was the primary end point. Results Ki67, HER2, and PR were expressed in 21%, 9%, and 62% of samples, respectively. Hazard ratios for relapse associated with docetaxel were 0.51 (95% CI, 0.26 to 1.01) in ER-positive/Ki67-positive tumors and 1.03 (95% CI, 0.69 to 1.55) in ER-positive/Ki67-negative tumors (ratio for interaction: 0.53; 95% CI, 0.24 to 1.16; P = .11). Five-year DFS rates were 81% (95% CI, 76% to 86%) and 84% (95% CI, 75% to 93%) in patients with ER-positive/Ki67-negative and ER-positive/Ki67-positive tumors treated with docetaxel and 81% (95% CI, 76% to 86%) and 62% (95% CI, 52% to 72%) in patients with ER-positive/Ki67-negative and ER-positive/Ki67-positive tumors treated with fluorouracil, epirubicin, and cisplatin. No trend for interaction was observed between docetaxel and HER2 (ratio for interaction: 0.83; 95% CI, 0.35 to 1.94; P = .66), nor between docetaxel and PR (ratio for interaction: 0.89; 95% CI, 0.47 to 1.66; P = .71). CONCLUSION Ki67 expression identifies a subset of patients with ER-positive breast cancer who could be sensitive to docetaxel treatment in the adjuvant setting.

Sorafenib in Combination With Capecitabine: An Oral Regimen for Patients With HER2-Negative Locally Advanced or Metastatic Breast Cancer

PURPOSE Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized, double-blind, placebo-controlled phase IIB trial assessed sorafenib with capecitabine for locally advanced or metastatic human epidermal growth factor receptor 2 (HER2) -negative breast cancer. PATIENTS AND METHODS Patients were randomly assigned to first- or second-line capecitabine 1,000 mg/m(2) orally twice a day for days 1 to 14 of every 21-day cycle with sorafenib 400 mg orally twice a day or placebo. The primary end point was progression-free survival (PFS). RESULTS In total, 229 patients were enrolled. The addition of sorafenib to capecitabine resulted in a significant improvement in PFS versus placebo (median, 6.4 v 4.1 months; hazard ratio [HR], 0.58; 95% CI, 0.41 to 0.81; P = .001) with sorafenib favored across subgroups, including first-line (HR, 0.50; 95% CI, 0.30 to 0.82) and second-line (HR, 0.65; 95% CI, 0.41 to 1.04) treatment. There was no significant improvement for overall survival (median, 22.2 v 20.9 months; HR, 0.86; 95% CI, 0.61 to 1.23; P = .42) and overall response (38% v 31%; P = .25). Toxicities (sorafenib v placebo) of any grade included rash (22% v 8%), diarrhea (58% v 30%), mucosal inflammation (33% v 21%), neutropenia (13% v 4%), hypertension (18% v 12%), and hand-foot skin reaction/hand- foot syndrome (HFSR/HFS; 90% v 66%); grade 3 to 4 toxicities were comparable between treatment arms except HFSR/HFS (44% v 14%). Reasons for discontinuation in the sorafenib and placebo arms included disease progression (63% v 82%, respectively), adverse events (20% v 9%, respectively), and death (0% v 1%, respectively). CONCLUSION Addition of sorafenib to capecitabine improved PFS in patients with HER2-negative advanced breast cancer. The dose of sorafenib used in this trial resulted in unacceptable toxicity for many patients. A phase III confirmatory trial has been initiated with a reduced sorafenib dose.

Docetaxel vs 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure

This multicentre, randomised phase III study compared docetaxel with 5-fluorouracil+vinorelbine in patients with metastatic breast cancer after failure of neo/adjuvant or one line of palliative anthracycline-based chemotherapy. One hundred and seventy-six metastatic breast cancer patients were randomised to receive docetaxel (100 mg m−2) every 3 weeks or 5-fluorouracil+vinorelbine: 5-fluorouracil (750 mg m−2 per day continuous infusion) D1–5 plus vinorelbine (25 mg m−2) D1 and D5 of each 3-week cycle. Eighty-six patients received 516 cycles of docetaxel; 90 patients received 476 cycles of 5-fluorouracil+vinorelbine. Median time to progression (6.5 vs 5.1 months) and overall survival (16.0 vs 15.0 months) did not differ significantly between the docetaxel and 5-fluorouracil+vinorelbine arms, respectively. Six (7%) complete responses and 31 (36%) partial responses occurred with docetaxel (overall response rate 43%, 95% confidence interval: 32–53%), while 4 (4.4%) complete responses and 31 (34.4%) partial responses occurred with 5-fluorouracil+vinorelbine (overall response rate 38.8%, 95% confidence interval: 29–49%). Main grade 3–4 toxicities were (docetaxel vs 5-fluorouracil+vinorelbine): neutropenia 82% vs 67%; stomatitis 5% vs 40%; febrile neutropenia 13% vs 22%; and infection 2% vs 7%. There was one possible treatment-related death in the docetaxel arm and five with 5-fluorouracil+vinorelbine. In anthracycline-pretreated metastatic breast cancer patients, docetaxel showed comparable efficacy to 5-fluorouracil+vinorelbine, but was less toxic.

A multicentre phase II study of docetaxel 75 mg m−2 as first-line chemotherapy for patients with advanced breast cancer : report of the Clinical Screening Group of the EORTC

In this phase II study, 39 women (median age 51 years) with advanced breast cancer received docetaxel (75 mg m-2) intravenously over 1 h every 3 weeks as first-line chemotherapy for advanced disease, without routine premedication for hypersensitivity reactions. In 31 evaluable patients, an overall response rate of 52% (95% CI 33-70%) was achieved, including a complete response rate of 13%. The median time to first response was 12 weeks (range 3-35+), the median duration of response was 34 weeks (range 11-42+) and the median time to progression was 24 weeks (range 0-42+). Docetaxel showed considerable activity in patients with visceral involvement (52% response), including lung (67%) and liver (44%) metastases. The safety profile was acceptable. Grade 4 neutropenia occurred in 82% of patients (53% of cycles); febrile neutropenia (grade 4 neutropenia with fever > 38 degrees C, requiring antibiotics) occurred in only three (7.7%) patients (1.4% of cycles) and none of these required hospitalisation. Acute adverse events were generally well tolerated, with only two grade 3 events and no grade 4 events reported. Despite no prophylactic premedication, the incidence of acute hypersensitivity reactions was only 13%. Fluid retention was widely experienced (72% of patients) but was severe in only five (12.8%) patients and was the reason for discontinuation of treatment in 16 patients. Nevertheless, patients were able to receive a median cumulative dose of approximately 592 mg m-2 before discontinuing treatment, and the syndrome was slowly reversible after treatment withdrawal. In conclusion, docetaxel, even at a dose of 75 mg m-2, is confirmed to be an active agent in breast cancer. Compared with an earlier study of first-line docetaxel at the usual dose of 100 mg-2, it appears that 75 mg m-2 produces a lower response rate (52% vs 68%), although this still compares favourably with that of doxorubicin monotherapy in a similar patient population (43%). This difference is particularly striking in subgroups of patients with particularly poor prognostic factors, such as liver metastases or involvement of more than two organs. The incidence of fluid retention appears to be similar at the two doses and, it is likely that premedication with corticosteroids will be preferable to dose reduction for managing this adverse event.

Pharmacokinetics of irinotecan and its metabolites in human blood, bile, and urine

Two patients were treated with CPT-11 for colorectal cancer and had a percutaneous biliary catheter for extrahepatic biliary obstruction. The first patient was treated with CPT-11 according to the 100-mg/m2 weekly therapeutic schedule, and the second patient was treated every 3 weeks, with a dose of 350 mg/m2 being given at the first course, after which it was decreased to 300 mg/m2 for the following courses. In plasma, the active identified metabolite of CPT-11, SN-38, occurred mainly in the form of a glucuronide conjugate. CPT-11 was mainly excreted in bile and urine as CPT-11. The cumulative biliary and urinary excretion of CPT-11 and its metabolites (SN-38 and SN-38 glucuronide conjugate) over a period of up to 48 h ranged from 25% (100 mg/m2 weekly) to 50% (300 mg/m2 every 3 weeks). This means that CPT-11 can be excreted under other, not yet identified metabolite forms. CPT-11 is active in vivo, the intensity of its in vitro activity seems rather low. It has been suggested that its major identified metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38) plays a key role in the antitumor activity of CPT-11 [4]. Some in vitro data suggest that SN-38 is 250-to 1,000-fold as potent as CPT-11 in the inhibition of topoisomerase I activity [5]. Although a glucuronide of SN-38 has been found in the bile and urine of rats [3], data have not been reported on humans. However, only Rothenberg et al. [10] have studies the bile concentrations of CPT-11 and SN-38. This report summarizes the pharmacokinetics of CPT-11 and SN-38 and their glucuronide metabolites in the blood, bile, and urine of two patients treated with CPT-11.

HFS-14, a Specific Quality of Life Scale Developed for Patients Suffering from Hand–Foot Syndrome

BACKGROUND Hand-foot syndrome (HFS) is a common reaction to certain chemotherapies and new targeted therapies, impairing patient quality of life (QoL). However, there is currently no specific tool to measure QoL in patients with HFS. Objective. The objective was to develop and validate a HFS-specific QoL questionnaire (HFS-14). PATIENTS AND METHODS From a list of 31 items identified from a literature review and patient interview notes, item reduction and pilot testing by cognitive debriefing resulted in a final 14-item questionnaire with excellent internal reliability. Clinical validity was assessed in 43 patients with HFS by comparing the HFS-14 score according to HFS clinical grade based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 3.0, and by measuring its correlation with the Dermatology Life Quality Index (DLQI), Skindex-16, and short-form 12 health-related questionnaires and pain measurement. RESULTS The mean HFS-14 score was significantly higher in patients with clinical grade 2 and grade 3 HFS than in those with grade 1 HFS. The higher the HFS-14 score, the greater the QoL impairment. The HFS-14 score was highly correlated with the DLQI and Skindex-16 scores. In the population of patients with severe grade 3 NCI-CTCAE HFS, the HFS-14 score was significantly higher in patients having both hands and feet severely involved than in those with severe involvement of one limb (hands or feet) with the other one less severely affected. CONCLUSIONS This scale specifically developed for patients with HFS is a valid and valuable tool for measuring HFS-related QoL impairment.

Population pharmacokinetics of carboplatin in children

In pediatric patients, administration of carboplatin according to body surface area results in a large variation in the area under the plasma ultrafilterable carboplatin concentration versus time curve. A population pharmacokinetic study using the NONMEM program was undertaken to determine the effects of a variety of covariates on the clearance of ultrafilterable carboplatin.

SOLTI-0701: A Multinational Double-Blind, Randomized Phase 2b Study Evaluating the Efficacy and Safety of Sorafenib Compared to Placebo When Administered in Combination with Capecitabine in Patients with Locally Advanced or Metastatic Breast Cancer (BC).

INTRODUCTION: Sorafenib (SOR) is a potent multikinase inhibitor with anti-angiogenic and anti-proliferation activity. It is indicated for the treatment of advanced renal cell carcinoma and unresectable hepatocellular carcinoma. As a single agent, SOR has shown modest activity in patients with advanced BC. Here, we report results from one (SOLTI-0701) of four Phase 2b trials of sorafenib in combination with chemotherapy for advanced breast cancer.METHODS: SOLTI-0701 is a multinational, double-blind, randomized, placebo-controlled phase 2b study in patients with locally advanced or metastatic BC. Eligibility criteria included HER-2 negative tumors and Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 45.

Formation of the eIF4F Translation–Initiation Complex Determines Sensitivity to Anticancer Drugs Targeting the EGFR and HER2 Receptors

Elucidating how cancer cells respond to antagonists of HER receptor family members is critical to understanding mechanisms of therapeutic resistance that arise in patients. In large part, resistance to such agents appears to arise from deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway. mTOR-dependent phosphorylation of the translation repressor 4E-BP1 leads to its dissociation from eIF4E, thereby causing an increase in the formation of the eIF4F complex, which also comprises eIF4G and eIF4A. In this study, we show that trastuzumab, cetuximab, and erlotinib all decrease the formation of the eIF4F complex in breast, colon, and head and neck cancer cells, respectively. Ectopic expression of eIF4E restores the trastuzumab-dependent defect in eIF4F formation, renders cells resistant to the trastuzumab-mediated decrease in cell proliferation, and rescues breast cancer xenografts from inhibition by trastuzumab. In breast tumor specimens, the level of eIF4E expression is associated with the therapeutic response to a trastuzumab-based regimen. Together, our findings suggest that formation of the eIF4F complex may be a critical determinant of the response to anticancer drugs that target HER2 and epidermal growth factor receptor.