Search

Summary Background In 2013, the interim analysis of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial could not show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. Here, we report the planned final analysis based on the prespecified number of occurring events. Methods PHARE is an open-label, phase 3, non-inferiority randomised trial of patients with HER2-positive early breast cancer comparing 6 months versus 12 months of trastuzumab treatment concomitant with or following standard neoadjuvant or adjuvant chemotherapy. The study was undertaken in 156 centres in France. Eligible patients were women aged 18 years or older with non-metastatic, operable, histologically confirmed adenocarcinoma of the breast and either positive axillary nodes or negative axillary nodes but a tumour of at least 10 mm. Participants must have received at least four cycles of a chemotherapy for this breast cancer and have started receiving adjuvant trastuzumab-treatment. Eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab therapy duration between the third and sixth months of adjuvant trastuzumab. The randomisation was stratified by concomitant or sequential treatment with chemotherapy, oestrogen receptor status, and centre. The primary objective was non-inferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival with a prespecified hazard margin of 1·15. This trial is registered with ClinicalTrials.gov, number NCT00381901. Findings 3384 patients were enrolled and randomly assigned to either 12 months (n=1691) or 6 months (n=1693) of adjuvant trastuzumab. One patient in the 12-month group and three patients in the 6-month group were excluded, so 1690 patients in each group were included in the intention-to-treat analysis. At a median follow-up of 7·5 years (IQR 5·3–8·8), 704 events relevant to disease-free survival were observed (345 [20·4%] in the 12-month group and 359 [21·2%] in the 6-month group). The adjusted hazard ratio for disease-free survival in the 12-month group versus the 6-month group was 1·08 (95% CI 0·93–1·25; p=0·39). The non-inferiority margin was included in the 95% CI. No differences in effects pertaining to trastuzumab duration were found in any of the subgroups. After the completion of trastuzumab treatment, rare adverse events occurred over time and the safety analysis remained similar to the previously published report. In particular, we found no change in the cardiac safety comparison, and only three additional cases in which the left ventricular ejection fraction decreased to less than 50% have been reported in the 12-month group. Interpretation The PHARE study did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months. Funding The French National Cancer Institute.

The risk of relapse after local therapy remains unacceptable for the majority of patients with early stage breast cancer. Adjuvant chemotherapy has been shown to prolong both disease-free survival (DFS) and overall survival. Several large phase III trials addressing the benefit of adding a taxane to conventional anthracycline-based regimen in early breast cancer showed a significant improves DFS in node-positive breast cancer patients. Taxane-based regimen seems to be more toxic in terms of myelosuppression. There seem to be fewer cardiac events after the taxane-based regimen attributable to the lower anthracycline cumulative dose. Therefore, the optimal adjuvant treatment in node positive breast cancer is still debated and several attempts are made to identify the patients, who will benefit most of taxane. The primary end point of this phase III randomized trial was to compare chemotherapy with 6 cycles of FEC100 versus 4 cycles of FEC100 followed by 4 cycles of Taxol, in patients with non-metastatic breast cancer with lymph node invasion (N+), in terms of DFS assessed by Kaplan-Meier analysis. The secondary end-points were overall survival (OS), local recurrence free interval, metastases free interval and tolerance. Material and Methods Between 10.3.2000 and 31.12.2002, 837 patients with invasive non-metastatic N+ breast cancer were randomized between (arm A) epirubicine 100 mg/m2 plus 5FU 500 mg/m2 plus cyclophosphamide 500 mg/m2 every 3 weeks (w) (FEC) for 6 cycles (417 patients) or (arm B) FEC every 3 w for 4 cycles then taxol 175 mg/m2 every 3 w for 4 cycles (FEC-T) (420 patients). Hormone-receptor-positive patients received either tamoxifen or anti-aromatize depending of their menopausal status, for 5 years after chemotherapy. Results The patients’ characteristics were well balanced between the 2 arms. The mean number of N+ was 4.5. Seventy-three % of the patients had oestrogen receptor positive (RO+) and 62 % progesterone receptor positive (RP+). The hazard ratio for DFS was 0.986 (95% confidence limits 0.773 — 1.257, P = 0.91). Five-year DFS rates were 78.5% with FEC and 78.4% with FEC-T. Nine-year DFS rates were 62.9% with FEC and 62.5% with FEC-T. The hazard ratio for OS was 0.848 (95% confidence limits 0.622 — 1.155, P = 0.29). The 5-y-OS was 86.1 % with FEC and 88.6 % with FEC-T) and the 9-y-OS was 73.9 % and 77 % respectively. The incidence of grade 3 to 4 neutropenia, infection, and nausea were higher with FEC without reaching significativity, neurotoxicity and hypersensitivity reactions were more frequent with FEC-T. There was no statistical difference in cardiac toxicity and febrile neutropenia between the 2 arms. Conclusion The final results of this trial suggest that adding taxol (every 3 weeks regimen) to an anthracycline-based regimen in patients with non-metastatic breast cancer with lymph node invasion (N+), confers little advantage in terms of DFS and OS. However, the present trial was powered to detect a 30% reduction in the risk of recurrence or death. A meta-analysis of all similar trials is needed to rule out smaller differences that could still be clinically worthwhile. This trial was supported by BMS Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-05.

Phyllodes tumors and sarcomas of the breast are non-epithelial tumors of the breast. Phyllodes tumors are benign tumors, tumors of intermediate malignancy or malignant tumors. The differential diagnosis with a very proliferant fibroadenoma may be difficult. Histological sub-type, type of surgery (definitive or not) and stromal proliferation determine the prognosis. There is a risk of local relapse and distant metastases, in particular to the lung. Surgery (often radical) is the standard treatment. Radiotherapy is recommended in case of high-grade tumor and after conservativetreatment. Breast sarcomas are even rarer. All histological types exist with a predominance of histiofibrocytome type tumors. Grade, involved margins and sometimes tumor necrosis are major prognostics factors. Among the various sub-types, angiosarcoma is characterized by a high risk of occurrence in irradiated fields and by a poor prognosis with a high risk of lung metastases. The treatment is mostly based on mastectomy without lymph node dissection given the exceptional flooding axillary. In some situations, a conservative treatment can be discussed, based on tumor size, grade and volume of the breast. Locoregional radiotherapy is often proposed for tumors over 5 cm and/or of high grade. Systemic chemotherapy is not a standard but should be discussed in the forms at high risk of relapse (like angiosarcoma).

Background This study assessed the feasibility and outcomes of combined colorectal and hepatic resection as the first step of two-stage hepatectomy in patients with bilobar synchronous colorectal liver metastases. Methods All patients with bilobar synchronous colorectal liver metastases who were considered for two-stage hepatectomy, combining resection of the primary tumour with the first stage of hepatectomy, between 2000 and 2008 were selected from a prospectively collected database at two institutions. Data were analysed retrospectively on an intention-to-treat basis. Results Thirty-three patients were studied. Twenty patients received neoadjuvant chemotherapy. Combined colorectal resection and clearance of left-sided liver metastases was the first-stage procedure in all but one patient, in whom right clearance was performed. In 17 patients right portal vein ligation was undertaken at the same time. No patient died. Two patients had anastomotic leakage. Interval chemotherapy was given to 25 patients, five of whom also had percutaneous portal vein embolization. Twenty-five patients had the second-stage hepatectomy, but not eight patients with disease progression. There was one postoperative death after the second stage, and eight patients experienced morbidity. Median follow-up from the first stage was 28·7 months. Overall and disease-free survival rates for patients who completed the procedure were 80 and 44 per cent respectively at 3 years, and 48 and 22 per cent at 5 years. Conclusion In patients with bilobar synchronous colorectal liver metastases who are candidates for two-stage hepatectomy, combined resection of the primary tumour and first-stage hepatectomy reduces the number of procedures, optimizes chemotherapy administration and may improve outcome.

The management of cancer in the elderly patients is becoming a major problem of public health. The population is becoming older, the risk of cancer is increasing with age and therapeutic tools are improving. The numerous pharmacological changes of age might influence the pharmacokinetic and pharmacodynamic variables of many drugs, in particular the agents of chemotherapy. The development of news drugs, with less toxicity, administrated weekly or orally, and of supportive care (hematological growth factors, nutritional support) allows proposing specific treatment to elderly patients with cancer. However, evidence-based medicine data are lacking to define optimal schedules in this population due to low inclusion rates in clinical trials. This paper explores the specificities of chemotherapy in elderly patients with cancer.

Purpose: This study explored factors affecting the pharmacokinetic variability of imatinib and CGP 74588, and the pharmacokinetic-pharmacodynamic correlations in patients with advanced gastrointestinal stromal tumors. Experimental Design: Thirty-five patients with advanced gastrointestinal stromal tumors received 400 mg of imatinib daily. Six blood samples were drawn: before intake, during 1- to 3- and 6- to 9-hour intervals after intake on day 1, and before intake on days 2, 30, and 60. Plasma imatinib and CGP 74588 concentrations were quantified by reverse-phase high-performance liquid chromatography coupled with tandem mass spectrometry, and analyzed by the population pharmacokinetic method (NONMEM program). The influence of 17 covariates on imatinib clearance (CL) and CGP 74588 clearance (CLM/fm) was studied. These covariates included clinical and biological variables and occasion (OCC = 0 for pharmacokinetic data corresponding to the first administration, or OCC = 1 for the day 30 or 60 administrations). Results: The best regression formulas were: CL (L/h) = 7.97 (AAG/1.15)−0.52, and CLM/fm (L/h) = 58.6 (AAG/1.15)−0.60 × 0.55OCC, with the plasma α1-acid glycoprotein (AAG) levels indicating that both clearance values decreased at a higher AAG level. A significant time-dependent decrease in CLM/fm was evidenced with a mean (+SD) CGP 74588/imatinib area under the curve (AUC) ratio of 0.25 (±0.07) at steady state, compared with 0.14 (±0.03) on day 1. Hematologic toxicity was correlated with pharmacokinetic variables: the correlation observed with the estimated unbound imatinib AUC at steady-state (r = 0.56, P < 0.001) was larger than that of the total imatinib AUC (r = 0.32, NS). Conclusions: The plasma AAG levels influenced imatinib pharmacokinetics. A protein-binding phenomenon needs to be considered when exploring the correlations between pharmacokinetics and pharmacodynamics.

Patients (pts) with HER2-positive breast cancer (BC) have a high risk of developing brain metastases (BM) that might be due to longer survival, low diffusion of Trastuzumab (T) in the CNS or an unknown incidence of occult BM at diagnosis. In a series of metastatic BC, occult metastasis was found in 15 % of the patients and Her2 over expression was an independent risk factor 1.In a series of early BC treated with T the cumulative incidence of BM at 12 and 24 months was 0.6 and 2 % respectively 2. Time to BM was 13.7 months in retrospective study 3 . Systematic cranial magnetic resonance imaging (MRI) in the staging of HER2-positive BC pts detected BM in 22 % of asymptomatic, metastatic pts versus 3.6 % in asymptomatic, non-metastatic pts 4. Early detection of BM decreases the cerebral death rate, but do not prolong survival in metastatic pts 4 . Therefore brain imaging is not recommended at diagnosis. However, retrospective trials assessing the incidence of BM in HER2-positive BC were mainly performed during follow up and not at the initial diagnosis. Pts treated for HER2-positive locally BC with adjuvant sequential chemotherapy including anthracycline and taxane associated with T, classified according to classical prognosis factor as histological subtype, TNM, SBR and hormonal receptor (HR), were systematically assessed for occult BM at initial diagnosis with CT scan or MRI. Retrospectively analyzed for the occurrence of BM was performed. Disease free metastatic survival (DFMS) and overall survival (OS) was estimated by Kaplan Meier estimation. Between March 2006 and July 2013 84 pts were included. The median follow up is 4.7 years. The characteristics pts were median age 57 years [30-86], ductal carcinoma 67 pts (93 %), lobular carcinoma 5 pts (7%), pT1 to 4 respectively 38 (48 %), 28 (36 %), 3 (4%), 9 pts (12%), pN 0 to 3 respectively 44 (54%), 27 (33%), 5 (6%), 5 pts (6%), SBR 1 to 3 respectively 1 (1%), 35 (43%), 43 pts (54%), RO positive 47 pts (59 %), RP positive 27 pts (63%). Thirty eight pts (45 %) had brain imaging at diagnosis or within 5 months of diagnosis. Only one pt with a pT4, pN2, ductal carcinoma, RO+, RP-, SBR 2 presented with BM (2.6 %) at initial diagnosis, with simultaneous lung, liver, bone and nodes metastasis. Four pts (4.8 %) presented BM during follow up, among those two symptomatic pts (2.4 %) as the only site of recurrence at 21 and 28 months. Median DFMS was 8.5 years and median OS was 16.7 years. This is the first report of systemic imaging at initial diagnosis of HER2 positive locally BC pts. The results did not support initial brain imaging in this subset of pts. Only pts with symptoms seems to benefit from brain imaging. Further prospective study should be launched to confirm this observation. Citation Format: Delbaldo C, Sarrade T, Brieau B, Billemont B, Denis J, Cojean-Zelek I, Bornier C, Vincens E. Assessing occult brain metastasis with CT scan or MRI in HER2-positive breast cancer patients at initial diagnosis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-03-06.

Background: To evaluate the efficacy and toxicity of irinotecan and oxaliplatin plus 5-fluorouracil (FU) and leucovorin (FOLFIRINOX) as second-line therapy in metastatic pancreatic adenocarcinoma (MPA). Patients and Methods: We retrospectively analyzed the medical records of 27 patients with MPA treated with FOLFIRINOX as second-line therapy between January 2003 and November 2009 in our hospital. The recommended schedule was oxaliplatin 85 mg/m2 on day 1 + irinotecan 180 mg/m2 on day 1 + leucovorin 400 mg/m2 on day 1 followed by FU 400 mg/m2 as a bolus on day 1 and 2,400 mg/m2 as 46-hour continuous infusion biweekly. Results: The median age of the 27 patients (13 males and 14 females) was 63 years (45–83). All patients had progressive disease after first-line chemotherapy by gemcitabine. A total of 167 cycles were administered, with a median number of 6 cycles (1–29) per patient. One toxic death occurred (sepsis). Tolerance of treatment was acceptable, and the relative dose density delivered per patient was 92.8% for oxaliplatin, 89.1% for irinotecan and 96.4% for FU. Grade 3–4 neutropenia occurred in 55.6% of the patients, including 1 febrile neutropenia. The other toxicities were manageable. Regarding efficacy, 22 of the 27 patients were evaluable (WHO and RECIST criteria). Five patients had partial responses and 12 stable disease, resulting in an overall disease control rate of 63%. Median time to progression was 5.4 months (0.7–25.48), and median event-free survival was 3 months (0.5–24.9). Median overall survival was 8.5 months (0–26). A clinical benefit was reported for 55% of the patients. Conclusions: These results confirmed the good safety profile and the efficacy of the FOLFIRINOX regimen as second-line treatment of MPA.

Premiere cause de deces par cancer de l’adulte jeune dans les annees 1970, les tumeurs germinales du testicule (TGT) sont aujourd’hui gueries dans environ 90 % des cas. Une telle revolution therapeutique a pu survenir grâce a l’introduction du cisplatine dans les protocoles de chimiotherapie, mais resulte egalement de l’individualisation de facteurs pronostiques qui permettent une adaptation optimale de la strategie medico-chirurgicale en fonction du stade clinique et de la biologie de la maladie.

Phyllodes tumors and sarcomas of the breast are non-epithelial tumors of the breast. Phyllodes tumors are benign tumors, tumors of intermediate malignancy or malignant tumors. The differential diagnosis with a very proliferant fibroadenoma may be difficult. Histological sub-type, type of surgery (definitive or not) and stromal proliferation determine the prognosis. There is a risk of local relapse and distant metastases, in particular to the lung. Surgery (often radical) is the standard treatment. Radiotherapy is recommended in case of high-grade tumor and after conservativetreatment. Breast sarcomas are even rarer. All histological types exist with a predominance of histiofibrocytome type tumors. Grade, involved margins and sometimes tumor necrosis are major prognostics factors. Among the various sub-types, angiosarcoma is characterized by a high risk of occurrence in irradiated fields and by a poor prognosis with a high risk of lung metastases. The treatment is mostly based on mastectomy without lymph node dissection given the exceptional flooding axillary. In some situations, a conservative treatment can be discussed, based on tumor size, grade and volume of the breast. Locoregional radiotherapy is often proposed for tumors over 5 cm and/or of high grade. Systemic chemotherapy is not a standard but should be discussed in the forms at high risk of relapse (like angiosarcoma).

In the last 10 years, oncology has been greatly modified by the introduction of new drugs especially designed for molecular targets. Sunitinib belongs to the category of new drugs that inhibit multityrosine kinase receptors involved in the key steps of tumorigenesis and angiogenesis.This article reviews the pharmacological and clinical aspects of sunitinib. Literature search was conducted in PubMed, and articles selected for relevance to pharmacology or clinical efficacy up to March 2010.Pharmacology of sunitinib, data regarding clinical efficacy, and challenges to overcome resistance and improve outcomes of patients.Sunitinib is an oral small molecule that displays mainly antiangiogenic properties and also direct antitumoral effects. Being well tolerated, this small molecule is now an essential treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors refractory or intolerant to imatinib, two localizations associated with a poor prognosis. Future developments include the extension of the indications of sunitinib in pancreatic neuroendocrine tumors, the evaluation of combinations with conventional cytotoxic and other targeted drugs and the development of strategy to overcome resistance to sunitinib.

The management of cancer in the elderly patients is becoming a major problem of public health. The population is becoming older, the risk of cancer is increasing with age and therapeutic tools are improving. The numerous pharmacological changes of age might influence the pharmacokinetic and pharmacodynamic variables of many drugs, in particular the agents of chemotherapy. The development of news drugs, with less toxicity, administrated weekly or orally, and of supportive care (hematological growth factors, nutritional support) allows proposing specific treatment to elderly patients with cancer. However, evidence-based medicine data are lacking to define optimal schedules in this population due to low inclusion rates in clinical trials. This paper explores the specificities of chemotherapy in elderly patients with cancer.

Management of patients with irresectable stage IV colorectal cancer is controversial. Since 2000, we have favoured primary chemotherapy with stent insertion in case of obstructive tumor. Our aim was to report the results of this strategy in an unselected consecutive series of patients.From 2000 to 2007, 68 of 115 consecutive patients admitted with stage IV colorectal cancer were considered irresectable. Data were collected prospectively. Feasibility and outcomes were analysed in an intention to treat basis.Of 68 patients, 37 received the intended primary chemotherapy, with stent insertion in 19, 13 required surgery as initial management and 18 patients received supportive care only. Twelve patients in the primary chemotherapy group developed local complication, including bowel obstruction in 9, successfully managed by stent in 6 of them. In patients requiring surgery at presentation, mortality and morbidity were 31% and 77%, respectively. Overall, 41 patients received chemotherapy, of whom, 6 were downstaged to undergo curative resection. Median survival was 6.7 and 15.4 months for the whole series and patients treated by primary chemotherapy, respectively (p0.0001). On multivariate analysis, age, CEA level, primary chemotherapy and secondary curative resection were independently associated with survival.In unselected patients with irresectable stage IV colorectal cancer, primary chemotherapy with or without stent is feasible in more than 50% of cases and is associated with a low rate of secondary surgery for complicated primary tumor. This strategy may represent the best palliation in these patients for both duration and quality of survival.

Purpose: The aim of this study was to explore the effect of several demographic, biological, and pharmacogenetic covariates on the disposition of imatinib and its main metabolite (CGP74588) in both adults and children. Experimental Design: Thirty-three children with solid malignancies included in a phase II exploratory study and 34 adults with gastrointestinal stromal tumors received 340 mg/m2 and 400 mg imatinib, respectively. Plasma imatinib and CGP74588 concentrations observed on day 1 and at steady-state were analyzed by a population pharmacokinetic method (NONMEM) to evaluate the effect of age, body weight, age, sex, albuminemia, plasma α1-acid glycoprotein (AGP), and eight polymorphisms corresponding to ABCB1, ABCG2, CYP3A4, CYP3A5, and AGP (pharmacogenetic data available for 46 of 67 patients). Results: Analysis of the whole data set in 67 patients showed that apparent clearance (CL/F) of imatinib was positively correlated with body weight and albuminemia and negatively with AGP. By considering these three covariates, the interindividual variability on CL/F decreased from 47% to 19%. The apparent clearance of CGP74588 was similarly dependent on both body weight and AGP and significantly lower (30% reduction) at steady-state. By adding genotype status to the final covariate imatinib model, a 22% reduction in CL/F was observed in heterozygous compared with wild-type patients corresponding to ABCG2 c.421C>A (P < 0.05). Conclusions: By considering morphologic and biological covariates, a unique covariate model could be used to accurately describe imatinib pharmacokinetics in patients ages 2 to 84 years. Morphologic and biological characteristics have a stronger influence than pharmacogenetics on imatinib pharmacokinetics.

This study characterizes the histological effect of chemotherapy (CT) on primary colonic tumors.Between 2000 and 2006, 38 patients with stage IV colon cancer underwent resection of the primary, after chemotherapy (CT group, n = 16) or without preoperative CT (control group, n = 22). For all primary tumors, histological analysis included: fibrosis, acellular necrosis, acellular mucin pools, lymphoplasmacytic infiltration, and changes at tumor surface. Tumor regression grade (TRG) was determined by the amount of residual tumor cells and was graded from 1 to 5.No patient had complete histological response. Major histological tumor regression (TRG2) was observed in 70% of patients treated by CT and none of the not treated patients (P0.0001). Fibrosis, acellular necrosis, and surface changes were significantly increased in the CT group. TRG in the primary was comparable to the TRG in the corresponding liver metastases for 7/9 patients who underwent both colonic and hepatic resection after CT.CT induces major histological response in 70% of colon cancers. Response to CT in the primary and the corresponding liver metastases are correlated. These results support a policy of initial CT management for stage IV colon cancer and may warrant future studies of neoadjuvant CT in locally advanced colon carcinomas.

We assessed the potential benefits of including systematic 18fluorodeoxyglucose positron emission tomography (FDG-PET) for detecting tumour recurrence in a prospective randomised trial. Patients (N=130) who had undergone curative therapy were randomised to undergo either conventional (Con) or FDG-PET procedures during follow-up. The two groups were matched at baseline. Recurrence was confirmed histologically. 'Intention-to-treat' analysis revealed a recurrence in 46 patients (25 in the FDG-PET group, and 21 in the Con group; P=0.50), whereas per protocol analysis revealed a recurrence in 44 out of 125 patients (23 and 21, respectively; P=0.60). In another three cases, PET revealed unexpected tumours (one gastric GIST, two primary pulmonary cancers). Three false-positive cases of FDG-PET led to no beneficial procedures (two laparoscopies and one liver MRI that were normal). We failed to identify peritoneal carcinomatosis in two of the patients undergoing FDG-PET. The overall time in detecting a recurrence from the baseline was not significantly different in the two groups. However, recurrences were detected after a shorter time (12.1 vs 15.4 months; P=0.01) in the PET group, in which recurrences were also more frequently (10 vs two patients) cured by surgery (R0). Regular FDG-PET monitoring in the follow up of colorectal cancer patients may permit the earlier detection of recurrence, and influence therapy strategies.

The more rapid and less complicated recovery after palliative stent insertion compared with surgery may theoretically facilitate the early administration of chemotherapy.A retrospective study.University tertiary care referral center.From January 1, 1996, to September 15, 2005, 58 patients with obstructing colon cancer and nonresectable synchronous metastases were treated with self-expanding colonic metallic stent (SEMS) (n = 31) or surgery (n = 27).Comparison of the use of SEMS and emergency surgery as palliative measures to treat obstructing colon cancer with special reference to time to chemotherapy administration and survival.Mortality and morbidity were comparable between the 2 groups. Median hospital stay was shorter after SEMS insertion than after surgery (median, 8.0 vs 13.5 days, respectively; P.01). Incidence of stoma creation was lower in patients treated with SEMS than in patients treated with surgery (6% vs 37%, respectively; P = .02). The median time to chemotherapy administration was shorter after SEMS insertion than after surgery (14.0 vs 28.5 days, respectively; P = .002). Three patients with SEMS and 0 patients in the surgical group underwent a curative colonic and hepatic resection after downstaging by chemotherapy (P = .27). Two patients (6%) with SEMS and undergoing chemotherapy had a tumor perforation requiring emergency surgery. There was no difference in survival between the 2 groups (median survival, 13.7 months for SEMS vs 11.4 months for surgery; P = .19).Insertion of SEMS should be the first step to treat obstructing colon cancer with nonresectable synchronous metastases because it allows chemotherapy to be administered earlier, may increase the resectability rate of metastases, and favorably impacts survival. The risk of tumor perforation while receiving chemotherapy requires attention.

Tyrosine kinases are implicated in the normal cellular proliferation and in malignant transformation. Among the tyrosine kinase receptors, one of best described is the Epidermal Growth Factor Receptor (EGFR), which is widely expressed in particular in epithelial cells and in many human carcinomas.Compounds have been developed that target either the extracellular ligand-binding region of EGFR (Cetuximab) or the intracellular tyrosine kinase ATP-binding (Iressa), Tarceva. Phase I studies showed that these molecules have a favorable pharmacokinetic and pharmacodynamic profile, with excellent tolerance and easy administration. Phase II and III studies are currently testing their efficacy.Preliminary results show interesting activity in different tumors, alone or in combination with either chemotherapy or radiotherapy. If these results are confirmed in larger trials including a high number of patients, these agents might be very useful in combination with chemotherapy, radiotherapy or other biological targeting agents such as cellular cycle inhibitors or antiangiogenics.

e14584 Background: The safety profile and efficacy of the Folfirinox regimen as first-line chemotherapy in metastatic pancreatic cancer (MPC) was previously reported in a phase II study (Conroy, J ...

A 47-year-old patient was treated with allogeneic bone marrow transplantation (BMT) for chronic myelogenous leukaemia in blast crisis. Three months after the procedure he developed bullous pemphigoid (BP) and symptoms suggestive of BP oesophageal involvement, associated with skin and liver acute graft-versus-host disease. The occurrence of BP is exceptional after BMT.

605 Background: In a randomized phase II study, P. Piedbois et al. explored a dose-dense docetaxel (T) followed by epirubicin/cyclophosphamide (EC) every two weeks versus the reverse sequence, versus standard-dose docetaxel, epiribucin and cyclophosphamide (TEC) every 3 weeks. The main purpose of this second analysis was to further explore the haematological safety of each regimen in patients receiving primary prophylactic pegfilgrastim. Methods: One hundred patients with node-positive invasive breast adenocarcinoma were randomized between (arm A) docetaxel 75 mg/m2, epiribucin 75 mg/m2 and cyclophosphamide 500 mg/m2 (TEC) every 3 weeks for 6 cycles (35 patients) or (arm B) epiribucin 100 mg/m2 and cyclophosphamide 600 mg/m2 every 2 weeks for 4 cycles, followed by T 100 mg/m2 (EC→T) every 2 weeks for 4 cycles (31 patients) or (arm C) T→ EC (34 patients). Among the 99 patients who received chemotherapy, 79 received pegfilgrastim 6 mg subcutaneous day 1 from the first cycle (27 in arm A, 23 in arm B and 29 in arm C). The safety data of these 79 patients were reported here. Results: Our results showed grade 3/4: neutropenia (arm A 30 %, arm B 39 %, arm C 31 %) and febrile neutropenia (FN) (arm A 11 %, arm B 13 %, arm C 3 %), grade 2–4: anaemia (arm A 26 %, arm B 61 %, arm C 55 %) and thrombocytopenia (arm A 15 %, arm B 9 %, arm C 3 %), respectively. Crude proportion and time to toxicity summaries showed that in dose-dense arms, patients allocated to the EC→ T sequence were more exposed to FN than patients allocated to the T→ EC. In the Cox model taking into account all allocated treatment and age, treatment was a predictor of grade 2–4 anaemia, whereas age was significantly correlated to grade 2–4 thrombocytopenia. There was no clear relationship between haematological toxicity and dose intensity across all treatment arms. Except for nausea (17 % versus 3 %) and neurological toxicity (13 % versus 3 %), non-haematological toxicities were similar in arm B and C. Conclusions: These analyzes confirmed that dose-dense regimens EC→ T or T→ EC are feasible with pegfilgrastim primary prophylaxis. The T→ EC sequence seems to be associated with a better haematological tolerance, and should be the preferred dose-dense regimen providing similar efficacy. The trial was supported by Amgen. No significant financial relationships to disclose.

Introduction Le role de la chimiotherapie dans les cancers gastriques avances ou en rechute demeure controverse. Plusieurs molecules et differentes associations ont ete evaluees, mais tres souvent avec de faibles effectifs limitant la portee des conclusions des essais. Le projet GASTRIC est une meta-analyse d’essais basee sur les donnees individuelles de patients en situation avancee, ayant pour but de quantifier le benefice potentiel de differents schemas de chimiotherapies incluant des fluoropyrimidines, des antracyclines, des sels de platine, des taxanes ou de l’irinotecan. Materiels et Methodes Tous les essais cliniques randomises, clos avant fin 2004, ont ete inclus. Les essais neo-adjuvants ou adjuvants ont ete exclus. L’objectif principal etait la survie globale (SG), et l’objectif secondaire la survie sans progression (progression ou deces). Une analyse en intention de traiter a ete realisee en utilisant le test logrank stratifie sur l’essai et le hazard ratio (HR) correspondant. Le benefice absolu a ete estime a partir du HR et du taux de survie a 6 mois dans le bras de reference. Le recueil des donnees a debute en janvier 2007. Resultats Quarante et un essais randomises eligibles (7 225 patients) ont ete identifies. A ce jour, les donnees individuelles des patients de 18 essais (3 226 patients) etaient disponibles pour la SG avec un suivi median de 8,1 mois. Les caracteristiques des patients etaient : âge median 58 ans, etat general OMS 0-1 86 %, metastatiques/localement avances 85 %/15 %, chirurgie avant traitement 53 %. La SG ne differait pas significativement entre les schemas a base d’anthracyclines versus les autres chimiotherapies (7 essais ; 1 501 patients ; HR = 1,03 ; 95 % IC = 0,91 - 1,17) ; p = 0,66), entre les schemas a base d’irinotecan versus les autres chimiotherapies (4 essais ; 670 patients ; HR = 0,89 ; 95 % IC = 0,76 - 1,05) ; p = 0,16), entre les schemas a base de taxanes versus les autres chimiotherapies (3 essais ; 572 patients ; HR = 0,91, 95 % IC = 0,76 - 1,08 ; p = 0,26) ou entre les schemas a base de sels de platine versus les autres chimiotherapies (7 essais ; 1 677 patients ; HR = 0,99 ; p = 0,84). Une heterogeneite significative etait detectee dans la derniere comparaison (p Conclusion Les meta-analyses basees sur les donnees individuelles des patients representent un des plus hauts niveaux de preuve. Nos resultats, bases sur une analyse partielle, ne demontrent pas de superiorite de l’un des schemas en termes de SG. Les medianes de survie demeurent inferieures a 10 mois. Le nombre important de chimiotherapies evaluees pourrait augmenter l’heterogeneite et diluer ainsi un effet potentiel.

Introduction Apres la resection d’un cancer de l’estomac les essais ayant testes une chimiotherapie adjuvante (CTadj) ont une puissance insuffisante et la preuve convaincante du benefice de la CTadj manque toujours. Notre groupe a initie en 2007 une meta-analyse sur donnees individuelles de tous les essais randomisees (ER) de CTadj pour quantifier le benefice potentiel de la CT. Materiels et Methodes Etaient eligibles, toutes les ER fermees aux inclusions a la fin 2003. Les essais de radiotherapie, de CT intra-peritoneales ou d’immunotherapie ont ete exclus. Ont ete etudie le role des monotherapies, des poly-CT a base de 5FU et MMC respectivement sans et avec anthracyclines et des poly-CT a base de sels de platine, methothrexate (groupe ≪autre poly-CT≫). Le critere principal etait la survie globale (SG), le critere secondaire etait la survie sans recidive (SSR) incluant recidive et deces toutes causes. Le test du log-rank stratifie sur l’essai et le hazard ratio (HR) correspondant ont ete utilises. Le benefice absolu est calcule a 5 ans a partir des estimations de survie ponctuelle. Resultats Trente et un ER (6 666 patients) ont ete identifies. Les donnees individuelles ont ete obtenues pour 14 essais (3 293 patients ; suivi median superieure a 8 ans). L’effet global sur la SG est statistiquement significatif en faveur de la CT adj (HR = 0,81, IC95 % = [0,73 ; 0,89], p Conclusion Les meta-analyses sur donnees individuelles representent le plus haut niveau de preuve. Sur une fraction encore insuffisante des donnees (50 %), nous montrons un benefice significatif (+ 7 %) des CT adj a base de 5FU, MMC que ce soit avec ou sans anthracyclines par rapport a la chirurgie seule tant en termes de SG que de SSR. Les effectifs sont pour l’instant insuffisants pour conclure avec les autres produits et en particulier les sels de platines. Remerciements, financements, autres Travail realise sous l’egide du groupe Gastric et de l’INCA.

2526 Background: The aim of this study was to explore the impact of several demographic, biological and pharmacogenetic covariates on imatinib and its main metabolite (CGP74588) disposition. Methods: Thirty three children included in a phase 2 study and thirty four adults with gastrointestinal stromal tumor received 340 mg/m² and 400 mg imatinib, respectively. Plasma imatinib and CGP74588 concentrations observed on day 1 and at steady-state were analyzed by population pharmacokinetic method (NONMEM) to evaluate the impact of age, body weight (BW), age, sex, albuminemia (ALB), plasma alpha1-acid glycoprotein (AGP), and several polymorphisms corresponding to ABCB1, ABCG2, CYP3A4, CYP3A5, AGP (pharmacogenetic data available in 46/67 patients). Results: Analysis of the whole data set (67 patients) showed that apparent clearance (CL/F) of imatinib was positively correlated with BW and ALB, and negatively with AGP. By considering these three covariates, the inter-individual variability on CL/F decreased from 47...

2070 Background: PK analyses of Imatinib showed large inter-individual variability in patients with advanced GIST. This study was designed to explore factors affecting PK variability of Imatinib and CGP 74588, along with PK-PD correlations. Methods: Thirty-five patients (26 males; median age 55 yrs, range 28–84 yrs) with advanced GIST, registered in a phase III study, received400 mg/day (d) of Imatinib. Five blood samples were obtained before intake, between 1 and 3 and 6 and 9 hours on d1, prior to next dose on d2 and at steady state on d30 and 60. Imatinib and CGP 74588 plasma levels were quantitated by reverse-phase HPLC coupled with tandem mass spectometry, and analysed by population PK using NONMEM program. We examined the influence of 17 covariates on Imatinib clearance (CL) and apparent CGP 74 588 clearance (CLM/fm, with fm = fraction of Imatinib converted to CGP 74588). These covariates included age, weight, gender, inflammatory proteins, renal, hematological and liver biological values at baselin...

International audience; Background: In 2013, the interim analysis of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial could not show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. Here, we report the planned final analysis based on the prespecified number of occurring events.Methods: PHARE is an open-label, phase 3, non-inferiority randomised trial of patients with HER2-positive early breast cancer comparing 6 months versus 12 months of trastuzumab treatment concomitant with or following standard neoadjuvant or adjuvant chemotherapy. The study was undertaken in 156 centres in France. Eligible patients were women aged 18 years or older with non-metastatic, operable, histologically confirmed adenocarcinoma of the breast and either positive axillary nodes or negative axillary nodes but a tumour of at least 10 mm. Participants must have received at least four cycles of a chemotherapy for this breast cancer and have started receiving adjuvant trastuzumab-treatment. Eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab therapy duration between the third and sixth months of adjuvant trastuzumab. The randomisation was stratified by concomitant or sequential treatment with chemotherapy, oestrogen receptor status, and centre. The primary objective was non-inferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival with a prespecified hazard margin of 1·15. This trial is registered with ClinicalTrials.gov, number NCT00381901.Findings: 3384 patients were enrolled and randomly assigned to either 12 months (n=1691) or 6 months (n=1693) of adjuvant trastuzumab. One patient in the 12-month group and three patients in the 6-month group were excluded, so 1690 patients in each group were included in the intention-to-treat analysis. At a median follow-up of 7·5 years (IQR 5·3-8·8), 704 events relevant to disease-free survival were observed (345 [20·4%] in the 12-month group and 359 [21·2%] in the 6-month group). The adjusted hazard ratio for disease-free survival in the 12-month group versus the 6-month group was 1·08 (95% CI 0·93-1·25; p=0·39). The non-inferiority margin was included in the 95% CI. No differences in effects pertaining to trastuzumab duration were found in any of the subgroups. After the completion of trastuzumab treatment, rare adverse events occurred over time and the safety analysis remained similar to the previously published report. In particular, we found no change in the cardiac safety comparison, and only three additional cases in which the left ventricular ejection fraction decreased to less than 50% have been reported in the 12-month group.Interpretation: The PHARE study did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months.