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Tailored neoadjuvant treatment of locally advanced rectal cancer (LARC) may improve outcomes. The aim of this study was to determine early MRI prognostic parameters with which to stratify neoadjuvant treatment in patients with LARC.All patients from a prospective, phase II, multicentre randomized study (GRECCAR4; NCT01333709) were included, and underwent rectal MRI before treatment, 4 weeks after induction chemotherapy and after completion of chemoradiotherapy (CRT). Tumour volumetry, MRI tumour regression grade (mrTRG), T and N categories, circumferential resection margin (CRM) status and extramural vascular invasion identified by MRI (mrEMVI) were evaluated.A total of 133 randomized patients were analysed. Median follow-up was 41·4 (95 per cent c.i. 36·6 to 45·2) months. Thirty-one patients (23·3 per cent) developed tumour recurrence. In univariable analysis, mrEMVI at baseline was the only prognostic factor associated with poorer outcome (P = 0·015). After induction chemotherapy, a larger tumour volume on MRI (P = 0·019), tumour volume regression of 60 per cent or less (P = 0·002), involvement of the CRM (P = 0·037), mrEMVI (P = 0·026) and a poor mrTRG (P = 0·023) were associated with poor outcome. After completion of CRT, the absence of complete response on MRI (P = 0·004), mrEMVI (P = 0·038) and a poor mrTRG (P = 0·005) were associated with shorter disease-free survival. A final multivariable model including all significant variables (baseline, after induction, after CRT) revealed that Eastern Cooperative Oncology Group performance status (P = 0·011), sphincter involvement (P = 0·009), mrEMVI at baseline (P = 0·002) and early tumour volume regression of 60 per cent or less after induction (P = 0·007) were associated with relapse.Baseline and early post-treatment MRI parameters are associated with prognosis in LARC. Future preoperative treatment should stratify treatment according to baseline mrEMVI status and early tumour volume regression.El tratamiento neoadyuvante personalizado del cáncer de recto localmente avanzado (locally advanced rectal cancer, LARC) puede mejorar los resultados. El objetivo de este estudio fue determinar factores pronósticos precoces mediante RMN para estratificar el tratamiento neoadyuvante en pacientes con LARC. MÉTODOS: Todos los pacientes de un eensayo prospectivo de fase II, multicéntrico y aleatorizado (GRECCAR4-NCT01333709) se incluyeron en este estudio y se les realizó una RMN antes del tratamiento, 4 semanas después de la quimioterapia de inducción y después de completar la quimiorradioterapia (chemoradiation, CRT). Se evaluó la volumetría tumoral, el grado de regresión tumoral mediante RMN (MRI Tumor Regression Grade, mrTRG), la estadificación T, la estadificación N, el estado del margen de resección circunferencial (circumferential resection margin, CRM) y la presencia de invasión extramural vascular en la RMN (extramural vascular invasion, mrEMVI).Se analizaron 133 pacientes aleatorizados. La mediana de seguimiento fue de 41,4 meses (i.c. del 95%: 36,6-45,2). En 31 pacientes (23%) se diagnosticó una recidiva. En el análisis univariado de la situación basal, mrEMVI fue el único factor pronóstico asociado con un peor resultado (P = 0,0152). Después de la quimioterapia de inducción, un volumen tumoral más alto en la RMN (P = 0,019), una regresión del volumen tumoral ≤ 60% (P = 0,002), la afectación del CRM (P = 0,037), mrEMVI (P = 0,026) y un grado escaso mrTRG (P = 0,023) se asociaron con un mal resultado. Después de completar la CRT, la ausencia de respuesta completa en la RMN (P = 0,004), la presencia de mrEMVI (P = 0,04) y una insuficiente mrTRG (P = 0,005) se asociaron con una supervivencia libre de enfermedad más corta. En el modelo multivariable final en el que se incluyeron todas las variables significativas (basales, postinducción, post-CRT), el estado de ECOG (P = 0,011), la afectación esfinteriana (P = 0,009), la presencia de EMVI al inicio (P = 0,002) y una regresión precoz del volumen tumoral ≤ 60% después de la inducción (P = 0,007) se asociaron con una recidiva. CONCLUSIÓN: Los parámetros basales y post-tratamiento precoces de la RMN se asocian con el pronóstico en el LARC. La estrategia terapéutica preoperatoria futura deberá estratificar el tratamiento de acuerdo con la presencia de EMVI al inicio y la regresión precoz del volumen tumoral.

Background Currently, metastatic colorectal cancer is treated as a homogeneous disease and only RAS mutational status has been approved as a negative predictive factor in patients treated with cetuximab. The aim of this study was to evaluate if recently identified molecular subtypes of colon cancer are associated with response of metastatic patients to first-line therapy. Patients and methods We collected and analysed 143 samples of human colorectal tumours with complete clinical annotations, including the response to treatment. Gene expression profiling was used to classify patients in three to six classes using four different molecular classifications. Correlations between molecular subtypes, response to treatment, progression-free and overall survival were analysed. Results We first demonstrated that the four previously described molecular classifications of colorectal cancer defined in non-metastatic patients also correctly classify stage IV patients. One of the classifications is strongly associated with response to FOLFIRI (P = 0.003), but not to FOLFOX (P = 0.911) and FOLFIRI + Bevacizumab (P = 0.190). In particular, we identify a molecular subtype representing 28% of the patients that shows an exceptionally high response rate to FOLFIRI (87.5%). These patients have a two-fold longer overall survival (40.1 months) when treated with FOLFIRI, as first-line regimen, instead of FOLFOX (18.6 months). Conclusions Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer and a strong impact of the first-line regimen on the overall survival of some patients. This however remains to be confirmed in a large prospective clinical trial.

The sequential FOLFOX7–FOLFIRI combination is not superior to FOLFOX4 in colorectal cancer patients with resectable metastases. Patients with synchronous metastases preferably received perioperative chemotherapy, while patients with metachronous metastases were given postoperative chemotherapy in preference. We observed the highest long-term survival rates ever reported in this setting. Background Perioperative FOLFOX4 (oxaliplatin plus 5-fluorouracil/leucovorin) chemotherapy is the current standard in patients with resectable metastases from colorectal cancer (CRC). We aimed to determine whether a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is superior to FOLFOX4. The chemotherapy timing was not imposed, and was perioperative or postoperative. Patients and methods In this open-label, phase III trial, patients with resectable or resected metastases were randomly assigned either to 12 cycles of FOLFOX4 (oxaliplatin 85 mg/m2) or 6 cycles of FOLFOX7 (oxaliplatin 130 mg/m2) followed by 6 cycles of FOLFIRI (irinotecan 180 mg/m2). Randomization was done centrally, with stratification by chemotherapy timing, type of local treatment (surgery versus radiofrequency ablation with/without surgery), and Fong's prognostic score. The primary end point was 2-year disease-free survival (DFS). Results A total of 284 patients were randomized, 142 in each treatment group. Chemotherapy was perioperative in 168 (59.2%) patients and postoperative in 116 (40.8%) patients. Perioperative chemotherapy was preferentially proposed for synchronous metastases, whereas postoperative chemotherapy was more frequently used for metachronous metastases. Two-year DFS was 48.5% in the FOLFOX4 group and 50.0% in the FOLFOX7–FOLFIRI group. In the multivariable analysis, more than one metastasis [hazard ratio (HR) = 2.15] and synchronous metastases (HR = 1.63) were independent prognostic factors for shorter DFS. Five-year overall survival (OS) rate was 69.5% with FOLFOX4 versus 66.6% with FOLFOX7–FOLFIRI. Conclusions FOLFOX7–FOLFIRI is not superior to FOLFOX4 in patients with resectable metastatic CRC. Five-year OS rates observed in both groups are the highest ever reported in this setting, possibly reflecting the pragmatic approach to chemotherapy timing. Clinical trials number NCT00268398.

Background While tumor-tissue remains the ‘gold standard’ for genetic analysis in cancer patients, it is challenged with the advent of circulating cell-free tumor DNA (ctDNA) analysis from blood samples. Here, we broaden our previous study on the clinical validation of plasma DNA in metastatic colorectal cancer patients, by evaluating its clinical utility under standard management care. Patients and methods Concordance and data turnaround-time of ctDNA when compared with tumor-tissue analysis were studied in a real-time blinded prospective multicenter clinical study (n = 140 metastatic colorectal patients). Results are presented according to STARD criteria and were discussed in regard with clinical outcomes of patients. Results Much more mutations were found by ctDNA analysis: 59%, 11.8% and 14.4% of the patients were found KRAS, NRAS and BRAF mutant by ctDNA analysis instead of 44%, 8.8% and 7.2% by tumor-tissue analysis. Median tumor-tissue data turnaround-time was 16 days while 2 days for ctDNA analysis. Discordant samples analysis revealed that use of biopsy, long delay between tumor-tissue and blood collection and resection of the tumor at time of blood draw, tumor site, or type of tissue analyzed seem to affect concordance. Altogether, the clinical data with respect to the anti-epidermal growth factor receptor response (RAS status) and the prognosis (BRAF status) of those discordant patients do not appear contradictory to the mutational status as determined by plasma analysis. Lastly, we present the first distribution profile of the RAS and BRAF hotspot mutations as determined by ctDNA analysis (n = 119), revealing a high proportion of patients with multiple mutations (45% of the population and up to 5 mutations) and only 24% of WT scored patients for both genes. Mutation profile as determined from ctDNA analysis with using various detection thresholds highlights the importance of the test sensitivity. Conclusion Our study showed that ctDNA could replace tumor-tissue analysis, and also clinical utility of ctDNA analysis by considerably reducing data turnaround time.

Most patients with pancreatic cancer present with advanced/metastatic disease and have a dismal prognosis. Despite the proven albeit modest benefits of gemcitabine demonstrated over a decade ago, subsequent advances have been slow, suggesting it may be time to take a different approach. It is thought that some key characteristics of pancreatic cancer, such as the desmoplasia, restricted vasculature and hypoxic environment, may prevent the delivery of chemotherapy to the tumour thereby explaining the limited benefits observed to-date. Moreover, there is evidence to suggest that the stroma is not only a mechanical barrier but also constitutes a dynamic compartment of pancreatic tumours that is critically involved in tumour formation, progression and metastasis. Thus, targeting the stroma and the tumour represents a promising therapeutic strategy. Currently, several stroma-targeting agents are entering clinical development. Among these, nab-paclitaxel appears promising since it combines cytotoxic therapy with targeted delivery via its proposed ability to bind SPARC on tumour and stromal cells. Preclinical data indicate that co-treatment with nab-paclitaxel and gemcitabine results in stromal depletion, increased tumour vascularization and intratumoural gemcitabine concentration, and increased tumour regression compared with either agent alone. Phase I/II study data also suggest that a high level of antitumor activity can be achieved with this combination in pancreatic cancer. This was recently confirmed in a Phase III study which showed that nab-paclitaxel plus gemcitabine significantly improved overall survival (HR 0.72) and progression-free survival (HR 0.69) versus gemcitabine alone for the first-line treatment of patients with metastatic pancreatic cancer. (C) 2013 Elsevier Ltd. All rights reserved

Summary Objectives The most commonly used schedules are 5-FU in combination with CDDP with or without epirubicin (ECF) or docetaxel (TCF) in treatment of MGA patients (pts), independently of HER status. We evaluated the efficacy of FOLFIRI regimen in a large retrospective series of MGA pts. Methods Two hundred and twelve pts from 13 French centers were treated with at least one cycle of FOLFIRI (irinotecan 180 mg/m 2 intravenous (i.v.) over 90 minutes on day 1 with folinic acid (FA) 400 mg/m 2 i.v. over two hours followed by 5-FU 400 mg/m 2 i.v. bolus then 5-FU 2400 mg/m 2 continuous infusion over 46 hours on day 1, repeated every 14 days). Primary tumour sites were 120 (58%) stomach and 92 (42%) gastroesophageal junction. FOLFIRI was administered as first-line in 137 (65%) pts and as later-line in 75 (35%) pts for MGA. Results There was no difference between chemonaive and not chemonaive pts treated as first-line in terms of response rate 37% (95% CI: 25–50) vs 44% (95% CI: 21–69), median PFS, 6.7 (95% CI: 5.5–9.9) vs 5.3 months (95% CI: 3.6–6.9) ( P = 0.25), and OS, 13.1 (95% CI: 11.7–18.7) vs 8.8 months (95% CI: 7.3–15.6) ( P = 0.19), respectively. There was no difference between pts treated as second or later-line in terms of response rate 20% (95% CI: 8–39) vs 22% (95% CI: 6–48), median PFS, four months (95% CI: 2.8–5.4) vs 3.5 months (95% CI: 2.3–4.5) ( P = 0.56), and OS, 10.4 months (95% CI: 5.4–14.4) vs 5.3 months (95% CI: 3.5–11.3) ( P = 0.58), respectively. The global grade 3–4 toxicities were: diarrhea 11%, vomiting 9%, neutropenia 18%, febril neutropenia 4% (one toxic death). Conclusions This retrospective study confirms the activity and good tolerance of FOLFIRI regimen in MGA as first-line as well as later-line.

We compared clinical outcome and pharmacokinetic (pK) parameters of a new pharmacokinetically-guided dosing strategy in two groups of patients (ageor65 years) with metastatic colorectal cancer (mCRC). We retrospectively analyzed all the patients with mCRC, receiving standard LV5FU2 regimen during cycle-1, intensified from cycle-2 onwards according to an adaptation schedule based on the area under the concentration-time curve (AUC) value (mg.h/l.m(2)) of 5-FU measured during cycle-1. Among the 103 eligible patients, the 48 elderly (median age 70 range 65-80) did not differ significantly from the 55 non-elderly patients (median age 59 range 33-64) in pPK parameters (including AUC at cycle-1 and cycle-2), efficacy (objective response rate of 27% [16.1-40.9] in younger and 35% [22.2-50.5] in older patients, p = 0.4) and tolerability (33.3% of overall grade 3-4 toxicities in older patients and 34.5% in younger, p = 0.9). Our data indicated high dose-intensity values, not significantly different between elderly and non-elderly patients. it was feasible to increase the 5-fU continuous infusion dose in 43/55 (78%) younger and 40/48 (83%) older patients (p=0.509) and even to double it in half of the patients of both groups. Aging did not seem to limit intensified chemotherapy or to affect the pK behavior of the 5-FU.

Colorectal cancer remains a leading cause of cancer deaths. Over the last decade, many new drugs have emerged in the treatment of metastatic colorectal cancers. Thus, significant progress has been achieved with daily use of oxaliplatin, irinotecan, or similar oral 5-fluorouracil (capecitabine or UFT). The identification of new molecular targets has allowed the development of new antitumor agents directed against receptors for growth factor or cons key factors involved in the process of angiogenesis. Large randomized trials of metastatic colorectal cancer have demonstrated significant clinical benefit with bevacizumab (inhibiting the vascular endothelial growth factor VEGF) and inhibitors of epidermal growth factor receptor (EGFR), namely cetuximab and the panitumumab. In this article, we review the role and impact of mutational status of KRAS in the care of patients with colorectal cancer metastasis.

Background: A phase-III trial showed the non-inferiority of oral capecitabine plus oxaliplatin (XELOX) vs 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) in terms of efficacy in first-line treatment of metastatic colorectal cancer. A secondary objective was to compare the quality of life (QoL) and health-care satisfaction of patients. Methods: Patients were randomised to receive XELOX (n=156) or FOLFOX-6 (n=150) for 6 months. Quality of life and satisfaction were assessed by the Quality of Life Questionnaire-C30 (QLQ-C30) and Functional Assessment of Chronic Illness Therapy Chemotherapy Convenience and Satisfaction Questionnaire (FACIT-CCSQ), respectively. Patients completed questionnaires at baseline, at Cycle3 (C3) and Cycle (C6) (XELOX) or at C4 and C8 visits (FOLFOX-6) and at their final visit. Results: A total of 245 and 225 patients were assessed using QLQ-C30 and FACIT-CCSQ, respectively. The completion rates were >80%. Global QoL scores did not differ significantly between groups during the study. According to FACIT-CCSQ, XELOX seemed more convenient (C3/C4, P

This dose escalation study was designed to determine the maximum tolerated dose (MTD) and recommended doses (RDs) of 5-fluorouracil (5FU), folinic acid and oxaliplatin (FOLFOX) with concomitant radiotherapy in inoperable/metastatic oesophageal squamous cell carcinoma or adenocarcinoma. Patients received three courses of LV5FU2 regimen (folinic acid 200 mg m(-2), bolus 5FU 300-400 mg/m(2), continuous infusion 5FU 400-600 mg m(-2) on days 1 and 2) and escalating doses of oxaliplatin 50 to 100 mg m(-2) on day 1 (FOLFOX). This regimen was repeated every 2 weeks, concomitant to a 50-gray radiotherapy per 5 weeks. Three more cycles were delivered after completion of radiation therapy. Three to six patients were allocated to each of the five dose levels until MTD was reached. Thirty-three patients were enroled and 21 had metastatic disease. Maximum tolerated dose was oxaliplatin 100 mg m(-2), and continuous infusion 5FU was 600 mg m(-2) day(-) (level 5). The most common toxicities were neutropenia, dysphagia and oesophagitis. The RDs were those of FOLFOX-4 regimen (oxaliplatin 85 mg m(-2) and full doses of LV5FU2). The overall response was 48.5%, including 12% complete response. Response rate on primary tumour was 62.9%. This FOLFOX-4 regimen was reasonably well tolerated and effective in inoperable/metastatic oesophageal carcinoma and warrants additional investigation.

To assess the rate of R(0) resection of liver metastases achieved after chemotherapy with FOLFIRINOX.Patients with histologically proven primary colorectal cancer and bidimensionally measurable liver metastasis, not fully resectable based on technical inability to achieve R(0) resection, but potentially resectable after tumor reduction, were given FOLFIRINOX: oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), bolus fluorouracil 400 mg/m(2) and fluorouracil 46-h continuous IV infusion 2,400 mg/m(2), every 2 weeks for a maximum of 12 cycles.Thirty-four patients were enrolled. Response rate before surgery was 70.6% (95%CI: 52.5-84.9). Twenty-eight patients (82.4%) underwent hepatic resection and nine achieved R(0) resection [26.5% (95% CI: 12.9-44.4%)]. The rate of clinical complete remission after surgery was 79.4%. Two-year overall survival was 83%. The most frequent grade 3 or 4 toxicities were neutropenia (64.8%), diarrhea (29.4%), fatigue (23.5%), abdominal cramps (14.7%), neuropathy and nausea (11.8% each), and AST/ALT elevation (14.7/11.8%). Only one patient experienced febrile neutropenia, four patients withdrew due to toxicity and no toxic death was observed.FOLFIRINOX, with an acceptable toxicity profile, shows a high response rate in liver metastases from colorectal cancer. The rate of hepatic resection in patients initially not resectable, is attractive and warrants further assessment of this regimen in randomized studies compared to standard regimens.

Background/Aims: To compare the cost consequences of oral capecitabine and two different intravenous regimens of 5-fluorouracil/folinic acid (de Gramont and Mayo Clinic regimens) as adjuvant therapy in stage III colon cancer in France. Methods: Clinical efficacy and safety data were taken from published clinical trials. Medical resource use was estimated from published data and expert opinion. Direct costs (drug acquisition, inpatient and home drug administration, laboratory tests, transportation, and management of adverse events) were considered over a time horizon of 46 months (3.8 years). The perspective taken was that of the French Sickness Funds. Results: In patients treated with capecitabine, relapse-free survival was 1.3 months longer than with the Mayo Clinic regimen, which has been shown to be as effective as the de Gramont regimen. In the base case analysis, capecitabine was less costly (3,654 EUR/patient) than the Mayo Clinic (10,481 EUR/ patient) and de Gramont (7,204 EUR/patient) regimens. In the sensitivity analysis, capecitabine remained dominant except when the intravenous regimens were assumed to be administered at home in all patients. Conclusions: In France, capecitabine is more effective and less costly than both the Mayo Clinic and de Gramont regimens as adjuvant therapy for colon cancer.

This multicenter, phase II, open-label study evaluated the antitumor efficacy and safety of oxaliplatin and raltitrexed (Tomudex) in non-pretreated advanced colorectal cancer patients.Seventy-one patients received oxaliplatin 130 mg/m(2) and raltitrexed 3 mg/m(2) intravenously on an outpatient basis every 3 weeks. All patients had histologically proven metastatic colorectal adenocarcinoma, performance statusor=2 and good baseline organ function. Most (56%) had only one disease site. All patients were assessed for safety, and 66 of 69 eligible patients were assessed for response.A total of 404 cycles were administered, with a median of six cycles per patient (range 1-12 cycles). Relative dose intensities were 0.98 and 0.98 for oxaliplatin and raltitrexed, respectively. The most common grade 3-4 toxicities (National Cancer Institute Common Toxicity Criteria) among treated patients were as follows: neutropenia (21 patients, 30%), asthenia (eight, 11%), diarrhea (12, 17%), liver function test abnormalities (24, 34%), nausea (nine, 13%) and vomiting (nine, 13%). Two treatment-related deaths occurred (hematotoxicity in one patient and gastrointestinal toxicity in the other) and two further deaths were possibly related to treatment (hepatic dysfunction in one patient and neuropathy in the other). Thirty-seven objective responses (one complete) were obtained [objective response rate 54%; 95% confidence interval (CI) 42% to 65%] in eligible patients. The median response duration was 8.5 months (95% CI 6.7-12.2 months), while median progression-free and overall survival among eligible patients were 6.2 (95% CI 5.1-6.9 months) and 14.6 months (95% CI 11.0-18.9 months), respectively.The present study confirms the feasibility of the raltitrexed plus oxaliplatin combination and its activity in non-pretreated advanced colorectal cancer patients.

Carcinoembryonic antigen (CEA) and CA 19-9 are both widely used in the follow up of patients with gastrointestinal cancer. More recently another tumor marker, named CA 72-4 has been identified and characterized using two different monoclonal antibodies B72.3 and CC49. Several reports evaluated CA 72-4 as a serum tumor marker for gastric cancer and compared its clinical utility with that of CEA or CA 19-9; few reports concerned its prognostic value. In the present study, CA 72-4 is evaluated and compared with CEA and CA 19-9 in various populations of patients with gastric cancer and benign disease; for 52 patients with gastric adenocarcinoma and 57 patients without neoplastic disease CEA, CA 19-9 and CA 72-4 were evaluated before treatment. Sensitivity of the tumor markers CA 72-4, CA 19-9 and CEA at the recommended cut-off level in all 52 patients were 58%, 50% the sensitivity increased to 75%. of these markers, for non metastatic patients, multivariate analyses indicated that none of the markers were significant, when adjusted for gender and age (which were indicators of poor prognosis); patients with abnormal values of CA72-4 tended to have shorter survival than patients with normal values (p< 0.07). In the metastatic population, only high values of CA19-9 (p< 0.02) and gender (women) (p< 0.03) were indicators of poor prognosis in univariate analysis; multivariate analysis revealed that both CA72-4 (p= 0.034) and CA19-9p= 0.009), adjusted for gender were independent prognostic factors. However, CA72-4 lost significance (p= 0.41) when adjusted for CA19-9 and gender, indicating that CA19-9 provides more prognostic information than CA72-4.When limited to the metastatic male population with normal values of CA 19-9 and CEA, CA 72-4 pretherapeutic positive levels were associated with a worse prognosis (p< 0.005).In conclusion, this study suggests that the addition of CA 72-4 to CEA and/or CA 19-9 could improve sensitivity in gastric cancer. The prognostic role of this marker is not yet clearly demonstrated but its usefulness in the monitoring of gastric cancer should be taken into account.

Unknown primary tumors are highly malignant diseases which portend a dire prognosis. We designed a prospective high dose-intensity policy with the aim of improving the results obtained with conventional chemotherapy.Chemotherapy regimens were determined according to clinical features. In patients younger than 61 years with an ECOG performance status of 0 or 1, poorly differentiated adenocarcinoma or poorly differentiated carcinoma, and no evidence of brain or bone marrow involvement (group A), the treatment plan included four sequential high-dose courses with hematopoietic progenitor cell and growth factor support. Peripheral blood progenitor cells were collected by apheresis as the leukocyte counts recovered from the nadir induced by the first cycle of chemotherapy (doxorubicin 75 mg/m2, cyclophosphamide 6000 mg/m2). Patients then received two cycles of etoposide (800 mg/m2) and carboplatin (900 mg/m2) separated by one cycle of doxorubicin (75 mg/m2) and cyclophosphamide (3000 mg/m2). G-CSF (5 micrograms/kg/d) was given until engraftment. It was planned that cycles would be delivered every three weeks. The remaining patients (group B) received alternative cycles of AC (doxorubicin 50 mg/m2, cyclophosphamide 1000 mg/m2) and EP (etoposide 300 mg/m2, cisplatin 100 mg/m2). Cycles were given at two-week intervals with GM-CSF support (5 micrograms/kg/d) from day 4 to day 10. Patients without measurable lesions were included, since the major endpoint was survival.Sixty patients entered the study. Twenty patients were assigned to group A and 40 patients to group B. In group A, 5 of 12 patients with measurable lesions (42%; 95% confidence interval (95% CI): 22%-62%) achieved major responses to chemotherapy, including one complete response. The duration of the overall median survival was 11 months. In group B, a major response was observed in 12 (39%; 95% CI: 28%-50%) of 31 patients with measurable lesions, including three complete responses. The overall median survival was 8 months. Hematological toxicities were noteworthy in both groups. Two toxic deaths occurred in group B.Using these doses and schedules of chemotherapy, a high-dose intensity policy does not appear to improve the outcome of patients with carcinoma of unknown primary site. Alternative studies dealing with new drugs are required.

Resume Propos. — Les carcinomes de site primitif inconnu constituent une entite clinique dont la frequence est elevee et dont la prise en charge quotidienne, tant diagnostique que therapeutique, demeure difficile. Methodes. — Cent patients pris en charge au centre regional de lutte contre le cancer de Montpellier pour un carcinome de site primitif inconnu ont fait l'objet d'une etude retrospective portant sur les caracteristiques cliniques et biologiques au moment du diagnostic, les examens realises lors du bilan initial, les traitements entrepris et l'evolution. Resultats. — Trois principaux types histologiques ont ete observes: adenocarcinome (66 patients), carcinome indifferencie (19 patients), et carcinome epidermoide (11 patients). Les sites metastatiques les plus frequemment envahis etaient les os, les poumons, les ganglions et le foie. Parmi les explorations complementaires realisees lors du bilan initial afin d'identifier la tumeur primitive (dont aucune, par definition, ne s'est averee contributive), 68 combinaisons differentes d'examens ont ete observees. Une anemie inferieure a 100 g/L a ete notee chez dix patients, alors qu'une elevation des phosphatase alcalines a ete observee chez 42 patients. Sept patients, decedes pendant ou au decours immediat du bilan initial, n'ont recu aucun traitement. Une chimiotherapie et une radiotherapie ont ete delivrees chez respectivement 70 et 59 patients, ces deux traitements ayant ete associes dans 36 cas. Un sel de platine a ete delivre chez 53 des 70 patients ayant recu une chimiotherapie. Le nombre median de cycles administre par patient a ete de quatre. Neuf reponses partielles ont ete observees, dont six chez des patients ayant recu une chimiotherapie comportant un sel de platine. Quatre-vingt-seize patients sont decedes, dont 95 a la suite de la progression de la maladie et un d'affection intercurrente. La survie mediane a ete de 9 mois. Deux variables pronostiques ont ete identifiees lors de l'analyse unifactorielle : le nombre de sites metastatiques et le taux serique des phosphatases alcalines. Conclusions. — Cette etude retrospective confirme les difficultes de prise en charge diagnostique et therapeutique des carcinomes de site primitif inconnu. L'analyse de la litterature permet de recommander, pour la pratique quotidienne, un bilan diagnostique limite ayant pour objectif principal d'identifier les tumeurs primitives susceptibles d'avoir un impact pronostique (sein et ovaire) ou therapeutique (prostate). En dehors des cas anatomocliniques particuliers, les indications et modalites de la chimiotherapie ne sont pas definies.

International audience; BACKGROUND:The combination of bevacizumab and bolus 5-fluorouracil, leucovorin and irinotecan is highly effective in patients with metastatic colorectal cancer (mCRC). This randomised, multicenter, non-comparative phase II trial assessed the efficacy and safety of bevacizumab plus oral capecitabine plus irinotecan (XELIRI) or infusional 5-fluorouracil, leucovorin plus irinotecan (FOLFIRI) as first-line therapy for patients with mCRC.PATIENTS AND METHODS:Patients received bevacizumab 7.5mg/kg on day 1 plus XELIRI (irinotecan 200mg/m(2) on day 1 and oral capecitabine 1,000 mg/m(2) bid on days 1-14) every 3 weeks or bevacizumab 5mg/kg on day 1 plus FOLFIRI (5-fluorouracil 400mg/m(2) on day 1 plus 2,400 mg/m(2) as a 46-h infusion, leucovorin 400mg/m(2) on day 1, and irinotecan 180 mg/m(2) on day 1) every 2 weeks. Patients aged ≥ 65 years received a lower dose of capecitabine (800 mg/m(2) twice daily). The primary endpoint was 6-month progression-free survival (PFS) rate.RESULTS:A total of 145 patients were enrolled (bevacizumab-XELIRI, n=72; bevacizumab-FOLFIRI, n=73). The 6-month PFS rate was 82% (95% confidence intervals (CI) 71-90%) in the bevacizumab-XELIRI arm and 85% (95% CI 75-92%) in the bevacizumab-FOLFIRI arm. In both the bevacizumab-XELIRI and bevacizumab-FOLFIRI arms, median PFS and overall survival (OS) were 9 and 23 months, respectively. The most frequent toxicities were grade 3/4 neutropenia (bevacizumab-XELIRI 18%; bevacizumab-FOLFIRI 26%) and grade 3 diarrhoea (12% and 5%, respectively).CONCLUSIONS:This randomised non-comparative study demonstrates that bevacizumab-XELIRI and bevacizumab-FOLFIRI are effective regimens for the first-line treatment of patients with mCRC with manageable toxicity profiles.

ML18147 evaluated continued bevacizumab with second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) progressing after the standard first-line bevacizumab-containing therapy.Evaluating outcomes according to tumor Kirsten rat sarcoma virus oncogene (KRAS) status was an exploratory analysis. KRAS data were collected from local laboratories (using their established methods) and/or from a central laboratory (mutation-specific Scorpion amplification-refractory mutation system). No adjustment was made for multiplicity; analyses were not powered to detect statistically significant differences.Of 820 patients, 616 (75%) had unambiguous KRAS data; 316 (51%) had KRAS wild-type tumors and 300 (49%) had mutant KRAS tumors. The median progression-free survival (PFS) was 6.4 months for bevacizumab plus chemotherapy and 4.5 months for chemotherapy [P0.0001; HR = 0.61; 95% confidence interval (CI): 0.49-0.77] for wild-type KRAS and 5.5 and 4.1 months, respectively (P = 0.0027; HR = 0.70; 95% CI: 0.56-0.89) for mutant KRAS. The median overall survival (OS) was 15.4 and 11.1 months, respectively (P = 0.0052; HR = 0.69; 95% CI: 0.53-0.90) for wild-type KRAS and 10.4 versus 10.0 months, respectively (P = 0.4969; HR = 0.92; 95% CI: 0.71-1.18) for mutant KRAS. In both analyses, no treatment interaction by KRAS status was observed (PFS, P = 0.4436; OS, P = 0.1266).Bevacizumab beyond first progression represents an option for patients with mCRC treated with bevacizumab plus standard first-line chemotherapy, independent of KRAS status.

e15688Background: FOLFIRINOX (FFX) and nab-paclitaxel/gemcitabine (AG) showed significant improvement in efficacy compared to gemcitabine alone in metastatic pancreatic cancer (mPC). Alternating AG...

Combined chemotherapy has demonstrated a degree of efficacy in gastric carcinoma. As 5-fluorouracil (5FU) and cisplatinum are two of the most active drugs, we have tested the efficacy of combined 5FU and cisplatinum in a prospective phase II trial. Cycles were administered every 4 weeks and consisted of 5FU 1000 mg/m 2 /day 5 days continuous intravenous (i.v.) infusion and cisplatinum 100 mg/m 2 on day 2. Cycles were repeated according to tolerance and efficacy. 87 patients entered the study, 57 with metastatic or recurrent tumour (M) and 30 with locally advanced gastric cancer (LAGC). The response rate for the 83 evaluable patients was 43% [95% confidence interval (CI) 30–56%]. There were four complete responses (5%), 32 partial responses (39%), 34 cases of stable disease and 13 cases of progressive disease. Responses were more frequent in patients with a good performance status ( P = 0.02), with their primary located in the cardia ( P = 0.003), with a non-linitis plastica tumour form ( P = 0.003) or a tumour containing less than 50% of independent cells ( P = 0.016). Median survival was 9 months for the total population. It was better in patients with a good performance status ( P = 0.01), and those who did not have linitis plastica ( P = 0.005). Toxicity was acceptable, although grade 3–4 neutropenia was reported in 22% of the cycles, mucositis in 14% and 3 patients died of septic complications. The combination of 5FU and cisplatinum is effective in terms of tumour response in advanced gastric cancer and warrants testing with the other active regimens.

20 patients with liver metastases from colorectal carcinoma undergoing laparotomy received 15–60 mg intravenously, either intact or fragments of, anti-carcinoembryonic antigen (anti-CEA) monoclonal antobodies labelled with 0.55–1.48 GBq (15–40 mCi) of 131 I, 3–8 days prior to operation. The uptake measured per gram of metastases ranged from 0.33 to 6.6 × 10 −3 % of injected dose. Tumour to liver uptake ratios ranged from 2 to 33. The radiation dose, estimated in 6 patients (3 of each group), for an extrapolated dose of 3.7 GBq (100 mCi) of 131 I ranged from 0.3 to 0.8 Gy in normal liver or spleen (an acceptable estimate for bone marrow radiation dose) and from 3.4 to 8.2 Gy to the hepatic metastases, indicating that probably other therapeutic modalities should be associated with radioimmunotherapy.

Objective: In a recent randomized study, we demonstrated that XELOX (oxaliplatin + oral capecitabine) was well tolerated and not inferior in terms of efficacy to the infusional FOLFOX-6 regimen in first-line treatment of metastatic colorectal cancer (mCRC). The objective of this additional analysis was to compare the cost of XELOX and FOLFOX-6. Methods: This cost-minimisation study took into account costs related to drug acquisition, hospital care for chemotherapy administration and for serious adverse event management. Hospital care costs were based on French ‘diagnosis-related group’ tariffs. Drug acquisition costs were drawn from French official sources. Analysis was performed from the French health insurance perspective. Results: Baseline characteristics of the 282 patients included (143 XELOX, 139 FOLFOX-6) were well balanced. Patients reported less and shorter hospitalisations (day and overnight hospital care) with XELOX: 6.4 ± 2.2 hospitalisations versus 9.7 ± 3.1 (p < 0.001); 11.4 ± 10.6 days versus 17.7 ± 11.8 (p < 0.001). Mean disease management cost per patient was significantly lower with XELOX (EUR 12,918 ± 5,075 vs. EUR 17,229 ± 8,665, p < 0.001). Conclusion: In the perspective of our analysis, taking into account hospitalisation and drug acquisition costs, the treatment of mCRC patients with XELOX in comparison to FOLFOX-6 significantly decreased the costs, as well as the mean overall hospitalisation length of stay.

Background: This multicenter adjuvant phase III trial evaluated the addition of irinotecan to LV5FU2 in colon cancer patients at high risk of relapse. Patients and methods: A total of 400 patients with histologically proven primary colon cancer with postoperative N1 detected by occlusion/perforation or N2 were randomised to: A-LV5FU2 [leucovorin 200 mg/m 2 , 2-h infusion, 5-fluorouracil (5-FU) 400 mg/m 2 bolus, 600 mg/m 2 22-h continuous infusion, days 1 and 2] or B-LV5FU2 + IRI (irinotecan 180 mg/m 2 90-min infusion day 1 + LV5FU2) fortnightly for 12 cycles. Primary end point was disease-free survival (DFS). Results: Median follow-up was 63 months. Significantly more T4 tumours and 15 or more positive lymph nodes were observed in arm B. 5-FU relative dose intensity (RDI) was >0.80 for 94% and 77% in arms A and B, respectively (P 0.80 for 70% patients. There were more grades 3 and 4 neutropenia in arm B (4% versus 28%, P < 0.001). The 3-year DFS was 60% [95% confidence interval (Cl) 53% to 66%] and 51 % (95% Cl 44% to 58) in arms A and B, respectively. No difference was observed [hazard ratio (HR) = 1.12, 95% Cl 0.85-1.47, P = 0.42] even when adjusted for prognostic factors (adjusted HR = 0.98, 95% Cl 0.74-1.31, P = 0.92). The 5-year overall survival (OS) was 67% (95% Cl 59% to 73%) and 61% (95% Cl 53% to 67%) in arms A and B, respectively. Conclusion: Adjuvant LV5FU2 + IRI compared with LV5FU2 alone in patients at high risk of relapse showed no improvement in DFS and OS.

Background To assess activity and safety of an experimental combination of irinotecan and oxaliplatin (IRINOX) as first-line treatment in advanced colorectal cancer. Patients and methods In this randomized phase II trial, 80 patients were treated: arm A (IRINOX) in 40 patients received at day 1 oxaliplatin 85 mg/m2 and irinotecan 180 mg/m2 biweekly, standard arm B received a biweekly simplified folinic acid (FA) and fluorouracil (FU), FA 200 mg/m2 in a 2-h infusion and bolus injection of 5FU 400 mg/m2 on day 1, then a two 400 mg/m2 continuous infusion of FU on days 1 and 2 with either oxaliplatin 85 mg/m2 (20 patients) or irinotecan 180 mg/m2 (20 patients). Results Twenty-one partial responses (52.5%, median duration 7.2 months) were observed with the IRINOX arm and two complete and 20 partial responses (55%, median duration 6.4 months) with arm B. Median progression-free and overall survival times were 8.4 and 19 months, respectively, in the IRINOX arm and 8.1 and 20.4 months in arm B. Main grade 3/4 toxic effects were, respectively, neutropenia 42.5% and 32.5%; febrile neutropenia 10% and 5%; diarrhea 32.5% and 7.5%; vomiting 10.0% and 5%; neurosensory toxicity 17.5% and 7.5%. Conclusion The IRINOX arm has a manageable toxicity and is active.

A prospective phase II study was performed to determine the feasibility, efficacy and safety of arterial hepatic infusion (HAI) using pirarubicin combined with intravenous chemotherapy.From December 1991 to April 1994, 75 patients with unresectable colorectal metastases confined to the liver were included in this multicenter study to receive intra-arterial hepatic pirarubicin and a systemic monthly regimen of 5-fluorouracil (5-FU) and folinic acid. Sixty-four patients were analyzed in the intention-to-treat analysis and 61 in the per-protocol analysis.Tolerance of this regimen was rather good; however, functional catheter problems were observed in 29 patients (45%) resulting in failure of HAI in 21 cases (33%) after a median of three cycles; vomiting grade 3 was present in 12.5% of patients, neutropenia grade 4 in 23% and alopecia grade 3 in 19%. The overall response rate was 31.9% in intention-to-treat analysis, and 39.3% in per-protocol analysis. Extrahepatic progression was reported in only 21.7% of patients. Time to hepatic progression and extra-hepatic progression was 8.3 and 15 months, respectively, in intention-to-treat analysis, and 11 and 18 months, respectively, in per-protocol analysis. Median survival was 19 and 20 months in intention-to-treat analysis and per-protocol, respectively.In our study, the combination of intra-arterial pirarubicin and intravenous chemotherapy demonstrated some efficacy and good tolerance in the treatment of isolated colorectal liver metastases. This treatment seems to prevent extra-hepatic spread and prolong survival time. The results of this study have to be confirmed by new trials using more active systemic chemotherapy.

Background: The aim of this study was to determine the maximum-tolerated dose (MTD) and the recommended dose of irinotecan and oxaliplatin with a fixed 5-fluorouracil (5-FU)/leucovorin (LV) regimen in patients with metastatic solid tumors. Patients and methods: The trial was designed to evaluate escalating doses of oxaliplatin and irinotecan, starting at 60 mg/m 2 and 90 mg/m 2 , respectively, given at day 1 with the full-dose LV5FU2 regimen, given on days 1 and 2 as follows: folinic acid 200 mg/m 2 followed by 5-FU 400 mg/m 2 bolus and 600 mg/m 2 22 h continuous infusion, every 2 weeks. The second cohort of patients was treated at the recommended dose for oxaliplatin and irinotecan with the simplified LVSFU regimen: on day I, a 2-h infusion of folinic acid (400 mg/m 2 ), followed by a 10-min intravenous bolus of 5-FU (400 mg/m 2 ), followed by a continuous infusion of 5-FU (2400 mg/m 2 ) over 46 h. Results: Thirty-four patients were treated at the following dose levels (oxaliplatin/irinotecan mg/m 2 ): 60/90, 60/120, 85/120, 85/150, 85/180, 85/200 and 85/220 and seven patients were treated at the recommended dose with the simplified LVSFU scheme. The MTD was reached at dose level 85/220 mg/m 2 but the recommended dose chosen for the second step was 85/180 mg/m 2 to keep a better compliance with the biweekly schedule. Main grade 3/4 toxicities per patient included the following: neutropenia in 78% (febrile episodes in 12%), diarrhea in 27%, nausea/vomiting in 24% and peripheral neuropathy in 37% (Levi's scale). Antitumor activity was observed at almost all dose levels. Most objective responses were observed in digestive malignancies, since 10 out of 11 were obtained in five colorectal cancers, two pancreatic cancers, two cholangiocarcinoma and one gastric cancer. Conclusion: The recommended dose for the triple association is 85/180 mg/m 2 of oxaliplatin and irinotecan, respectively, with LV5FU2 or simplified LV5FU. The antitumor activity in gastrointestinal malignancies should be evaluated in phase II studies in different tumor types.

Circulating DNA (ctDNA) analysis constitutes a hopeful approach to provide a non-invasive test potentially allowing diagnosis, prognosis, theranostics, therapeutic monitoring and follow-up in cancer patients. We studied tumour-derived ctDNA by an original approach focusing on its size distribution. We observed that tumour-derived ctDNA is mainly of size below 100 bp and exhibits a specific size distribution profile compared to healthy subjects [ 1 , 2 ]. Based upon these discoveries, we set up a refined allele-specific Q-PCR based method termed Intplex and adapted it to detect the 6 more frequent KRAS mutations in colorectal cancer (CRC) and the BRAFV600E point mutation [ 3 ]. In a single step, it determines simultaneously the ctDNA concentration, the ctDNA fragmentation, the mutational status and the mutation load (% mutant ctDNA from the total). Intplex sensitivity is 0.01% appearing unprecedented among Q-PCR-based methods. We reported higher plasma ctDNA concentrations and fragmentation levels in CRC patients than in healthy individuals 2 . Proof of concept of point mutation detection by Intplex was given by the full agreement of the results obtained on a cohort of 15 CRC patients between ctDNA analysis and tumour tissue analysis. Concordance of the mutational status determined by the two analyses examined in a clinical study on a cohort of 79 metastatic CRC patients will be presented [ 4 ]. This is the first blinded prospective study to compare KRAS and BRAF mutational status data obtained from the analysis of tumor tissue by routine gold standard methods and of plasma DNA using a novel method. Examination of the mutation load in a cohort of 48 mutated clinical samples from CRC patients revealed a wide inter-individual variation as values extended from 0.037% to 68.8% [ 5 , 6 ]. The opportunity in detecting quantitatively and dynamically mutation could constitute a non-invasive attractive tool for therapeutic monitoring and patient follow-up and expand the scope of personalized cancer medicine.

Chemotherapy is moderately efficient as a treatment for pancreatic adenocarcinoma, but patient survival and quality of life has improved with this modality in some trials. In a previous phase II trial, 5-fluorouracil (5-FU) plus cisplatin (FUP) yielded a 26.5% response rate and a 29% survival rate at 1 year. The present study aimed to compare FUP with 5-FU alone, which was the control arm in former Mayo Clinic trials.Patients with untreated cytologically or histologically proven metastatic or locally advanced adenocarcinoma of the pancreas were deemed measurable or evaluable. Chemotherapy regimens consisted of a control FU arm (5-FU 500 mg/m(2)/day for 5 days) and the investigational FUP arm (continuous 5-FU 1000 mg/m(2)/day for 5 days plus cisplatin 100 mg/m(2) on day 1 or day 2). In both arms, chemotherapy was repeated at day 29.Two-hundred and seven patients from 18 centres were randomised: 103 in the FU arm and 104 in FUP arm. Treatment arms were balanced with respect to performance status grade 0-1 (83% versus 86%, respectively) and the presence of metastases (92% versus 89%, respectively). The median number of cycles administered was two in both arms (range 0-14). Five patients did not receive any chemotherapy and 45 received only one cycle. Toxicity (WHO grade 3-4) was lower with FU than with FUP (20% versus 48%, P0.001), as was neutropenia (6% versus 23%), vomiting (4% versus 17%) and toxicity-related deaths (one versus four early in the trial). The response rate was low in both arms, but superior in the FUP arm: 12% versus 0% (intention-to-treat analysis, P0.01). The survival rates at 6 months were 28% and 38% for the FU and FUP arms, respectively, and 1-year survival rates were 9% and 17% (log-rank test, P = 0.10). One-year progression-free survival was 0% with FU versus 10% with FUP (log-rank test, P = 0.0001).In advanced pancreatic carcinomas with a poor prognosis, FUP was superior to FU in terms of response and progression-free survival, but not in terms of overall survival. The low response rate is partly related to the number of patients who received only one cycle of chemotherapy. A more effective, better tolerated version of this FUP combination is needed.

Purpose. The efficacy and safety of single-agent, high-dose irinotecan (CPT-11, Campto) 500 mg/m2 every 3 weeks were investigated as first-line treatment for advanced colorectal cancer (CRC). Patients and methods. Patients were enrolled into the study to receive a first cycle of therapy with irinotecan at a dose of 350 mg/m2 every 3 weeks, which could be escalated to 500 mg/m2 for the second and subsequent cycles depending on toxicity. Efficacy, safety and pharmacokinetics were determined in the intent to treat (ITT) population and the high-dose population (i.e. patients who had received at least three cycles of irinotecan, the second and third at 500 mg/m2). Results. Of 49 patients enrolled into the study (ITT population), 31 (63%) received at least three cycles of treatment with cycles 2 and 3 at an irinotecan dose of 500 mg/m2 (the high-dose population). The response rates (RR) for the ITT and high-dose populations were 24.5% and 35.5%, respectively. The main grade 3/4 toxicities per cycle in the ITT and high-dose populations were neutropenia 22% and 17%, febrile neutropenia 5% and 3%, and diarrhoea 12% and 7%, respectively. The pharmacokinetics of irinotecan and its metabolite SN-38 were investigated in 31 patients in cycle 1 and 22 patients in cycle 2. Irinotecan clearance and SN-38 exposure were not sufficiently correlated with toxicity in cycle 1 to identify patients for dose increase in subsequent cycles. The exposure to irinotecan and SN-38 increased in proportion to dose from 350 to 500 mg/m2. Conclusion. These results suggest that high-dose irinotecan can be safely administered as first-line monotherapy to approximately two-thirds of patients who present with advanced CRC following a selective first cycle.

The comparative saliva/plasma pharmacokinetics of 5-fluorouracil (5-FU) were investigated in 21 patients with metastatic colorectal cancer receiving high-dose folinic acid (LV (leucovorin) 200 mg/m2) followed by 5-FU bolus (400 mg/m2) and continuous infusion (600, 750, 900 or 1200 mg/m2) on days 1 and 2. Quantitation of unchanged drug was assessed by a highly specific high-performance liquid chromatographic method. Large patient-to-patient variations in plasma and saliva 5-FU concentrations were observed. Saliva pharmacokinetics could be described using a bi-exponential pattern. The half-life of the rapid phase averaged 8.0 min, and was of the same order of magnitude as the 5-FU elimination half-life determined from plasma data. The half-life of the terminal part of the curve averaged 8 h; such decrease in salivary concentrations could be due to changes in salivary gland function caused by 5-FU, which results in reduced salivary flow rate. Between individual 5-FU concentrations in parotid saliva and plasma a statistically significant straight line could be fitted with a coefficient of correlation of 0.675. Moreover, the risk of developing 5-FU-related mucositis was significantly linked to 5-FU salivary exposure. Diarrhoea was the most frequent toxicity encountered during the trial.

Summary Background: Despite recent progress in modern chemotherapy, metastatic solid tumors still have a poor outcome. The delivery of increased dose intensities of cytotoxic agents could improve response rates. We assessed the feasibility and safety of a high-dose sequential chemotherapy program in chemotherapy-naive patients with solid tumors. Patients and methods: Thirty patients (14 with carcinoma of unknown primary site, seven with metastatic breast cancer, six with small-cell lung cancer, and three with other diseases) were treated by an induction therapy regimen consisting of four cycles of high-dose chemotherapy with hematopoietic progenitor cell and growth factor support. Peripheral blood progenitor cells were collected by apheresis as the leukocyte counts recovered from the nadir induced by the first cycle of chemotherapy (doxorubicin 75 mg/m 2, cyclophosphamide 6000 mg/m2). Patients then received two cycles of etoposide (800 mg/m2) and carboplatin (900 mg/m2) separated by one cycle of doxorubicin (75 mg/m2) and cyclophosphamide (3000 mg/m2). G-CSF (5 ug/kg/d) was given until engraftment. Cycles were scheduled to be delivered every three weeks. Results: A total of 108 cycles of chemotherapy were administered. Six patients went off study before the end of the program (three because of progressive disease, three because of toxicity). After the first cycle, a median number of 10 x 10 6/ kg CD34+ cells (range 8-30) were collected. The median number of apheresis procedures was 1 (range 1-3). From cycle 2 to cycle 4, the median number of days when there was an absolute neutrophil count of less than 500/ul increased from three to five, and the median number of days when the platelet count was less than 25,000/ul increased from three to six. Episodes of febrile neutropenia occurred in 36%, 50% and 46% of cycles during cycles 2, 3 and 4, respectively. The median numbers of days between cycle 1 and cycle 2, cycle 2 and cycle 3, cycle 3 and cycle 4 were 24 (range 20-30), 22 (range 20-36) and 22 (range 18—35), respectively. There were no treatment-rel ated deaths. Non-hematologic toxicity included severe (WHO grades 3 or 4) nausea/vomiti ng in 19 (18%) cycles, mucositis in 8 (7%) cycles and diarrhea in 7 (6%) cycles. Conclusion: Support with hematopoietic progenitor cells and growth factors allows the timely administration of repetitive cycles of high-dose chemotherapy in chemotherapy- naive patients, resulting in a significant increase in dose intensity. Toxicity is noteworthy but manageable and does not compromise further therapy.

PURPOSE To assess the efficacy of irinotecan (CPT-11) in the treatment of advanced colorectal cancer in both chemotherapy-naive and pretreated patients. PATIENTS AND METHODS Two hundred thirteen patients (aged 18 to 75 years) with metastatic colorectal cancer, World Health Organization (WHO) performance status < or = 2, and life expectancy > or = 3 months were treated with CPT-11 350 mg/m2 every 3 weeks. All 178 patients eligible for efficacy analysis had not received more than one prior fluorouracil (5-FU)-based chemotherapy regimen (adjuvant or palliative) and had adequate hematologic, renal, and hepatic function. RESULTS Primary tumor sites were the colon (71%) and rectum (28%). Sixty-six percent of the patients had > or = two metastatic sites. Ninety-eight percent of the patients had undergone previous surgery, and 77.5% had received prior chemotherapy. Thirty-two of 178 eligible patients achieved on objective response (four complete responses [CRs] and 28 partial responses [PRs]; response rate, 18%; 95% confidence interval, 12.6% to 24.4%), 65 were stable, and 59 progressed. The response rate was 17.7% in the pretreated group and 18.8% in the chemotherapy-naive group. Within the former subgroup, response rates of 16.1% were reported in patients who were progressive on prior 5-FU chemotherapy and 19.1% in patients who were progressive off such treatment. The median duration of objective response (9.1 months) and median time to achievement of a response (9.3 weeks) did not differ between chemotherapy-naive and pretreated patients. The most frequent adverse events were neutropenia, which developed in 80% of the patients, delayed diarrhea (87%), alopecia (88%), fatigue (81%), and nausea/vomiting (77%). All these adverse events were manageable. Severe (WHO grade 3 or 4) neutropenia was only observed in 18% of the cycles, leukopenia in 11%, delayed diarrhea in 11%, and nausea and vomiting in 3%. Development of simultaneous grade 3 or 4 neutropenia and delayed diarrhea during 4% of the cycles was the safety issue of greatest concern. CONCLUSION CPT-11 has definite activity in the treatment of advanced metastatic colorectal cancer both in chemotherapy-naive and in pretreated patients who experienced disease progression on 5-FU, which suggests a lack of cross-resistance between CPT-11 and 5-FU. Diarrhea and neutropenia, the major toxicities of CPT-11, contribute to the risk to develop febrile neutropenic sepsis.

The modulation of 5-fluorouracil (5-FU) with folinic acid (leucovorin, LV) is more efficacious than 5-FU alone in the treatment of metastatic colorectal cancer, and the combination of 5-FU with cisplatin is currently one of the most active regimens in advanced gastric cancer. A phase II study was therefore conducted to test the efficacy and toxicity of the combination of 5-FU, LV and cisplatin (FLP) in metastatic gastric cancer. 28 patients entered the study. Metastatic sites were observed in the liver (in 21 patients), the peritoneum (in 8), the lymph nodes (in 7) or the bones (in 1) and a local recurrence was noted in 4 cases. The performance status (using World Health Organisation criteria) was 0 for 13 patients and 1 or 2 for the others. Cycles of treatment were administered every 28 days and consisted of LV 200 mg/m2/day for 5 days followed by 5-FU 400 mg/m2/day for 5 days with cisplatin 100 mg/m2 on day 2. The response rate for the 27 evaluable patients was 51.8% (95% confidence interval (CI), 33-70.6%). There were four complete responses (14.8%) and 10 partial responses (37%). Median survival was 11 months and 4 patients were alive at 2 years. Both response rate and survival were better for patients with a good performance status. The overall toxicity was very low, except for 1 patient who died of dehydration and cardiac failure. In conclusion, the FLP protocol was effective and well tolerated in patients with metastatic gastric cancer.

Regorafenib (BAY 73-4506) is an oral multikinase inhibitor of a broad range of angiogenic, oncogenic, and stromal kinases. The phase III CORRECT trial was conducted to evaluate efficacy and safety of regorafenib in patients with mCRC who had progressed after all approved standard therapies. Methods Enrollment criteria included documented mCRC and progression during or ≤3 months after last standard therapy. Patients were randomized 2:1 to receive regorafenib (160 mg od po, 3 weeks on/1 week off) plus BSC, or placebo (PL) plus BSC. Patients continued on treatment until progression, death, or unacceptable toxic effect. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), safety, and quality of life. Results From May 2010 to March 2011, 760 patients were randomized (regorafenib: 505; PL: 255). Baseline characteristics were balanced between the two arms. Results are available from a pre-planned formal interim analysis. The estimated hazard ratio (HR) for OS was 0.77 (95% CI: 0.64, 0.94; 1-sided P = 0.0052). Median OS was 6.4 months (95% CI: 5.9, 7.3) for regorafenib and 5.0 months (95% CI: 4.4, 5.8) for PL. The estimated HR for PFS was 0.49 (95% CI: 0.42, 0.58; one-sided P Conclusions Statistically significant benefit in OS and PFS was observed for regorafenib over PL in patients with mCRC who have failed all approved standard therapies. No new or unexpected safety signal was found.

Background Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1–3. In the phase III AXIS study in second-line metastatic renal cell carcinoma (mRCC), axitinib demonstrated significant improvement in progression-free survival (PFS) compared with sorafenib (median PFS, 6.7 versus 4.7 months; hazard ratio [HR] 0.665; one-sided P Methods Eligible patients had clear-cell mRCC; progressive disease per RECIST after one prior systemic first-line therapy; and Eastern Cooperative Oncology Group performance status (PS) of 0 or 1. Patients were stratified by PS and prior therapy, then randomized 1:1 to receive axitinib or sorafenib. Tumour imaging was assessed by an independent review committee. Results Of the 723 enrolled patients, 158 were Asian (axitinib arm: n = 77; sorafenib arm: n = 81). Of the Asian patients, 74% were male, median age was 61 years, and 59% had PS = 0; prior therapies were 54% cytokine-, 41% sunitinib-, 4% bevacizumab-, and 1% temsirolimus-based regimens. Median PFS in the Asian patients was 10.3 months in the axitinib arm and 4.7 months in the sorafenib arm (HR 0.578; 95% confidence interval, 0.362–0.924; one-sided P = 0.0096). The objective response rate (ORR) was 31.2% versus 7.4% (one-sided P = 0.0003) in the Asian patients receiving axitinib and sorafenib, respectively. Common adverse events (AEs) in the Asian patients receiving axitinib were hypertension (53%), diarrhoea (53%), hand-foot syndrome (47%), fatigue (45%), decreased appetite (36%), dysphonia (36%), and hypothyroidism (31%). Common AEs in the Asian patients receiving sorafenib were hand-foot syndrome (70%), diarrhoea (46%), hypertension (34%), and alopecia (30%). Conclusions Axitinib is effective and well tolerated in the Asian patients with mRCC. Consistent with global phase III trial results, PFS and ORR were higher with axitinib versus sorafenib in the Asian patients.

Background The efficacy/safety of bevacizumab in combination with chemotherapy was investigated in patients (pts) with advanced progressive digestive neuroendocrine tumors (DigNET) (phase II BETTER study (ML20383)). Circulating endothelial cell levels were explored as potential prognostic or predictive marker. Methods Pts were enrolled in two arms depending on tumor primary localisation. Pts with duodeno-pancreatic NET were treated with 5-FU/streptozocin combined to bevacizumab (arm 1, n = 34). Patients with other digNET received capecitabine combined to bevacizumab (arm 2, n = 49). In 50 dig NET patients, CEC levels were monitored at several time points: -before treatment (baseline, BL), -on day 2 (d2) of cycle 1 (C1), -on day 22 (d22) of cycle 1 (C1) for arm 1 and day 1 (d1) of cycle 2 (C2) for arm 2, -at day 1 of each of the subsequent cycles and at the end of treatment. CECs were measured in 1ml erythocyte lysed whole blood by four color flow cytometry (FCM) and identified by a CD45-CD31+CD1467-amino-actinomycin (7AAD)- phenotype. Relation between CEC levels and clinico-biological characteristics, response to treatment and progression/death at 1 or 2 years (1 yr-, 2 yr-PFS) was examined. Non parametric Wilcoxon tests were used to analyze change from baseline and to evaluate the association beteween CEC values and efficacy parameters. Results Median CEC values were low at BL (4 CEC/mL) and similar for the 2 arms. CEC levels significantly increased on C1d2 onlv (media value: 7CEC/mL for the 2 pooled arms, p = 0.019). A trend towards an association between changes in CEC levels between BL and C1d2, and progression/death during the first two years of treatment was observed (p = 0.078). Conclusions Increased CECs at baseline could be an indicator of shorter PFS in digNET treated with the combination of bevacizumab and chemotherapy. The mechanism of increased CECs at day 2 of treatment remains to be understood. Disclosure E. Mitry: Honoraries: Roche. K. Joly: Employment: Roche. M. Ducreux: Consultant: Roche, Merck Serono Honoraries: Roche, Merck Serono, Amgen, Bayer, Fresenus, Pfizer, Sanofi Clinical research project: Pfizer, Chugai, Merck Serono. E. Baudin: Honoraries : Scientific committee of BETTER Trial. All other authors have declared no conflicts of interest.

Background The CORRECT trial was conducted to evaluate the oral multikinase inhibitor regorafenib (REG) in patients (pts) with mCRC whose disease had progressed after all approved standard therapies. This trial met its primary endpoint at a pre-planned interim analysis, the results of which were presented previously (J Clin Oncol 30, 2012 [suppl; abstr 3502]). The updated overall survival (OS) data are reported here. Methods Enrollment criteria included documented mCRC and progression during or ≤3 months after last standard therapy. Pts were randomized 2:1 to receive best supportive care plus either REG (160 mg od po) or placebo (PL) on a 3 weeks on/1 week off schedule. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate, and disease control rate. Safety and quality of life were also evaluated. Results From May 2010 to March 2011, 760 pts were randomized (REG: 505; PL: 255). Baseline characteristics were balanced between the two arms. A descriptive updated analysis of OS was performed, based on a database cutoff of Nov 13, 2011 with 566 total events (97% of events originally required). In this analysis, the hazard ratio (HR, REG/PL) for OS was 0.79 (95% CI, 0.66-0.94, 1-sided p = 0.0038). Median OS was 6.4 months (95% CI, 5.8-7.0) in the REG arm vs 5.0 months (95% CI, 4.4-5.9) in the PL arm. OS rate at 6 and 12 months was 52.2% and 24.1% in the REG arm vs 43.1% and 17% in the PL arm, respectively. These data serve as an update to previously reported OS data from the earlier interim analysis based on 432 (74%) events, which showed a HR for OS of 0.77 (95% CI, 0.64-0.94, 1-sided p = 0.0052). Pts in the REG arm received an average of 78.9% of the planned dose, and pts in PL arm 90.2% of the planned dose. The mean treatment duration was 12.1 ± 9.7 wks (REG) and 7.8 ± 5.2 wks (PL), respectively. Incidence of treatment-emergent, REG-related adverse events was similar in subgroups by age, sex, renal function and hepatic function, whereas the incidence was higher in Asian pts (98.6%) compared with Caucasian pts (92.3%), and higher in pts with a baseline ECOG score of 0 (97.0%) compared with pts with ECOG score of 1 (88.6%). Conclusions This updated OS analysis demonstrated the robustness and consistency of the OS benefit of REG treatment over PL in pts with previously treated mCRC. Disclosure E. Van Cutsem: Received research funding from Bayer A. Grothey: Mayo Clinic received research funding and honoraria for my consulting activity from Bayer, Genentech, Sanofi, Bayer, Daiichi, Imclone. Onyx and BMS A. Sobrero: Advisory board member and has spoken at symposia for: Roche, Merck, Bayer, Amgen, Sanofi S. Siena: Advisory board member for Amgen, AstraZeneca, Bayer, Genentech, Merck-Serono, Roche, Sanofi A. Falcone: Received honoraria from Bayer for speaking, consultancy and sitting on advisory boards. Also received research support from Bayer M. Ychou: Received honoraria from Bayer for sitting on advisory board Y. Humblet: Has received honoraria from Bayer to act as consultant. Has also received research funding from Bayer O. Bouche: Received honoraria from Roche, Merck-Sereno, Amgen L. Mineur: No conflicts of interest to declare C. Barone: Received honoraria for lecturing and advisory boards from Bayer, Merck, Roche, Novartis. Received honoraria for lecturing from GlaxoSmithKline, Amgen A. Adenis: Received honoraria from Bayer (conference and research funding) J. Tabernero: No conflicts of interest to declare T. Yoshino: Received consulting fee from Takeda; honoraria from Chugai, Takeda, Yakult, Bristol-Meyers Squibb and Merck-Serono; research funding from Daiichi Sankyo, Taiho, Bayer and Imclone H-J. Lenz: No conflicts of interest to declare R. Goldberg: Research support to hip State University from Sanofi, Bayer, Myriad, Jennerex. Consulting (unpaid) for Bayer, Sanofi. Payment for a Data Safety Monitoring Board, Lilly D. Sargent: Consulting fees from the CORRECT steering committee of F. Cihon: Employee of Bayer (sponsor of the study) L. Cupit: Employee of Bayer (sponsor of the study) A. Wagner: Employee of Bayer (sponsor of the study) D. Laurent: Employee of Bayer (sponsor of the study) All other authors have declared no conflicts of interest.