Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial.

Background: Elderly patients are often under-represented in clinical trials of metastatic colorectal cancer. We aimed to assess the efficacy and safety of bevacizumab plus capecitabine compared with capecitabine alone in elderly patients with metastatic colorectal cancer.

Methods: For this open-label, randomised phase 3 trial, patients aged 70 years and older with previously untreated, unresectable, metastatic colorectal cancer, who were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens, were randomly assigned in a 1:1 ratio via an interactive voice-response system, stratified by performance status and geographical region.

Panitumumab and irinotecan every 3 weeks is an active and convenient regimen for second-line treatment of patients with wild-type K-RAS metastatic colorectal cancer.

Purpose: To evaluate the efficacy and safety profile of the combination of panitumumab and irinotecan every 3 weeks in a phase II trial as second-line treatment in patients with advanced wild-type (WT) K-RAS colorectal cancer (CRC).

Methods: Fifty-three patients received 9 mg/kg of panitumumab followed by 350 mg/m(2) of irinotecan every 21 days until disease progression, unacceptable toxicity or consent withdrawal.

Results: Median age of patients included was 67 years.

Role of Kras status in patients with metastatic colorectal cancer receiving first-line chemotherapy plus bevacizumab: a TTD group cooperative study.

Background: In the MACRO study, patients with metastatic colorectal cancer (mCRC) were randomised to first-line treatment with 6 cycles of capecitabine and oxaliplatin (XELOX) plus bevacizumab followed by either single-agent bevacizumab or XELOX plus bevacizumab until disease progression. An additional retrospective analysis was performed to define the prognostic value of tumour KRAS status on progression-free survival (PFS), overall survival (OS) and response rates.

Methodology/principal Findings: KRAS data (tumour KRAS status and type of mutation) were collected by questionnaire from participating centres that performed KRAS analyses.

Circulating tumor cell count is a prognostic factor in metastatic colorectal cancer patients receiving first-line chemotherapy plus bevacizumab: a Spanish Cooperative Group for the Treatment of Digestive Tumors study.

Background: The Maintenance in Colorectal Cancer trial was a phase III study to assess maintenance therapy with single-agent bevacizumab versus bevacizumab plus chemotherapy in patients with metastatic colorectal cancer. An ancillary study was conducted to evaluate the circulating tumor cell (CTC) count as a prognostic and/or predictive marker for efficacy endpoints.

Patients And Methods: One hundred eighty patients were included.

Oxaliplatin in combination with infusional 5-fluorouracil as first-line chemotherapy for elderly patients with metastatic colorectal cancer: a phase II study of the Spanish Cooperative Group for the Treatment of Digestive Tumors.

Background: We previously reported a 35% overall response rate (ORR) with biweekly 5-fluorouracil (5-FU) continuous infusion (TTD [Spanish Cooperative Group for Digestive Tumour Therapy] schedule) plus irinotecan as first-line therapy in elderly patients with metastatic colorectal cancer (mCRC). The present study also was carried out in elderly patients to determine the efficacy and safety of the same 5-FU schedule plus oxaliplatin.

Patients And Methods: Patients (aged ≥72 years old) with mCRC, measurable disease, ECOG (Eastern Cooperative Oncology Group) ≤2, and no prior treatment were treated with oxaliplatin 85 mg/m(2) plus 5-FU 3000 mg/m(2) as a 48-hour infusion every 2 weeks.

First-line cetuximab plus capecitabine in elderly patients with advanced colorectal cancer: clinical outcome and subgroup analysis according to KRAS status from a Spanish TTD Group Study.

Unlabelled: Single-agent cetuximab is safe and active in elderly patients with advanced colorectal cancer (CRC). A cetuximab-capecitabine combination has not previously been tested in elderly patients with advanced CRC.

Material And Methods: Sixty-six patients with advanced CRC were treated with cetuximab as a 400 mg/m2 i.

First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study.

Purpose: The aim of this phase III trial was to compare the efficacy and safety of bevacizumab alone with those of bevacizumab and capecitabine plus oxaliplatin (XELOX) as maintenance treatment following induction chemotherapy with XELOX plus bevacizumab in the first-line treatment of patients with metastatic colorectal cancer (mCRC).

Patients And Methods: Patients were randomly assigned to receive six cycles of bevacizumab, capecitabine, and oxaliplatin every 3 weeks followed by XELOX plus bevacizumab or bevacizumab alone until progression. The primary endpoint was the progression-free survival (PFS) interval; secondary endpoints were the overall survival (OS) time, objective response rate (RR), time to response, duration of response, and safety.

A genotype-directed phase I-IV dose-finding study of irinotecan in combination with fluorouracil/leucovorin as first-line treatment in advanced colorectal cancer.

Background: Infusional fluorouracil/leucovorin (FU/LV) plus irinotecan (FOLFIRI) is one of the standard first-line options for patients with metastatic colorectal cancer (mCRC). Irinotecan is converted into 7-ethyl-10-hydroxycamptothecin (SN-38) by a carboxylsterase and metabolised through uridine diphosphate glucuronosyl transferase (UGT1A1). The UGT1A1*28 allele has been associated with the risk of developing severe toxicities.

Pharmacogenetic study in rectal cancer patients treated with preoperative chemoradiotherapy: polymorphisms in thymidylate synthase, epidermal growth factor receptor, GSTP1, and DNA repair genes.

Purpose: Several studies have been performed to evaluate the usefulness of neoadjuvant treatment using oxaliplatin and fluoropyrimidines for locally advanced rectal cancer. However, preoperative biomarkers of outcome are lacking. We studied the polymorphisms in thymidylate synthase, epidermal growth factor receptor, glutathione S-transferase pi 1 (GSTP1), and several DNA repair genes to evaluate their usefulness as pharmacogenetic markers in a cohort of 128 rectal cancer patients treated with preoperative chemoradiotherapy.

Bladder preservation strategy based on combined therapy in patients with muscle-invasive bladder cancer: management and results at long-term follow-up.

Objective: To evaluate a bladder preservation strategy in patients with either muscle-invasive bladder cancer (MIBC) or development of MIBC cancer due to progression of non-muscle-invasive bladder cancer (NMIBC).

Methods: Between October 1982 and March 1998, 48 patients (mean age 61 years, range 45-75) with MIBC (T2a-b and T3a) were treated using transurethral resection followed by three cycles of systemic chemotherapy. 42 patients (87.

Absence of large intragenic rearrangements in the DPYD gene in a large cohort of colorectal cancer patients treated with 5-FU-based chemotherapy.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Dihydropyrimidine dehydrogenase (DPD) is the enzyme responsible for the elimination of approximately 80% of the administered dose of 5-fluorouracil (5-FU). * Mutations in the DPD-coding gene have been shown to increase the risk of severe toxicity in 5-FU treated patients. * The IVS14+1G>A is the most common DPYD mutation.

UGT1A and TYMS genetic variants predict toxicity and response of colorectal cancer patients treated with first-line irinotecan and fluorouracil combination therapy.

Background: The impact of thymidylate synthase (TYMS) and UDP-glucoronosyltransferase 1A (UGT1A) germline polymorphisms on the outcome of colorectal cancer (CRC) patients treated with irinotecan plus 5-fluorouracil (irinotecan/5FU) is still controversial. Our objective was to define a genetic-based algorithm to select patients to be treated with irinotecan/5FU.

Methods: Genotyping of TYMS (5'TRP and 3'UTR), UGT1A1(*)28, UGT1A9(*)22 and UGT1A7(*)3 was performed in 149 metastatic CRC patients treated with irinotecan/5FU as first-line chemotherapy enrolled in a randomised phase 3 study.

Immunoglobulin G fragment C receptor polymorphisms and KRAS mutations: are they useful biomarkers of clinical outcome in advanced colorectal cancer treated with anti-EGFR-based therapy?

KRAS mutations have been identified as a strong predictor of resistance to anti-epidermal growth factor receptor (EGFR) therapies. Besides inhibiting the EGFR pathway, anti-EGFR monoclonal antibodies may exert antitumor effects through antibody-dependent cell-mediated cytotoxicity (ADCC). Through this mechanism, the antibody fragment C portion (Fcγ) interacts with Fc receptors (FcγRs) expressed by immune effectors cells.

Thymidylate synthase germline polymorphisms in rectal cancer patients treated with neoadjuvant chemoradiotherapy based on 5-fluorouracil.

Purpose: Chemoradiotherapy using 5-fluorouracil has shown to be effective treatment for rectal cancer. Thymidylate synthase (TS) is an important target enzyme for the fluoropyrimidines. However, the predictive role of TS levels in early stage rectal cancer is not yet well understood.

Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study.

PURPOSE The optimal therapeutic sequence of the adjuvant chemotherapy component of preoperative chemoradiotherapy (CRT) for patients with locally advanced rectal cancer is controversial. Induction chemotherapy before preoperative CRT may be associated with better efficacy and compliance. PATIENTS AND METHODS A total of 108 patients with locally advanced rectal cancer were randomly assigned to arm A-preoperative CRT with capecitabine, oxaliplatin, and concurrent radiation followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)-or arm B-induction CAPOX followed by CRT and surgery.

Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving oxaliplatin/5-fluorouracil as first-line chemotherapy.

To determine whether molecular parameters could be partly responsible for resistance or sensitivity to oxaliplatin (OX)-based chemotherapy used as first-line treatment in advanced colorectal cancer (CRC). We studied the usefulness of the excision repair cross-complementing 1 (ERCC1), xeroderma pigmentosum group D (XPD), XRCC1 and GSTP1 polymorphisms as predictors of clinical outcome in these patients. We treated 126 CRC patients with a first-line OX/5-fluorouracil chemotherapeutic regimen.

Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study.

Background: Irinotecan plus infusional 5-fluorouracil/leucovorin (FOLFIRI) is accepted as a reference treatment for the first-line treatment of patients with metastatic colorectal cancer (MCRC). The aim of this study was to demonstrate that a regimen without leucovorin (LV) (FUIRI) is not inferior to the standard FOLFIRI (response rate).

Patients And Methods: Chemotherapy-naive patients with MCRC were randomized to receive either irinotecan (180 mg/m(2) on day 1) + 5-fluorouracil (5-FU) (400 mg/m(2) bolus and 600 mg/m(2) 22-h infusion) + LV (200 mg/m(2) on days 1-2) (FOLFIRI) every 2 weeks or irinotecan (80 mg/m(2)) + 5-FU (2.

Irinotecan pharmacogenetics: influence of pharmacodynamic genes.

Purpose: Irinotecan is an important drug for the treatment of solid tumors. Although genes involved in irinotecan pharmacokinetics have been shown to influence toxicity, there are no data on pharmacodynamic genes. CDC45L, NFKB1, PARP1, TDP1, and XRCC1 have been shown to influence the cytotoxic action of camptothecins, including irinotecan.

Colorectal cancer metastasis resectability after treatment with the combination of oxaliplatin, irinotecan and 5-fluorouracil. Final results of a phase II study.

Purpose: To investigate the response rate of the triple combination of oxaliplatin (L-OHP) in combination with irinotecan (CPT-11) and 5-fluorouracil (5-FU) and to assess its impact on secondary resectability of previously non-resectable liver metastasis (LM).

Patients And Methods: Patients > or = 18 with MCRC, ECOG grade 0-2, and no prior treatment received L-OHP (85 mg/m(2)), CPT-11 (150 mg/m(2)) and 5-FU (2 250 mg/m(2) in 48 h CI) on D1 every 15 days.

Results: Forty-seven patients with initially non-resectable metastatic disease were included.

[Inversion of the sequence of surgery after neoadjuvant chemotherapy for synchronous liver metastases from colorectal cancer].

In some patients with colorectal cancer and synchronous liver metastases, chemotherapy and current combinations of chemotherapy allow the size of these metastases to be reduced so that they can be surgically resected. However, in many patients, the initial systematic treatment of the primary tumor is associated with growth of the metastases (which predict the patient's life expectancy). This metastatic growth contraindicates surgical treatment that might otherwise be curative.

Transcription factor-binding sites in the thymidylate synthase gene: predictors of outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin?

The identification of clinical and genetic parameters to predict the outcome in advanced colorectal cancer is a key issue in the management of this disease. We ascertained whether the clinical determinants of survival defined in a large cohort of patients treated with 5-fluorouracil (5-FU) (European Organization for the Research and Treatment of Cancer, EORTC model) also apply to 109 colorectal cancer patients receiving a therapy including oxaliplatin/5-FU as their first-line treatment. Our results confirm the considerable discriminatory power of the clinical model proposed in patients treated with a combined chemotherapy regimen.

[Surgical resection of liver metastases from colorectal carcinoma. Experience in Sant Pau Hospital].

Introduction: Surgical resection is the only available treatment that improves survival in patients with liver metastases from colorectal cancer, particularly when carried out by a multidisciplinary team.

Material And Method: We retrospectively analyzed a consecutive series of 116 patients who underwent 138 liver resections (65.4% minor and 35.

Description and management of cutaneous side effects during cetuximab or erlotinib treatments: a prospective study of 30 patients.

Background: Drugs such as cetuximab or erlotinib, which inhibit the epidermal growth factor receptor, are increasingly being used in treatment of solid tumors. This has led to the appearance of new secondary effects.

Objective: We sought to describe the cutaneous side effects and their management in patients with cancer treated with cetuximab or erlotinib.

K-ras Asp12 mutant neither interacts with Raf, nor signals through Erk and is less tumorigenic than K-ras Val12.

Different mutant amino acids in the Ras proteins lead to distinct transforming capacities and different aggressiveness in human tumors. K-Ras Asp12 (K12D) is more prevalent in benign than in malignant human colorectal tumors, whereas K-Ras Val12 (K12V) associates with more advanced and metastatic carcinomas, higher recurrence and decreased survival. Here, we tested, in a nude mouse xenograft model, whether different human K-Ras oncogenes mutated at codon 12 to Val, Asp or Cys would confer NIH3T3 fibroblasts distinct oncogenic phenotypes.