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Andrés Cervantes
The lancet oncology 09/2012; · 14.47 Impact Factor
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Albert Abad,
Enrique Aranda,
Matilde Navarro,
Alfredo Carrato,
Javier Sastre,
Manuel Gallén,
Eugenio Marcuello,
Carlos Fernández-Martos, Andrés Cervantes,
Antonio Antón,
Fernando Rivera,
Bertomeu Massutí,
Isidoro Barneto,
Mónica Guillot,
Eduardo Díaz-Rubio
[show abstract]
[hide abstract]
ABSTRACT: BackgroundThe continuous oral administration of UFT simulates protracted continuous intravenous infusion of fluorouracil, making this
oral therapy a possible substitute for intravenous chemotherapy. Currently, 70% of cases of cancer will occur in patients
over 65, and the feasibility of oral administration makes UFT a good drug for the elderly. The main objective of our trials
was to evaluate the tolerance and benefits of this oral treatment in elderly patients with advanced colorectal cancer (CRC).
Patients and methodsA total of 214 patients were included in two consecutive trials. Study number 1 included 106 patients treated with a continuous
fixed dose of UFT 400 mg/24 hours plus oral folinic acid 45 mg/24 hours. Study number 2 included 108 patients treated with
a continuous dose of UFT 400 mg/m2/24 hours without folinic acid. In both trials the main inclusion criterion was age >72 years. Patient characteristics of
Study number 1 were: 46 females and 60 males, median age 74, median Karnofsky index 70, and liver metastasis 56%. Those of
Study number 2 were: 42 females and 66 males, median age 76, median Karnofsky index 80, and liver metastasis 65%.
ResultsStudy number 1: Ninety-six patients were evaluable for response and 98 for toxicity. The overall response rate (RR) was 18%
(95% CI, 10–27%). Toxicity was mild with only one case of grade 3 thrombocytopenia, one case of grade 3 mucositis and 11 cases
of grade 3–4 diarrhea. Overall median survival was 13.7 months. Study number 2: Ninety-two patients were evaluable for response
and 108 for toxicity. The overall RR was 13% (95% CI, 6–20%). Toxicity was also mild without hematological toxicity and only
nine cases of grade 3–4 diarrhea. Overall median survival was 11.8 months.
ConclusionUFT with or without modulation with folinic acid is an effective and comfortable treatment for elderly CRC patients.
JustificaciónLa administración oral continuada de UFT puede simular la infusión intravenosa de fluorouracilo de larga duración, convirtiendo
esta terapia oral en un sustituto de la quimioterapia intravenosa. Actualmente se calcula que el 70% de los pacientes con
cáncer tienen edad superior a 65 años y la facilidad de la administratión oral de UFT lo convierte en un buen fármaco para
este grupo de pacientes. El objetivo principal de nuestros estudios fue evaluar la tolerancia y efectividad de este tratamiento
en pacientes ancianos con cancer de colon y recto avanzado.
Pacientes y métodosUn total de 214 pacientes fueron incluidos en 2 estudios consecutivos. El estudio 1 incluyó a 106 pacientes tratados con una
dosis fija de 400 mg/24 h de UFT con 45 mg/24 h de ácido folínico por vía oral. El estudio 2 incluyó a 108 pacientes tratados
con una dosis continuada de 400 mg/m2/24 h sin ácido folínico. En ambos estudios el criterio principal de inclusión fue una edad >72 años. Las características
de los pacientes en el estudio 1 fueron: 46 mujeres y 60 varones, edad media de 74 años, mediana del indice de Karnofsky 70
y metástasis hepáticas del 56%. En el estudio 2 fueron: 42 mujeres y 66 varones, edad media de 76 años, mediana del índice
de Karnofsky de 80 y un 65% de metástasis hepáticas.
ResultadosEstudio 1: 96 pacientes fueron valorables para respuesta y 98 para toxicidad. El porcentaje de respuestas objetivas fue del
18% (IC del 95%, 10–27%). La toxicidad fue leve con un solo caso de trombopenia de grado 3, un caso de mucositis de grado
3 y 11 casos con diarrea de grados 3–4. La supervivencia mediana actuarial fue de 13,7 meses. En el estudio 2: 92 pacientes
fueron evaluables para respuesta y 108 para la toxicidad. La respuesta global fue del 13% (IC del 95%, 6–20%). La toxicidad
fue también leve sin toxicidad hematológica y 9 casos de diarrea de grados 3–4. La supervivencia mediana actuarial fue de
11,8 meses.
ConclusiónUFT con o sin modulatión bioquímica con ácido folínico es un tratamiento activo y confortable para los pacientes ancianos
con cáncer de colon y recto.
Clinical and Translational Oncology 04/2012; 2(3):154-158. · 1.33 Impact Factor
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Clinical and Translational Oncology 04/2012; 12(4):241-242. · 1.33 Impact Factor
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Eduardo Díaz-Rubio,
Auxiliadora Gómez-España,
Bartomeu Massutí,
Javier Sastre,
Albert Abad,
Manuel Valladares,
Fernando Rivera,
Maria J Safont,
Purificación Martínez de Prado,
Manuel Gallén, [......],
Pilar Escudero,
Antonio Arrivi, Andrés Cervantes,
Rosario Dueñas,
Amelia López-Ladrón,
Adelaida Lacasta,
Marta Llanos,
Jose M Tabernero,
Antonio Antón,
Enrique Aranda
[show abstract]
[hide abstract]
ABSTRACT: 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 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.
The intent-to-treat population comprised 480 patients (XELOX plus bevacizumab, n = 239; bevacizumab, n = 241); there were no significant differences in baseline characteristics. The median follow-up was 29.0 months (range, 0-53.2 months). There were no statistically significant differences in the median PFS or OS times or in the RR between the two arms. The most common grade 3 or 4 toxicities in the XELOX plus bevacizumab versus bevacizumab arms were diarrhea, hand-foot syndrome, and neuropathy.
Although the noninferiority of bevacizumab versus XELOX plus bevacizumab cannot be confirmed, we can reliably exclude a median PFS detriment >3 weeks. This study suggests that maintenance therapy with single-agent bevacizumab may be an appropriate option following induction XELOX plus bevacizumab in mCRC patients.
The Oncologist 01/2012; 17(1):15-25. · 3.91 Impact Factor
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Eduardo Díaz-Rubio,
Auxiliadora Gómez-España,
Bartomeu Massutí,
Javier Sastre,
Margarita Reboredo,
José Luis Manzano,
Fernando Rivera,
M José Safont,
Clara Montagut,
Encarnación González,
Manuel Benavides,
Eugenio Marcuello, Andrés Cervantes,
Purificación Martínez de Prado,
Carlos Fernández-Martos,
Antonio Arrivi,
Inmaculada Bando
[show abstract]
[hide abstract]
ABSTRACT: 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. These data were then cross-referenced with efficacy data for relevant patients in the MACRO study database. KRAS status was analysed in 394 of the 480 patients (82.1%) in the MACRO study. Wild-type (WT) KRAS tumours were found in 219 patients (56%) and mutant (MT) KRAS in 175 patients (44%). Median PFS was 10.9 months for patients with WT KRAS and 9.4 months for patients with MT KRAS tumours (p = 0.0038; HR: 1.40; 95% CI:1.12-1.77). The difference in OS was also significant: 26.7 months versus 18.0 months for WT versus MT KRAS, respectively (p = 0.0002; HR: 1.55; 95% CI: 1.23-1.96). Univariate and multivariate analyses showed that KRAS was an independent variable for both PFS and OS. Responses were observed in 126 patients (57.5%) with WT KRAS tumours and 76 patients (43.4%) with MT KRAS tumours (p = 0.0054; OR: 1.77; 95% CI: 1.18-2.64). CONCLUSIONS/SIGNIFICANCE: This analysis of the MACRO study suggests a prognostic role for tumour KRAS status in patients with mCRC treated with XELOX plus bevacizumab. For both PFS and OS, KRAS status was an independent factor in univariate and multivariate analyses.
PLoS ONE 01/2012; 7(10):e47345. · 4.09 Impact Factor
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Andrés Cervantes
European journal of cancer (Oxford, England: 1990) 09/2011; 47 Suppl 3:S324-5. · 4.12 Impact Factor
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Josep Tabernero,
Luc Dirix,
Patrick Schöffski, Andrés Cervantes,
Jose Antonio Lopez-Martin,
Jaume Capdevila,
Ludy van Beijsterveldt,
Suso Platero,
Brett Hall,
Zhilong Yuan,
Roland Knoblauch,
Sen Hong Zhuang
[show abstract]
[hide abstract]
ABSTRACT: Originally isolated on the basis of its ability to induce p53, serdemetan showed potent activity in various preclinical models, inducing S-phase arrest and apoptosis in TP53 wild-type and mutant tumors. This study evaluated the safety and tolerability of serdemetan, determined the pharmacokinetic and pharmacodynamic profiles, and identified a recommended phase II dose.
Patients (71) with refractory solid tumors were allocated to dose-escalating cohorts (3+3 patients each) and received oral serdemetan once daily in 21-day cycles to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Plasma was collected for pharmacokinetic analyses. Paired baseline and on-treatment skin and tumor biopsies were done; blood samples were collected for pharmacodynamic analyses, including p53 and macrophage inhibitory cytokine-1 induction.
The MTD of serdemetan was determined to be 350 mg once daily. During this study, grade 3 QTc prolongation was the most common DLT and nausea (66.2%) was the most frequent treatment-emergent adverse event. Serdemetan was rapidly absorbed after oral administration and exhibited dose-proportional pharmacokinetics. At steady state, mean maximum plasma concentration (C(max)) was 2,330 ng/mL and mean area under plasma concentration curve (AUC(0-24h)) was 43.0 μg.h/mL, with serdemetan 300 mg/d. There was a dose- and exposure-dependent p53 induction. One patient with breast cancer showed a partial response; 22 (38.6%) patients had stable disease.
Serdemetan treatment was associated with p53 induction in both tumor and surrogate tissue pharmacodynamic studies and modest clinical activity. Although serdemetan was well tolerated with dose-proportional pharmacokinetics, exposure-related QTc liability was observed.
Clinical Cancer Research 08/2011; 17(19):6313-21. · 7.74 Impact Factor
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Francesco Atzori,
Josep Tabernero, Andrés Cervantes,
Ludmila Prudkin,
Jordi Andreu,
Edith Rodríguez-Braun,
Amparo Domingo,
Jorge Guijarro,
Cristina Gamez,
Jordi Rodon, [......],
Holly Brown,
Jason Clark,
James S Hardwick,
Robert A Beckman,
William D Hanley,
Karl Hsu,
Emiliano Calvo,
Susana Roselló,
Ronald B Langdon,
José Baselga
[show abstract]
[hide abstract]
ABSTRACT: Insulin-like growth factor-1 receptor (IGF-1R) mediates cellular processes in cancer and has been proposed as a therapeutic target. Dalotuzumab (MK-0646) is a humanized IgG1 monoclonal antibody that binds to IGF-1R preventing receptor activation. This study was designed to evaluate the safety and tolerability of dalotuzumab, determine the pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and identify a recommended phase II dose.
Patients with tumors expressing IGF-1R protein were allocated to dose-escalating cohorts of three or more patients each and received intravenous dalotuzumab weekly, every 2 or 3 weeks. Plasma was collected for PK analysis. Paired baseline and on-treatment skin and tumor biopsy samples were collected for PD analyses.
Eighty patients with chemotherapy-refractory solid tumors were enrolled. One dose-limiting toxicity was noted, but a maximum-tolerated dose was not identified. Grade 1 to 3 hyperglycemia, responsive to metformin, occurred in 15 (19%) patients. At dose levels or more than 5 mg/kg, dalotuzumab mean terminal half-life was 95 hours or more, mean C(min) was more than 25 μg/mL, clearance was constant, and serum exposures were approximately dose proportional. Decreases in tumor IGF-1R, downstream receptor signaling, and Ki67 expression were observed. (18)F-Fluorodeoxy-glucose positron emission tomography metabolic responses occurred in three patients. One patient with Ewing's sarcoma showed a mixed radiologic response. The recommended phase II doses were 10, 20, and 30 mg/kg for the weekly, every other week, and every third week schedules, respectively.
Dalotuzumab was generally well-tolerated, exhibited dose-proportional PK, inhibited IGF-1R pathway signaling and cell proliferation in treated tumors, and showed clinical activity. The low clearance rate and long terminal half-life support more extended dosing intervals.
Clinical Cancer Research 08/2011; 17(19):6304-12. · 7.74 Impact Factor
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Ana Oaknin,
Desamparado Roda,
Antonio González-Martín,
Luis Chiva,
Jesús García-Donas,
Ana de Juan,
Andrés Redondo,
Sergio Martínez,
Yolanda García,
Sílvia Catot,
Jordi Ponce,
J M Del Campo, Andrés Cervantes,
Andrés Poveda
[show abstract]
[hide abstract]
ABSTRACT: The objective of the study was to assess the feasibility, toxicity, and reasons for early discontinuation of a modified outpatient intraperitoneal/intravenous (IP/IV) chemotherapy regimen for the treatment of patients with optimally debulked stage III ovarian cancer.
Between February 2006 and November 2008, 51 consecutive patients from Institutions of the Spanish Ovarian Cancer Group (GEICO) were treated with a modified outpatient IP chemotherapy regimen. Patients received IV paclitaxel 175 mg/m over 3 hours on day 1, followed by IP cisplatin 100 mg/m (or 75 mg/m according to the principal investigator's criteria) on day 2. On day 8, patients received IP paclitaxel 60 mg/m. To homogenize the IP administration and supportive measures, a GEICO guideline for IP chemotherapy was established. Patients were treated with the intention to receive 6 courses of chemotherapy every 21 days.
The median age of the patients was 49 years (range, 36-75 years), and most of them had papillary serous ovarian cancer (78%), International Federation of Gynecology and Obstetrics stage IIIC (76%). Thirty-nine patients completed 4 or more IP cycles, and 28 (61%) completed all 6 IP cycles. Twenty-two patients discontinued the IP/IV treatment, mainly because of chemotherapy toxicity (10 patients) and catheter-related complications (5 patients). The most prevalent grade 3/4 toxicities were neutropenia (14 patients; 30%) and gastrointestinal events (12 patients; 26%).
The GEICO outpatient modified regimen resulted in a lesser toxicity and a greater rate of treatment completion than previously reported. The accurate selection of patients and the administration following well-defined guidelines can increase the feasibility of IP chemotherapy administration.
International Journal of Gynecological Cancer 08/2011; 21(6):1048-55. · 1.65 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Preoperative chemoradiation is becoming the standard treatment for patients with locally advanced rectal cancer. However, since the introduction of total mesorectal excision (TME), local recurrence rates have been reduced significantly, and some patients can be spared from potentially toxic over treatment. The current study was designed to assess the factors that predict recurrence in an institutional series of patients with rectal cancer who had clinical T2 lymph node-positive (cT2N+) tumors or cT3N0/N+ tumors and underwent radical surgery without receiving preoperative chemoradiation.
Between November 1997 and November 2008, the authors' multidisciplinary group preoperatively staged 398 patients with rectal cancer by using endorectal ultrasonography and/or magnetic resonance imaging. The analysis included 152 consecutive patients with cT2N+, cT3N0, or cT3N+ rectal cancer who underwent TME without receiving preoperative chemoradiation. Macroscopic assessment of the mesorectal excision and circumferential resection margins were determined. Factors potentially related to local recurrence (LR), disease-free survival (DFS) and cancer-specific survival (CSS) were analyzed.
After a median follow-up of 39 months, the 5-year actuarial LR, DFS, and CSS rates were 9.5%, 65.4%, and 77.8%, respectively, for the whole group. Threatened mesorectal fascia at preoperative staging was the only independent preoperative factor that predicted a higher risk for LR (P = .007), shorter DFS (P = .007), and shorter CSS (P = .05). In particular, the 5-year LR rates for patients with and without preoperative threatened circumferential resection margins were 19.4% and 5.4%, respectively.
The current results suggested that patients with rectal cancer clinically staged as T3N0/N+ or T2N+ with a free margin >2 mm from mesorectal fascia may undergo TME alone, avoiding over treatment with preoperative chemoradiation.
Cancer 01/2011; 117(14):3118-25. · 4.77 Impact Factor
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Marc Peeters,
Timothy Jay Price, Andrés Cervantes,
Alberto F Sobrero,
Michel Ducreux,
Yevhen Hotko,
Thierry André,
Emily Chan,
Florian Lordick,
Cornelis J A Punt,
Andrew H Strickland,
Gregory Wilson,
Tudor-Eliade Ciuleanu,
Laslo Roman,
Eric Van Cutsem,
Valentina Tzekova,
Simon Collins,
Kelly S Oliner,
Alan Rong,
Jennifer Gansert
[show abstract]
[hide abstract]
ABSTRACT: Panitumumab is a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS) in chemotherapy-refractory metastatic colorectal cancer (mCRC). This trial evaluated the efficacy and safety of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone after failure of initial treatment for mCRC by tumor KRAS status.
Patients with mCRC, one prior chemotherapy regimen for mCRC, Eastern Cooperative Oncology Group performance status 0 to 2, and available tumor tissue for biomarker testing were randomly assigned 1:1 to panitumumab 6.0 mg/kg plus FOLFIRI versus FOLFIRI every 2 weeks. The coprimary end points of PFS and overall survival (OS) were independently tested and prospectively analyzed by KRAS status.
From June 2006 to March 2008, 1,186 patients were randomly assigned 1:1 and received treatment. KRAS status was available for 91% of patients: 597 (55%) with wild-type (WT) KRAS tumors, and 486 (45%) with mutant (MT) KRAS tumors. In the WT KRAS subpopulation, when panitumumab was added to chemotherapy, a significant improvement in PFS was observed (hazard ratio [HR] = 0.73; 95% CI, 0.59 to 0.90; P = .004); median PFS was 5.9 months for panitumumab-FOLFIRI versus 3.9 months for FOLFIRI. A nonsignificant trend toward increased OS was observed; median OS was 14.5 months versus 12.5 months, respectively (HR = 0.85, 95% CI, 0.70 to 1.04; P = .12); response rate was improved to 35% versus 10% with the addition of panitumumab. In patients with MT KRAS, there was no difference in efficacy. Adverse event rates were generally comparable across arms with the exception of known toxicities associated with anti-EGFR therapy.
Panitumumab plus FOLFIRI significantly improved PFS and is well-tolerated as second-line treatment in patients with WT KRAS mCRC.
Journal of Clinical Oncology 10/2010; 28(31):4706-13. · 18.37 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: This study evaluated the prognostic importance of circumferential tumour position of mid and low rectal cancers.
All uT2, uT3 and uT4 tumours of the middle and lower rectum that underwent total mesorectal excision (TME) with curative intent between 1996 and 2006 were included. The predominant circumferential tumour position (anterior, posterior or circumferential) was defined on preoperative endorectal ultrasound examination (ERUS). The relationships between tumour position and other characteristics and recurrence were explored.
Two hundred and five patients with distal rectal cancer were operated on for a uT2-T4 tumour. Median follow up was 49 months. The location of the tumour was predominantly anterior, posterior or circumferential in 128, 49 and 27 patients, respectively. Anterior tumours were more likely to receive neoadjuvant therapy (P = 0.016) and perioperative blood transfusion (P = 0.012). No significant differences were observed between circumferential position and pT or pN stage, circumferential resection margin involvement or mesorectal excision quality. Sixty-three (30.7%) patients developed recurrence, which was local only in 16 (7.8%). Although tumours involving 360° of the rectal wall had a higher risk of local recurrence (P = 0.048), those with a predominant anterior or posterior position were not related to a higher risk of local or overall recurrence.
Anterior rectal tumours do not differ in pathological characteristics from posterior tumours, and their prognosis is no worse when circumferential resection is complete.
Colorectal Disease 03/2010; 13(6):650-7. · 2.93 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The present review gives a perspective on the Aurora kinase family members, their function in normal cells, their role in cancer progression as well as their potential as target for anticancer treatment. Mitosis has been an important target for anticancer therapy development, leading to some specific drugs mainly addressing Tubulines, as a key structure of the mitotic spindle. Vinca alkaloids, taxanes or epotilones are good examples of conventionally developed antimitotic agents. However, novel classes of antineoplastic drugs are being studied, targeting the regulatory system that controls functional aspects of mitosis, such as Aurora or Polo-like kinases or Kinespondin inhibitors. The specific role of the different Aurora kinase proteins as regulator enzymes of the mitotic process in normal cells is discussed. Some of the mechanisms that link Aurora overexpression with cancer are also considered. Thereafter, the clinical and preclinical development of the different Aurora kinase inhibitors is presented. This is nowadays a very active area of therapeutic research and at least, sixteen new compounds are being studied as potential antineoplastic drugs. Most of them are in a very early phase of clinical development. However, we summarized the most recently published findings related with these drugs: main characteristics, way of administration, dose limiting toxicities and recommended doses for further studies. Another important aspect in Aurora kinase inhibition is the study and validation of potential biomarkers to optimize the clinical development. Several studies included pharmacodynamic assessments in normal blood cells, skin or/and tumor biopsies. Several proposals included a higher mitotic index, a decreased number of mitosis with bipolar spindles or normal alignment of chromosomes and inhibition of histone H3 phosphorylation. Future strategies and challenges for trials with Aurora kinase inhibitors are also discussed.
Clinical and Translational Oncology 12/2009; 11(12):787-98. · 1.33 Impact Factor
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Luis Sabater,
Julio Calvete,
Luis Aparisi,
Raul Cánovas,
Elena Muñoz,
Ramón Añón,
Susana Roselló,
Edith Rodríguez,
Bruno Camps,
Raquel Alfonso,
Carlos Sala,
Juan Sastre, Andrés Cervantes,
Salvador Lledó
[show abstract]
[hide abstract]
ABSTRACT: To evaluate postoperative morbidity and mortality, pancreatic function and long-term survival in patients with surgically treated pancreatic or periampullar tumours.
Cohort study including 160 patients consecutively operated on: 80 pancreaticoduodenectomies (PD), 30 distal pancreatectomies (DP), 7 total pancreatectomies, 4 central pancreatic resections and 3 ampullectomies. The tumour was not resected in 36 patients. Pancreatic function was evaluated by oral glucose tolerance test, faecal fat excretion and elastase.
Resectability rate was 77.5%. In resected patients (n = 124), 38.7% had complications with a pancreatic fistula rate of 6.4% and a mortality rate of 4%. In PD, endocrine function worsened in 41% and 58.6% had steatorrhoea; these figures in DP were 53.6% and 21.7% respectively. In the 36 non-resected patients, postoperative morbidity was 27.7% and mortality 8.3%. Two and five-year survival rates in resected patients with pancreatic cancer were 42% and 9% respectively; in malignant ampulloma 71% and 53%; in mucinous adenocarcinomas 83% and 33%; in duodenal adenocarcinoma 100% and 75%; and in distal cholangiocarcinoma 50% and 50%.
Morbidity associated with resective pancreatic surgery is still high, but perioperative mortality is low. Endocrine and exocrine disturbances are very common depending on the type of resection. Despite the associated morbidity and functional disorders, surgery provides long-term survival in selected cases.
Cirugía Española 08/2009; 86(3):159-66. · 0.87 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: High quality of surgical technique and the use of descriptive measures to assess and report surgical proficiency have been shown to influence locoregional tumor control in patients with rectal cancer. In this study, the authors have aimed to audit the implementation of a macroscopic assessment of mesorectal excision (MAME) and to investigate factors that influenced surgical quality and disease recurrence.
All curative resections for rectal cancer were prospectively evaluated for MAME between 1998 and 2007. Mesorectal specimens were graded into 3 types: complete, nearly complete, and incomplete categories. Univariate and multivariate analyses identified independent risk factors for noncomplete mesorectum categories as well as local and overall tumor recurrence.
Of 359 specimens, 294 (81.9%) underwent evaluation; 82.3% were "complete." Abdominoperineal resection (APR) was the sole covariate associated with inadequate mesorectal excision (odds ratio [OR]=2.7; P=.003). Independent predictors of local recurrence were circumferential resection margin (CRM) involvement (OR=3.6; P=.027) and noncomplete mesorectum (OR=4.4; P=.008). CRM+ (OR=3.1; P=.004), poorly differentiated tumors (OR=14.2; P=.010), nodal involvement (OR=2.9; P=.010), and APR (OR=2.9; P=.006) were independent risk factors for overall recurrence. In lower third tumors, noncomplete mesorectum occurred more frequently in APR compared with sphincter-saving procedures (31.1% vs 18.8%; P=.088).
This study demonstrates the value of auditing MAME. Good proficiency of mesorectal excision is associated with lower tumor recurrences after curative surgery, and is a morphological tool found to be useful in clinical practice.
Cancer 06/2009; 115(15):3400-11. · 4.77 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The primary purpose of this paper is to present the available evidence for the administration of cetuximab on an every-2-weeks basis in combination with irinotecan in metastatic colorectal cancer (mCRC). Cetuximab is an epidermal growth factor receptor-targeted IgG(1) monoclonal antibody that is approved for use in combination with irinotecan or as monotherapy in the treatment of mCRC. The currently approved dosing regimen for cetuximab is a 400-mg/m(2) initial dose followed by 250 mg/m(2) weekly. Many commonly used chemotherapy agents for mCRC (including irinotecan alone or in combination with 5-fluorouracil [5-FU]/folinic acid [FA] and oxaliplatin plus 5-FU/FA) are administered on an every-2-weeks basis. The ability to synchronize the administration of cetuximab and concomitant chemotherapy is desirable for both patients and health care workers. A cetuximab dose of 500 mg/m(2) every 2 weeks exhibited predictable pharmacokinetics, which were similar to those of the approved weekly dosing regimen. Active serum concentrations of cetuximab were maintained throughout the 2-week dosing period with this regimen. There was no difference between the dosing regimens on pharmacodynamic parameters in skin. The efficacy and safety of the every-2-weeks dosing regimen were similar to those reported for the approved weekly dosing regimen. The indication from these preliminary findings is that every-2-weeks administration of cetuximab (500 mg/m(2)) may be a potentially convenient alternative to the approved weekly dosing regimen of 250 mg/m(2) (following an initial dose of 400 mg/m(2)) in the treatment of mCRC.
The Oncologist 03/2008; 13(2):113-9. · 3.91 Impact Factor
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Josep Tabernero,
Eric Van Cutsem,
Eduardo Díaz-Rubio, Andrés Cervantes,
Yves Humblet,
Thierry André,
Jean-Luc Van Laethem,
Patrick Soulié,
Esther Casado,
Chris Verslype,
Javier Sastre Valera,
Giampaolo Tortora,
Fortunato Ciardiello,
Oliver Kisker,
Aimery de Gramont
[show abstract]
[hide abstract]
ABSTRACT: This phase II study investigated the efficacy and safety of cetuximab combined with standard oxaliplatin-based chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX-4]) in the first-line treatment of epidermal growth factor receptor-expressing metastatic colorectal cancer (mCRC).
The activity of cetuximab plus oxaliplatin was investigated in colon cancer cell lines and xenograft models. In the clinical study, patients with mCRC received on day 1 of a 14 day cycle, cetuximab (initial dose 400 mg/m(2) during week 1, then 250 mg/m(2) weekly) followed by FOLFOX-4 (oxaliplatin 85 mg/m(2) on day 1; leucovorin 200 mg/m(2) on days 1 and 2, followed by fluorouracil 400 mg/m(2) bolus then 600 mg/m(2) intravenous infusion during 22 hours on days 1 and 2).
The preclinical studies confirmed the supra-additive activity of cetuximab to oxaliplatin. In the clinical study, 43 patients were included, with a median age of 65 years (range, 43 to 78 years). Response rates (RRs) were 79% (unconfirmed) and 72% (confirmed), with 95% disease control. Median progression-free survival (mPFS) and median duration of response were 12.3 and 10.8 months, respectively. Ten patients (23%) underwent resection with curative intent of previously unresectable metastases. After a median follow-up of 30.5 months, median overall survival (mOS) was 30.0 months. Cetuximab did not increase the characteristic toxicity of FOLFOX-4 and was generally well tolerated.
Cetuximab in combination with FOLFOX-4 is a highly active first-line treatment for mCRC, showing encouraging RR, mPFS, and mOS values. The treatment resulted in a high resectability rate, which could potentially result in an improved cure rate. This combination is under phase III development.
Journal of Clinical Oncology 12/2007; 25(33):5225-32. · 18.37 Impact Factor
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[show abstract]
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ABSTRACT: Surgery is the treatment of choice in patients with colorectal liver metastases. However, only 10% to 20% of these cases are resectable. The use of neoadjuvant chemotherapy may allow surgery in patients with tumors initially considered unresectable. The aim of this study was to compare the results of liver resection due to colorectal liver metastases in patients with and without neoadjuvant chemotherapy.
We studied 105 patients who underwent surgery for liver metastases from colorectal cancer. The patients were divided into two groups according to treatment: surgery in patients with initially resectable tumors (group 1) and neoadjuvant chemotherapy plus surgery (group 2) in patients with initially irresectable tumors, who were considered for surgery after response to chemotherapy. Age, sex, origin of primary tumor, time of presentation, number, maximum size and location of metastases, CEA, resection margin, postoperative morbidity and mortality, length of hospital stay, recurrence rate, survival and disease-free survival were compared between the 2 groups of patients.
When group 1 was compared with group 2, statistically significant differences were observed in synchronicity (30.8% vs 77.4%), bilobarity (13.5% vs 58.5%), number and size of metastases (1 vs 3 nodules and 4 cm vs 2 cm), resectability rate (96.1% vs 81.1%), disease-free interval (25 vs 11 months) and long-term survival at 1, 3 and 5 years (93%, 67% and 36% vs 78%, 26% and 12%). However, no statistically significant differences were found in postoperative morbidity and mortality (28.8% and 0% in group 1 and 22.6% and 1.8% in group 2, respectively).
Neoadjuvant chemotherapy was not associated with greater postoperative morbidity and mortality after resection of colorectal liver metastases, but long-term survival was lower in the group of patients receiving this treatment modality than in those with tumors initially considered resectable.
Cirugía Española 10/2007; 82(3):166-71. · 0.87 Impact Factor
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ABSTRACT: RNA interference has emerged as a new and potent tool to knockdown the expression of target genes and to investigate their functions. For short time experiments with mammalian cell lines, RNA interference is typically induced by transfecting small interfering RNAs (siRNAs). Primary cells constitute important experimental systems in many studies because of their similarity to their in vivo counterparts; however, transfection of these cells has been found to be difficult. As a consequence, RNA interference of primary cells may result in mixed phenotypes because of the simultaneous presence in the same preparation of transfected and nontransfected cells. This may be particularly inconvenient when certain experiments (for example, biochemical analysis) should be performed.
We use fluorescently labeled siRNAs to induce RNA interference in fibroblasts, and flow-cytometry associated cell sorting to separate subpopulations of transfected cells according to fluorescence intensity.
Flow cytometry allows one to discriminate between strongly- and weakly- or nonsilenced fibroblasts, since the fluorescence intensity of transfected cells is related to the number of internalized siRNA copies and to the mRNA knockdown efficiency.
The use of fluorescently labeled siRNAs may allow one to isolate by flow-cytometry associated cell sorting the most efficiently silenced primary cells for subsequent analysis.
Cytometry Part A 09/2007; 71(8):599-604. · 3.73 Impact Factor
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José I Martinez-Ferrandis,
Raquel Rodríguez-López,
Roger L Milne,
Emilio González,
Elvira Cebolla,
Isabel Chirivella,
Pilar Zamora,
José I Arias,
Santiago Palacios, Andrés Cervantes,
Orland Díez,
Javier Benitez,
M-Eugenia Armengod
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ABSTRACT: TRAIL is a potent inducer of apoptosis in malignant but not in normal cells. TRAIL binds to the proapoptotic death receptor DR4 and DR5 as well as to the decoy receptors DcR1 and DcR2. To evaluate the involvement of TRAIL receptor genes in breast cancer, we carried out a case-control study of eight selected polymorphisms in a large sample of Spanish women. Three of the eight selected SNPs (626G/C and 1322G/A in DR4 and 2699A/G in DcR2) showed some evidence of different genotype distributions in a random selection of 535 cases and 480 controls and were therefore studied in our entire sample (1008 cases and 768 controls). For the two DR4 polymorphisms, no differences in genotype or haplotype distribution were found between cases and controls. Interestingly, allele 2699G in the decoy receptor DcR2 appears associated with reduced breast cancer risk (P=0.05). Given that it is located in the 3' UTR, its effect might be related to DcR2 mRNA instability, or linkage disequilibrium with a functional variant residing in either DcR2 or neighbouring genes. A decreased efficiency of DcR2 to work as decoy receptor for TRAIL, would facilitate the apoptotic pathway in cells at risk.
Cancer biomarkers: section A of Disease markers 02/2007; 3(2):89-93. · 1.08 Impact Factor
