-
[show abstract]
[hide abstract]
ABSTRACT: The FAS/FASL system, comprising membrane-bound (mFAS and mFASL) and soluble forms (sFAS and sFASL), has been related to apoptosis driven by chemotherapy administration. In vitro experiments show chemotherapy upregulating membrane-bound forms, leading to an increase of receptor availability (at 24-72 h) and favoring apoptosis. The regulatory effect of chemotherapy on sFAS in patients has never been explored prospectively in advanced colorectal cancer (ACRC). We performed a pharmacodynamic study to address sFAS/sFASL variation. A prospective phase II translational multicenter study was designed to evaluate progression-free rate (PFR) in patients with ACRC treated with irinotecan and cetuximab in third-line therapy. The effect of sFAS was studied in vitro in colorectal cancer cell lines. Our results showed that statistically significant changes were observed in sFAS at 24-72 h compared to baseline levels in the pharmacodynamic study. Of the 93 patients enrolled in the prospective study in third-line therapy with cetuximab-irinotecan, 85 were evaluated for sFAS/sFASL changes at 48 h. There was no difference in PFR at 4 months between patients with sFAS and sFASL changes. In vitro analysis showed that although LoVo cell lines were sensitive to oxaliplatin and fluorouracil due to modulation of sFAS and FAS, HT29 lines were not. In summary, chemotherapy regulates FAS soluble fractions in vitro and in vivo, but does not predict PFR in ACRC patients undergoing third-line therapy with the combination of cetuximab and irinotecan.
Medical Oncology 03/2013; 30(1):428. · 2.14 Impact Factor
-
María Dolores Giráldez,
Juan José Lozano,
Míriam Cuatrecasas,
Virginia Alonso-Espinaco,
Joan Maurel,
Maribel Mármol,
Carlos Hörndler,
Javier Ortego,
Vicente Alonso, Pilar Escudero,
Gina Ramírez,
Christoph Petry,
Luis Lasalvia,
Kerstin Bohmann,
Ralph Wirtz,
Aurea Mira,
Antoni Castells
[show abstract]
[hide abstract]
ABSTRACT: Although receiving adjuvant chemotherapy after radical surgery, a disappointing proportion of patients with colorectal cancer will develop tumor recurrence. Probability of relapse is currently predicted from pathological staging, there being a need for additional markers to further select high-risk patients. This study was aimed to identify a gene-expression signature to predict tumor recurrence in patients with Stages II and III colon cancer treated with 5'fluoruracil (5FU)-based adjuvant chemotherapy. Two-hundred and twenty-eight patients diagnosed with Stages II-III colon cancer and treated with surgical resection and 5FU-based adjuvant chemotherapy were included. RNA was extracted from formalin-fixed, paraffin-embedded tissue samples and expression of 27 selected candidate genes was analyzed by RT-qPCR. A tumor recurrence predicting model, including clinico-pathological variables and gene-expression profiling, was developed by Cox regression analysis and validated by bootstrapping. The regression analysis identified tumor stage and S100A2 and S100A10 gene expression as independently associated with tumor recurrence. The risk score derived from this model was able to discriminate two groups with a highly significant different probability of tumor recurrence (HR, 2.75; 95%CI, 1.71-4.39; p = 0.0001), which it was maintained when patients were stratified according to tumor stage. The algorithm was also able to distinguish two groups with different overall survival (HR, 2.68; 95%CI, 1.12-6.42; p = 0.03). Identification of a new gene-expression signature associated with a high probability of tumor recurrence in patients with Stages II and III colon cancer receiving adjuvant 5FU-based chemotherapy, and its combination in a robust, easy-to-use and reliable algorithm may contribute to tailor treatment and surveillance strategies.
International Journal of Cancer 07/2012; · 5.44 Impact Factor
-
Ramon Salazar,
Matilde Navarro,
Ferran Losa,
Vicente Alonso,
Manel Gallén,
Fernando Rivera,
Manuel Benavides, Pilar Escudero,
Encarnación González,
Bartomeu Massutí,
Auxiliadora Gómez,
Margarita Majem,
Enrique Aranda
[show abstract]
[hide abstract]
ABSTRACT: A prospective phase II study was conducted to assess the clinical activity and tolerability of oxaliplatin, capecitabine, and radiotherapy (RT) for neoadjuvant therapy of stages II-III rectal cancer.
Patients with histologically confirmed stages II-III (T3-T4 and/or N+) resectable rectal adenocarcinoma were eligible. Capecitabine was administered at 825 mg/m(2) twice daily for 5 days/week and oxaliplatin at 50 mg/m(2) on day 1 weekly for 5 weeks starting the first day of RT (before RT). RT consisted of a total dose of 45 Gy delivered in 25 fractions of 1.8 Gy, 5 days per week, for 5 weeks.
A total of 46 patients were included (35 male, 10 female, median age 62 years). TNM Stage was T3 in 43 patients and T4 in 2. Twenty-eight patients had suspected nodal involvement. The intended chemoradiation treatment was completed in 94 % patients. Grade 3/4 toxicity included lymphocytopenia (6 patients), diarrhea (4 patients), emesis (2 patients), asthenia (3 patients), anorexia (1 patient), and hepatic toxicity (1 patient). Grade 1 neurotoxicity occurred in 18 patients, Grade 2 neurotoxicity in 3, and Grade 1 palmoplantar erythrodysesthesia in 2. Forty-two patients underwent surgery (complete resection 95 %, sphincter-saving operation 55 %). The overall pathologic response rate was 83 %, with a pathologic complete response (pCR) rate of 11.9 % (95 % CI 4.0-25.6).
The pCR rate observed with oxaliplatin plus capecitabine and RT did not reach the pre-specified criteria of efficacy in this trial, which is in line with recent results of randomized phase III trials.
Clinical and Translational Oncology 07/2012; 14(8):592-8. · 1.33 Impact Factor
-
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
-
[show abstract]
[hide abstract]
ABSTRACT: The purpose of the study was to prospectively explore the role of serum MMP-7 as a predictive and prognostic marker of anti-epidermal growth factor receptor (EGFR) therapy and irinotecan efficacy in third-line advanced colorectal cancer therapy. One hundred patients were recruited prospectively from six Spanish hospitals. Patients were treated with biweekly irinotecan 180 mg/m(2) and cetuximab 400 mg/m(2) (loading dose) and weekly cetuximab 250 mg/m(2) until progressive disease or unacceptable toxicity. Baseline MMP-7 was determined using a quantitative solid-phase sandwich ELISA. KRAS and BRAF mutational status were also assessed. The clinical endpoints examined were overall survival (OS), progression-free survival (PFS), and response rate. No association between serum MMP-7 and neither KRAS nor BRAF mutational status was found. The multivariate analysis revealed that MMP-7 predicts PFS both in wild-type (WT) KRAS patients (HR 1.03, 95% CI 1.00-1.06; p = 0.046) and in mutant KRAS patients (HR 1.18, 95% CI 1.01-1.35; p = 0.036). The presence of mutant BRAF was associated with shorter PFS (HR 8.49, 95% CI 2.88-25.0; p < 0.001) and worse OS (HR 3.55, 95% CI 1.39-9.09; p = 0.008) in the subset of WT KRAS patients. Serum MMP-7 is associated with PFS in colorectal patients treated with anti-EGFR therapy as third-line treatment independently of KRAS status.
Tumor Biology 04/2011; 32(2):417-24. · 1.94 Impact Factor
-
Carlos Hörndler,
Rosa Gallego,
Xabier García-Albeniz,
Virginia Alonso-Espinaco,
Vicente Alonso, Pilar Escudero,
Mireya Jimeno,
Javier Ortego,
Jordi Codony-Servat,
Carlos Fernández-Martos,
Ana Calatrava,
Mercedes Marín-Aguilera,
Jenifer Muñoz,
Sergi Castellví-Bel,
Antoni Castells,
Michele Rubini,
Pere Gascón,
Joan Maurel
[show abstract]
[hide abstract]
ABSTRACT: By transactivacion, phosphorylated insulin growth factor receptor I (IGF-1R) can activate epidermal growth factor receptor (EGFR). MMP-7, produced by colorectal cancer cells, also can activate IGF-1R by degrading IGFBP-3 and releasing IGF-I.
A cohort of patients (pts) with advanced colorectal cancer (CRC), under second- or third-line treatment with cetuximab or panitumumab, was tested using immunohistochemistry for expression of the activated form of IGF-1R (p-IGF-1R) and MMP-7. KRAS and BRAF mutation status was determined by sequencing and allelic discrimination analysis, respectively. Analyses were performed in primary CRC tumor samples or metastases, and the association of immunohistochemistry findings, mutational results, and treatment outcomes was investigated in both univariate and multivariate analyses.
Expression of activated IGF-1R and MMP-7 was observed in 51 and 49% of pts, respectively. Co-expression of MMP-7 and pIGF-1R (double positivity, DP) was observed in 28 pts (25%). There was no association between KRAS or BRAF mutational status and DP (p=0.52). Pts with DP responded more poorly to first-line chemotherapy (p=0.005) and to anti-EGFR treatment (p=0.01) than non-DP pts. In wild type (WT) KRAS pts, those with DP have poorer PFS (2.7 months vs. 3.5m, p=0.036; HR 1.98, 95% CI 1.05-3.75) and OS (6.4 months vs. 8.6 m, p=0.010; HR 2.33, 95%CI 1.23-4.43) in the adjusted multivariate analysis.
Our study suggests that concomitant expression of MMP-7 and activation of p-IGF-1R (DP) correlates with poor prognosis in WT KRAS pts treated with anti-EGFR.
Cancer biology & therapy 01/2011; 11(2):177-83. · 2.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Local excision of malignant rectal tumors remains controversial due to the lack of prospective studies. The principal aim of this paper is to analyze survival and recurrence of patients with rectal cancer who were operated by transanal endoscopic microsurgery with curative intention.
In 1997, we started a prospective protocol for patients who had T1/T2 rectal tumors: transanal local full-thickness excision was considered curative in T1 low risk (group A); patients with T1 high-risk and T2 low-risk tumors received postoperative radiotherapy (group B). From 1997 to 2006, 88 patients were enrolled. Sixty eight entered the study after the preoperative workup and 20 patients with an initial diagnosis of adenoma after postoperative definitive pathological assessment.
After definitive histological findings, 54 patients were to group A, 28 to group B, and 6 had immediate radical surgery. One patient was lost for follow-up. At a mean follow-up of 71 months, 7 (4 from group A and 3 from group B) out of 81 patients recurred. Five-year overall survival was of 94% and cancer-specific survival of 96%.
Our data support that transanal endoscopic microsurgery is an adequate treatment for T1 low-risk tumor, and no additional measures are required. For T2 low-risk lesions, our study showed a higher local recurrence rate than that reported after radical surgery but a similar survival outcome.
International Journal of Colorectal Disease 01/2011; 26(4):437-43. · 2.38 Impact Factor
-
Carlos Fernández-Martos,
Carles Pericay,
Jorge Aparicio,
Antonieta Salud,
Mariajose Safont,
Bertomeu Massuti,
Ruth Vera, Pilar Escudero,
Joan Maurel,
Eugenio Marcuello,
Jose Luis Mengual,
Eugenio Saigi,
Rafael Estevan,
Moises Mira,
Sonia Polo,
Ana Hernandez,
Manuel Gallen,
Fernando Arias,
Javier Serra,
Vicente Alonso
[show abstract]
[hide abstract]
ABSTRACT: 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. The primary end point was pathologic complete response rate (pCR). Results On an intention-to-treat basis, the pCR for arms A and B were 13.5% (95% CI, 5.6% to 25.8%) and 14.3% (95% CI, 6.4% to 26.2%), respectively. There were no statistically significant differences in other end points, including downstaging, tumor regression, and R0 resection. Overall, chemotherapy treatment exposure was higher in arm B than in arm A for both oxaliplatin (P < .0001) and capecitabine (P < .0001). During CRT, grades 3 to 4 adverse events were similar in both arms but were significantly higher in arm A during postoperative adjuvant CT than with induction CT in arm B. There were three deaths in each arm during the treatment period. CONCLUSION Compared with postoperative adjuvant CAPOX, induction CAPOX before CRT had similar pCR and complete resection rates. It did achieve more favorable compliance and toxicity profiles. On the basis of these findings, a phase III study to definitively test the induction strategy is warranted.
Journal of Clinical Oncology 02/2010; 28(5):859-65. · 18.37 Impact Factor
-
José-María Roca,
Vicente Alonso,
Carles Pericay, Pilar Escudero,
Antonieta Salud,
Ferrán Losa,
Luis-Jesús López,
Imma Guasch,
Miguel Méndez,
Guillermo Quintero-Aldana,
Carlos Grande,
Pilar Vicente,
Antonio Arrivi,
Cristina Martin,
Isabel Moreno,
Pilar García,
Isabel Antón,
Manuel Constenla,
Alfonso Yubero,
Luis Cirera
[show abstract]
[hide abstract]
ABSTRACT: We gathered data from multiple institutions on the cetuximab regimen of patients with metastatic colorectal cancer.
126 patients from 19 centers were included from July 2006 to July 2007 in this prospective non-controlled study. Irinotecan-refractory metastatic colorectal cancer patients with Karnofsky >or=70 received cetuximab 500 mg/m(2) every 2 weeks (q2w) in combination with irinotecan 180 mg/m(2) q2w until disease progression or unacceptable toxicity. The primary endpoint was the progression-free rate at 12 weeks.
Median age was 65 years; 65.9% male; colon/rectum 64.3/34.1%; Karnofsky status <or=80/>or=90% in 45.3/54.7% of the patients. The progression-free rate was 42.7 (95% CI 32.8-52.6) and 22.4% (95% CI 14.2-30.7) at 12 and 24 weeks, respectively. The main grade 3 or 4 toxicities were: diarrhea 13.5% and acne-like rash 10.3%. No grade 3 or 4 infusional or allergic reactions were reported.
The progression-free rates confirm that cetuximab q2w in combination with irinotecan is an option, and is as active and safe as the standard weekly regimen.
Chemotherapy 01/2010; 56(2):142-6. · 1.82 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Removing rectal adenomas not only relieves symptoms, but also eradicates the incidence of carcinoma. There are many techniques for local removal of rectal polyps. Transanal endoscopic microsurgery (TEM) is the most recent. The purpose of this study is to present our long-term results using TEM for rectal adenomas, paying special attention to the risk factors of harboring a malignancy.
Data from all patients undergoing TEM from December 1995 to December 2005 were collected prospectively. The selection criteria were benign sessile adenomas below the peritoneal reflection. In the study period, 173 patients were operated on for an apparently benign rectal adenoma. The mean distance of lower tumor was 7.6 cm (range, 1-18 cm), and the mean distance to upper edge was 11 cm (2-20 cm). Full-thickness local excision was performed in all procedures. Patients were followed for a minimum of 1 year.
According to the histologic findings, 14% of the specimens were invasive carcinomas. No statistical differences were found when comparing the histologic findings by tumor size, distance to the anal verge, or location.In 10 (5.8%) cases, the dissection was considered uncompleted because of a normal mucosa margin smaller than 1 mm. The mean hospital stay was 4 days (2-30 days). The morbidity rate was 14.5%. There was 1 postoperative death (0.6%). There were 9 (5.4%) histologically proven recurrences. Four of the patients with recurrence had uncompleted microscopic circumferential resection (P = 0.001). At a mean follow-up of 35 months (range, 12-82 months), all carcinoma patients were alive with no evidence of disease.
In conclusion, a significant number of adenomas that we assumed preoperatively to be benign were already carcinomas and we were unable to find any reliable predictor to identify them. TEM full-thickness excision provided a low rate of postoperative morbidity and potentially avoided a significant number of major abdominal operations and local recurrences.
Annals of surgery 03/2009; 249(2):225-8. · 7.90 Impact Factor
-
Raquel Andrés,
Jose I Mayordomo,
Carmen Visus,
Dolores Isla,
Javier Godino, Pilar Escudero,
Alberto Saenz,
Eugenia Ortega,
Rodrigo Lastra,
Julio Lambea, [......],
Manuel Ruiz-Echarri,
Esther Millastre,
Berta Sáez-Gutierrez,
Laura Asin,
Maria J Vidal,
Ana Ferrer,
Armando Giner,
Luis Larrad,
Francisco J Carapeto,
Alejandro Tres
[show abstract]
[hide abstract]
ABSTRACT: The utility of many molecules as tumor markers in melanoma has been investigated with different results. The aims of this study was to compare the value of tyrosinase mRNA by reverse transcription polymerase chain reaction (RT-PCR) in peripheral blood and of serum S-100 protein in patients with melanoma at different stages of disease.
We have studied 90 peripheral blood samples corresponding to 90 patients that had been diagnosed with melanoma. The clinical staging at the time of blood sampling was performed according to the American Join Committee on Cancer guidelines. S-100 protein in serum was measured by enzyme-linked immunosorbent assay (normal range: 0-0.150 microg) and the presence of tyrosinase mRNA was assessed by RT-PCR.
Median progression-free survival was 281 days for tyrosinase positive patients and it has not been reached for tyrosinase negative patients (P = 0.03). Median progression free survival was 213 days for patients with elevated serum S-100 and it has not been reached for patients with normal level of serum S-100 (P < 0.001). Median overall survival (OS) was 396 days for tyrosinase positive patients and it has not been reached for negative patients (P = 0.0096). Median OS was 282 days for patients with elevated serum S-100 and it has not been reached for patients with normal level of serum S-100 (P < 0.001). In a multivariate analysis, both markers have significant prognostic value for time to progression and for survival (chi(2) test).
RT-PCR for tyrosinase mRNA and S-100 are significant prognostic factors for progression-free survival and OS in melanoma. S-100 has higher sensitivity and specificity than tyrosinase.
American journal of clinical oncology 08/2008; 31(4):335-9. · 2.21 Impact Factor
-
Miquel Nogué,
Antonieta Salud,
Eduard Batiste-Alentorn,
Eugeni Saigí,
Ferran Losa,
Lluís Cirera,
Miguel Méndez,
Juan Manuel Campos,
Antonio Galan, Pilar Escudero,
Angels Arcusa,
Hermini Manzano,
Edelmira Vélez de Mendizábal,
Joaquim Pérez de Olaguer,
Montserrat Boleda,
Immaculada Guasch,
Pilar Vicente
[show abstract]
[hide abstract]
ABSTRACT: This randomised, open-label trial compared oral tegafur (FT)/leucovorin (LV) with the intravenous bolus 5-fluorouracil (5-FU)/LV as first-line chemotherapy for advanced colorectal cancer (CRC). Patients were randomised to receive oral FT 750 mg/m2/day for 21 days and LV 15 mg/m2 every 8 h in cycles repeated every 28 days (n=114), or intravenous LV 20 mg/m2 followed by 5-FU 425 mg/m2 daily for 5 days every 4 weeks for 2 cycles, and later every 5 weeks (n=123). Response rate was significantly higher in the FT/LV arm (27%, 95% CI 19-35) than in the 5-FU/LV arm (13%, 95% CI 7-19) (p<0.004). The median time to progression was 5.9 months (95% CI, 5.3-6.5; FT/LV arm) and 6.2 months (95% CI, 5.4-6.9; 5-FU/LV arm). Median overall survival was 12.4 months (95% CI, 10.3-14.5 months; FT/LV arm) and 12.2 months (95% CI, 8.9-15.7 months; 5-FU/LV arm) (p=n.s.; hazard ratio FT/LV:5-FU/LV=1.02). 5-FU/LV showed a higher incidence of grade 3/4 neutropenia (4.1 vs. 0%). Non-hematological toxicities showed similar incidences in the two treatment arms. Oral FT/LV was more active than IV 5-FU/LV in terms of objective response rate with similar overall survival, and with a favorable toxicity profile. This makes FT/LV a valid alternative to the IV 5-FU schedule in CRC patients.
European Journal of Cancer 10/2005; 41(15):2241-9. · 5.54 Impact Factor
-
Javier Martín,
Andrés Poveda,
Antonio Llombart-Bosch,
Rafael Ramos,
José A López-Guerrero,
Javier García del Muro,
Joan Maurel,
Silvia Calabuig,
Antonio Gutierrez,
José L González de Sande, [......],
Ana De Juan,
Nuria Laínez,
Ferrán Losa,
Valentín Alija, Pilar Escudero,
Antonio Casado,
Paula García,
Pilar García,
Remei Blanco,
José M Buesa
[show abstract]
[hide abstract]
ABSTRACT: To explore the prognostic value of mutations in c-KIT and PDGFR-alpha genes with respect to relapse-free survival (RFS) in patients with gastrointestinal stromal tumors (GIST). We have investigated the prognostic relevance of the type and position of the mutations, in addition to other clinicopathologic factors, in a large series of patients with GIST.
For this study, 162 patients were selected according to the following criteria: completely resected tumors with negative margins attended between 1994 and 2001; no metastasis at diagnosis; tumor larger than 2 cm, c-KIT-positive immunostaining; and no other primary tumors.
The median follow-up was 42 months for patients free of recurrence. Mutations were detected in 96 tumors (60%): 82 cases involving c-KIT and 14 cases involving PDFGR-alpha. Univariate analysis demonstrated the following as poor prognostic factors for RFS: tumors larger than 10 cm (P < .0001); mitotic count higher than 10 mitoses per 50 high-power fields (P < .0001); high risk index (P < .0001); intestinal GIST location (P = .0041); high cellularity (P < .0001); tumor necrosis (P < .0001); deletions affecting exon 11 (P = .0007); and deletions affecting codons 557 to 558 (P < .0001). After the multivariate analysis, only the high risk index (relative risk [RR], 12.36), high cellularity (RR, 3.97), and deletions affecting codons 557 to 558 of c-KIT (RR, 2.57) corresponded to independent prognostic factors for RFS in GIST patients.
Deletions affecting codons 557 to 558 are relevant for the prognosis of RFS in GIST patients. This critical genetic alteration should be considered to be a new prognostic stratification variable for randomized trials exploring imatinib mesylate in the adjuvant setting in GIST patients.
Journal of Clinical Oncology 09/2005; 23(25):6190-8. · 18.37 Impact Factor
-
Raquel Andres,
Jose Ignacio Mayordomo,
Ricardo Lara,
Rodrigo Lastra,
Eugenia Ortega,
Eduardo Polo,
Julio Lambea,
Dolores Isla,
Alberto Saenz-Cusi, Pilar Escudero,
Alejandro Tres
[show abstract]
[hide abstract]
ABSTRACT: Gemcitabine and capecitabine are 2 anticancer drugs with a mechanism of action involving metabolism of pyrimidine nucleotides. Both are among the few agents active in patients with metastatic breast cancer (MBC) progressing after therapy with anthracyclines and taxanes. We have conducted a phase II trial of gemcitabine/capecitabine in patients with disease progression after treatment with anthracyclines and taxanes.
Treatment included gemcitabine 2000 mg/m2 on day 1 every 3 weeks and capecitabine 2500 mg/m2 daily (divided into 2 doses) on days 1-14 every 3 weeks; treatment was administered until disease progression or unacceptable toxicity was documented. All patients received concomitant oral pyridoxine 300 mg twice daily to prevent hand-foot syndrome (HFS). Of 39 patients treated, 33 had received previous treatment with anthracyclines, 6 had medical contraindication to anthracyclines, 35 had previously received taxanes, and 23 had received vinorelbine. Fourteen patients had previous high-dose chemotherapy with stem cell rescue and 5 had previously received trastuzumab. Patients were 31-79 years of age (median, 55 years) and, altogether, were given 386 courses of therapy (range, 1-36 courses per patient; median, 6 courses).
Grade 3/4 toxicities included HFS (11 courses, 6 patients), stomatitis (6 courses, 2 patients), diarrhea (5 courses, 4 patients), anemia (5 courses, 2 patients), thrombocytopenia (5 courses, 2 patients), and neutropenia (1 course, 1 patient). Response rate (all 39 patients were evaluable) was 48.7% (partial response, n = 19; stable disease, n = 7; progressive disease, n = 13). Thirty-six patients died because of disease progression, and 3 are alive with progressive disease. Median follow-up was 26 months or until death. Median duration of response was 15 months (range, 3-26 months). Median time to disease progression was 5 months (range, 1-26 months). Median overall survival duration was 10 months (range, 1-37 months).
In this cohort of patients heavily pretreated with anthracyclines and taxanes, the response rate to gemcitabine/capecitabine is encouraging, although response duration is limited.
Clinical Breast Cancer 07/2005; 6(2):158-62. · 2.38 Impact Factor
-
Jaime Feliu, Pilar Escudero,
Ferrán Llosa,
Matilde Bolaños,
Jose-Manuel Vicent,
Alfonso Yubero,
Jose-Javier Sanz-Lacalle,
Rafael Lopez,
Luis Lopez-Gómez,
Enrique Casado,
María-José Gómez-Reina,
Manuel González-Baron
[show abstract]
[hide abstract]
ABSTRACT: To determine the tolerability of capecitabine in elderly patients with advanced colorectal cancer (CRC).
Fifty-one patients with advanced CRC who were >/= 70 years and considered ineligible for combination chemotherapy received oral capecitabine 1,250 mg/m(2) twice daily on days 1 to 14 every 3 weeks. Patients with a creatinine clearance of 30 to 50 mL/min received a dose of 950 mg/m(2) twice daily.
A total of 248 cycles of capecitabine were administered (median, five cycles; range, one to eight cycles). The overall response rate was 24% (95% CI, 15% to 41%), including two complete responses (CR; 4%) and 10 partial responses (PR; 20%). Disease control (CR + PR + stable disease) was achieved in 67% of patients. The median times to disease progression and overall survival were 7 months (95% CI, 6.4 to 9.5 months) and 11 months (95% CI, 8.6 to 13.3 months), respectively. Of the 35 patients evaluated for clinical benefit response, 14 (40%; 95% CI, 24% to 58%) showed clinical benefit. Capecitabine was well tolerated. Treatment-related grade 3 and 4 adverse events were observed in only six patients (12%), and the most common events were diarrhea, hand-foot syndrome, and thrombocytopenia. One patient (2%) had an episode of angina, but no treatment-related deaths were reported.
Our findings suggest that capecitabine is effective and well tolerated in elderly patients with advanced CRC who are considered ineligible for combination chemotherapy.
Journal of Clinical Oncology 05/2005; 23(13):3104-11. · 18.37 Impact Factor
-
Journal of Clinical Oncology 10/2003; 21(18):3540-1. · 18.37 Impact Factor
-
Javier Cassinello, Pilar Escudero,
Antonieta Salud,
Fernando Marcos,
Eduardo Pujol,
Ramón Pérez-Carrión,
Antonio Colmenarejo,
Ricardo González del Val,
José Valero,
Mauro J Oruezábal,
Vicente Guillem,
Inés García,
Alberto Arcediano,
Xavier Marfà
[show abstract]
[hide abstract]
ABSTRACT: This study was designed to evaluate the safety and tolerability of oxaliplatin combined with weekly boluses of 5-fluorouracil (5-FU) and low doses of leucovorin (LV) and to determine objective response, progression-free survival, and overall survival of patients with previously untreated advanced colorectal cancer. Seventy-nine patients enrolled in an observational, multicenter, prospective, open-label phase II study received intravenous (I.V.) infusions of oxaliplatin 85 mg/m2 over the course of 2 hours on days 1 and 14 and LV 20 mg/m2 over the course of 2 hours and 5-FU 500 mg/m2 as a bolus on days 1, 7, and 14 every 4 weeks until disease progression or unacceptable toxicity occurred. Seventy-nine patients were evaluable for safety, and data from 70 patients were used for efficacy analysis. The objective response rate was 51.4%. Complete responses occurred in 7 patients (10%), and partial responses occurred in 29 patients (41.4%). Disease control, defined as response or stable disease, was obtained in 56 of 70 patients (80%). The median duration of response was 8.34 weeks (range, 7.3-11.5 weeks). The median time to progression was 7.13 months (range, 6.28-7.72 months), and median overall survival time was 15 months (range, 12.32-18.37 months). Acute dose-limiting toxicities were grade 3/4 diarrhea and neutropenia, which occurred in 10.5% and 3.9% of patients, respectively. Among the 70 patients who experienced neurosensory toxicity, it was estimated that only 1.3% had grade 3 symptoms. Preliminary data showed that the regimen is at least as active as other regimens combining oxaliplatin and infusional schedules of 5-FU and might be more convenient for patients because it avoids the need for I.V. catheter implantation.
Clinical Colorectal Cancer 09/2003; 3(2):108-12. · 1.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To compare the results on disease control and toxicity of two different schedules of adjuvant combined treatment in advanced rectal cancer.
From January 1995 to September 1998, 127 patients with stage B2-C rectal cancer were treated with postoperative chemotherapy and radiotherapy with two different schemes: three cycles of 5-fluorouracil and leucovorin followed by pelvic radiotherapy and three weeks after radiation therapy was completed, another three cycles of chemotherapy were administered (alternating arm), or two cycles of 5-fluorouracil and leucovorin followed by concurrent radiochemotherapy and three weeks after ending another two cycles of 5-fluorouracil and leucovorin were administered (concomitant arm).
Grade 3 acute toxicity was more frequent in the concomitant schedule group (33% vs 13%, P = 0.014). In the alternating schedule group, the acute adverse effects were observed after an average radiation dose of 28.4 Gy and in the concomitant schedule group after an average dose of 22.7 Gy (P = 0.012). In the arm of concomitant treatment, 37.8% of patients had to interrupt the irradiation for severe toxicity compared to 10.4% in the arm of alternating treatment (P = 0.001). There was no difference in the rate of late toxicity. The actuarial overall survival rates at 3 and 5 years were, respectively, 68.8% and 56.6% in the alternating arm and 75.5% and 61.8% in the concomitant arm (P = 0.4599). There were no differences between the two arms in the 5-year actuarial rates of overall recurrence (47% vs 51.3%, P = 0.722), local recurrence (34.6% vs 35.7%, P = 0.935) or distant recurrence (32.7% vs 31.8%, P = 0.983).
For patients with B2-C rectal cancer, postoperative treatment with an alternating scheme of chemoradiotherapy is as effective as a concomitant scheme in control of the disease. The concomitant scheme had a higher incidence, earlier appearance and higher severity of intestinal acute toxicity than the alternating scheme, with a lower completion rate of chemoradiotherapy but without any influence on late toxicity incidence.
Tumori 90(2):216-24. · 0.86 Impact Factor
-
Jose Ignacio Mayordomo,
Raquel Andres,
Maria Dolores Isla,
Laura Murillo,
Rosana Cajal,
Alfonso Yubero,
Carmen Blasco,
Pilar Lasierra,
Luis Palomera,
Miguel Angel Fuertes, [......], Pilar Escudero,
Alberto Saenz,
Javier Godino,
Ivan Marco,
Berta Saez,
Carmen Visus,
Laura Asin,
Gabriel Valdivia,
Luis Larrad,
Alejandro Tres
[show abstract]
[hide abstract]
ABSTRACT: The purpose of the study was to test the immunological and clinical effects of infusions of dendritic cells pulsed with autologous tumor lysate in patients with advanced cancer.
Peripheral blood mononuclear cells from 15 patients with metastatic cancer (melanoma in 10, lung cancer in 2, renal cell carcinoma in 1, sarcoma in 1, breast cancer in 1) were harvested by leukapheresis after mobilization with GM-CSF (5 microg/kg/day s.c. for 4 days). Mononuclear cells were separated and cultured in GM-CSF (1000 U/ml) and interleukin-4 (1000 U/ml) for 7 days. Phenotype was assessed by 2-color flow cytometry and immunocytochemistry. On day 6, dendritic cells were pulsed with 1 g of fresh autologous tumor lysate for 24 h and infused intravenously. Interleukin-2 (6 million IU), interferon a (4 million IU) and GM-CSF (400 microg) were injected s.c. daily for 10 days beginning on the day of dendritic cell infusion. Treatment was repeated every 21 days for 3 courses.
The morphology, immunocytochemistry and phenotype of cultured cells was consistent with dendritic cells: intense positivity for HLA-DR and CD86, with negativity for markers of other lineages, including CD3, CD4, CD8 and CD14. More than 5 x 10(7) dendritic cells were injected in all patients. Nine patients developed >5 mm delayed type cutaneous hypersensitivity reactions to tumor lysate+/-GM-CSF after the first immunization (larger than GM-CSF in all cases). Median delayed type cutaneous hypersensitivity to lysate +/- GM-CSF was 3 cm after the third immunization. One melanoma patient with skin, liver, lung and bone metastases had a partial response lasting 8 months (followed by progression in the brain). Seven patients had stable disease for >3 months, and 7 had progression.
Infusion of tumor lysate-pulsed dendritic cells induces a strong cell-mediated antitumor immune reaction in patients with advanced cancer and has some clinical activity.
Tumori 93(1):26-30. · 0.86 Impact Factor
-
Raquel Andrés,
José I Mayordomo,
Pedro Zaballos,
Javier Rodino,
Dolores Isla, Pilar Escudero,
Luis Elosegui,
Elena Filipovich,
Alberto Saenz,
Eduardo Polo,
Alejandro Tres
[show abstract]
[hide abstract]
ABSTRACT: Although there is no established tumor marker of proven value for patients with melanoma, high serum levels of S-100B protein have been found in patients with melanoma and distant metastases. This study was performed to assess the prognostic value of this marker.
Serum S-100B protein was measured by means of the LIA-mat System 300 (Sangtec S-100B LIA, AB Sangtec Medical, Bromma, Sweden) in 85 patients with melanoma.
Mean serum S-100B protein was 0.075 microg/L (range, 0.001-0.470) in 66 patients with non-metastatic melanoma (stage I-III) versus 0.441 microg/L (range, 0.001-16.840) in 19 patients with metastatic melanoma (stage IV) (P <0.001, Mann Whitney U test). The median follow-up time was 329 days. Serum levels above 0.150 microg/L were found in 10 of patients with non-metastatic melanoma (15.2%) and in 17 of 19 patients with metastatic disease (89.4%). Median survival was 256 days for the 27 patients with serum S-100B levels above 0.150 microg/L versus 561 days for the 58 patients with normal values (P <0.3973).
Serum S-100B is a useful tumor marker in melanoma.
Tumori 90(6):607-10. · 0.86 Impact Factor
