Publications (26)132.63 Total impact
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Article: 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.
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ABSTRACT: 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 (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. The study included 134 patients, of whom, 129 were eligible. The main comorbidities were hypertension (44%), diabetes (17%), and chronic obstructive pulmonary disease (11%). The ORR and disease control rate (ORR plus stable disease) were 52% and 80%, respectively. With a median follow-up of 14 months, the median progression-free survival and overall survival were 9.1 and 16.3 months, respectively. The most frequent grade 3/4 adverse events included neutropenia (16%), diarrhea (11%), and grade 3 neurotoxicity (18%). No correlation was found between efficacy or safety and comorbidities. To our knowledge, this is the largest phase II prospective study in elderly patients with mCRC. The observed efficacy and safety of this schedule compared favorably with those reported in this population, including regimens with monoclonal antibodies.Clinical Colorectal Cancer 09/2012; 11(3):200-6. · 1.68 Impact Factor -
Article: 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.
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ABSTRACT: 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. One hundred eighty patients were included. Blood samples were obtained at baseline and after three cycles. CTC enumeration was carried out using the CellSearch® System (Veridex LLC, Raritan, NJ). Computed tomography scans were performed at cycle 3 and 6 and every 12 weeks thereafter for tumor response assessment. The median progression-free survival (PFS) interval for patients with a CTC count ≥3 at baseline was 7.8 months, versus the 12.0 months achieved by patients with a CTC count <3 (p = .0002). The median overall survival (OS) time was 17.7 months for patients with a CTC count ≥3, compared with 25.1 months for patients with a lower count (p = .0059). After three cycles, the median PFS interval for patients with a low CTC count was 10.8 months, significantly longer than the 7.5 months for patients with a high CTC count (p = .005). The median OS time for patients with a CTC count <3 was significantly longer than for patients with a CTC count ≥3, 25.1 months versus 16.2 months, respectively (p = .0095). The CTC count is a strong prognostic factor for PFS and OS outcomes in metastatic colorectal cancer patients.The Oncologist 05/2012; 17(7):947-55. · 3.91 Impact Factor -
Article: Two consecutive studies using oral UFT-based chemotherapy regimens in elderly patients with advanced colorectal cancer
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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 -
Article: 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.
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ABSTRACT: 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. Sixty-six patients with advanced CRC were treated with cetuximab as a 400 mg/m2 i.v. infusion followed by 250 mg/m2 i.v. weekly plus capecitabine at a dose of 1,250 mg/m2 every 12 hours. After the inclusion of 27 patients, the protocol was amended for safety reasons, reducing the dose of capecitabine to 1,000 mg/m2 every 12 hours. Thirty-nine additional patients were treated with the reduced dose of capecitabine. The overall response rate was 31.8%. KRAS status was determined in 58 patients (88%). Fourteen of 29 patients with wild-type KRAS tumors responded (48.3%; 95% confidence interval [CI], 29.4%-67.5%), compared with six of 29 patients with mutant KRAS tumors (20.7%; 95% CI, 8.0%-39.7%). The median progression-free survival (PFS) interval was 7.1 months. The median PFS interval for patients whose tumors were wild-type KRAS was significantly longer than for those with mutant KRAS tumors (8.4 months versus 6.0 months; p = .024). The high incidence of severe paronychia (29.6%) declined (7.7%) after capecitabine dose adjustment. Cetuximab plus capecitabine at a dose of 1,000 mg/m2 every 12 hours may be an alternative to more aggressive regimens in elderly patients with advanced wild-type KRAS CRC.The Oncologist 02/2012; 17(3):339-45. · 3.91 Impact Factor -
Article: Role of Kras Status in Patients with Metastatic Colorectal Cancer Receiving First-Line Chemotherapy plus Bevacizumab: A TTD Group Cooperative Study.
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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 -
Article: 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.
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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 -
Article: Pharmacogenetic study in rectal cancer patients treated with preoperative chemoradiotherapy: polymorphisms in thymidylate synthase, epidermal growth factor receptor, GSTP1, and DNA repair genes.
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ABSTRACT: 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. Blood samples were obtained from 128 patients with Stage II-III rectal cancer. DNA was extracted from the peripheral blood nucleated cells, and the genotypes were analyzed by polymerase chain reaction amplification and automated sequencing techniques or using a 48.48 dynamic array on the BioMark system. The germline polymorphisms studied were thymidylate synthase, (VNTR/5'UTR, 2R G>C single nucleotide polymorphism [SNP], 3R G>C SNP), epidermal growth factor receptor (Arg497Lys), GSTP1 (Ile105val), excision repair cross-complementing 1 (Asn118Asn, 8092C>A, 19716G>C), X-ray repair cross-complementing group 1 (XRCC1) (Arg194Trp, Arg280His, Arg399Gln), and xeroderma pigmentosum group D (Lys751Gln). The pathologic response, pathologic regression, progression-free survival, and overall survival were evaluated according to each genotype. The ∗3/∗3 thymidylate synthase genotype was associated with a greater response rate (pathologic complete remission and microfoci residual tumor, 59% in ∗3/∗3 vs. 35% in ∗2/∗2 and ∗2/∗3; p=.013). For the thymidylate synthase genotype, the median progression-free survival was 103 months for the ∗3/∗3 patients and 84 months for the ∗2/∗2 and ∗2/∗3 patients (p=.039). For XRCC1 Arg399Gln SNP, the median progression-free survival was 101 months for the G/G, 78 months for the G/A, and 31 months for the A/A patients (p=.048). The thymidylate synthase genotype and XRCC1 Arg399Gln polymorphism might help to identify Stage II-III rectal cancer patients with a better outcome after preoperative concomitant chemoradiotherapy.International journal of radiation oncology, biology, physics 05/2011; 81(5):1319-27. · 4.59 Impact Factor -
Article: 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?
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ABSTRACT: 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. We investigated the association of FcγR polymorphisms and KRAS mutation with the clinical outcome of 104 refractory metastatic colorectal cancer (mCRC) patients treated with anti-EGFR antibodies. FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms were analyzed in genomic DNA using a 48.48 dynamic array on the BioMark system (Fluidigm, South Sanfrancisco, CA, USA). Tumor tissues from 96 cases were screened for KRAS mutations. KRAS mutation was associated with a lower response rate (RR) (P = 0.035) and a shorter progression-free survival (PFS) (3 vs 7 months; P = 0.36). FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms did not show statistically significant associations with response, PFS, or KRAS status. In the logistic regression analysis, KRAS status (P = 0.04) and skin toxicity (P = 0.03) were associated with RR. By multivariate analysis, the clinical risk classification (P = 0.006) and skin toxicity (P < 0.0001) were found to be independent risk factors for PFS. In conclusion, the FcγRIIa and FcγRIIIa polymorphisms are not useful as molecular markers for clinical outcome in mCRC patients. To date, the EORTC (European Organization for Research and Treatment of Cancer Classification), skin toxicity, and KRAS status are the only reliable biomarkers to identify patients that would benefit from anti-EGFR therapy.Cancer Science 09/2010; 101(9):2048-53. · 3.33 Impact Factor -
Article: Absence of large intragenic rearrangements in the DPYD gene in a large cohort of colorectal cancer patients treated with 5-FU-based chemotherapy.
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ABSTRACT: 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. WHAT THIS STUDY ADDS * The intragenic rearrangements of DPYD using multiplex ligation-dependent probe amplification (MLPA) were studied for the first time in a large series of 234 colorectal cancer patients treated with 5-FU-containing chemotherapy. * No deletions or duplications of one or more DPYD exons were detected. The presence of the IVS14+1G>A mutation was also excluded. * These data show that neither the large genomic rearrangements in the DPYD gene nor the IVS14+1G>A mutation are responsible for the serious toxicity associated with a 5-FU containing regimen in this cohort of Spanish patients. AIMS To study the relationship between the toxicity associated with a 5-FU-based therapy and the presence of (i) the large intragenic rearrangements in the DPYD gene and (ii) the IVS14+1G>A mutation. METHODS We used the multiplex ligation-dependent probe amplification technique (MLPA) to study genomic DNA from 234 colorectal cancer patients treated with 5-FU-based chemotherapy. RESULTS We did not detect any deletion/duplication in the DPYD gene. The presence of the IVS14+1G>A mutation was also excluded. CONCLUSIONS Neither the large genomic rearrangements in the DPYD gene nor the IVS14+1G>A mutation play a significant role in the development of serious toxicity associated with a 5-FU containing regimen.British Journal of Clinical Pharmacology 08/2010; 70(2):268-72. · 2.96 Impact Factor -
Article: 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.
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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 -
Article: Thymidylate synthase germline polymorphisms in rectal cancer patients treated with neoadjuvant chemoradiotherapy based on 5-fluorouracil.
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ABSTRACT: 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. We analyzed the value of TS gene polymorphisms as a predictive marker in patients with stage II and III rectal cancer treated with preoperative concomitant radiotherapy and fluoropyrimidine-based chemotherapy. Between 1998 and 2007, blood samples were obtained from 51 patients with stage II/III rectal cancer. Forty patients were T2-3 (78%), 11 were T4 (22%), and 59% were N+. DNA was extracted from peripheral blood, and the genotypes were analyzed using PCR-restriction fragment length polymorphism and automated sequencing techniques. The *3/*3 thymidylate synthase genotype was associated with a higher response rate (pathological complete remission and microfoci residual tumor; 61 vs. 22% in *2/*2 and *2/*3; P = 0.013). In the multivariate analysis, the *3/*3 thymidylate synthase genotype was also an independent prognostic factor for better survival (P < 0.05). The thymidylate synthase genotype might help to identify patients with stage II/III rectal cancer who could benefit from pre- and postoperative fluorouracil-based chemotherapy.Journal of Cancer Research and Clinical Oncology 02/2010; 136(11):1681-9. · 2.56 Impact Factor -
Article: Bladder preservation strategy based on combined therapy in patients with muscle-invasive bladder cancer: management and results at long-term follow-up.
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ABSTRACT: 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). 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 (87.5%) had primary MIBC and 6 (12.5%) had MIBC subsequent to NMIBC. After chemotherapy, 39 patients (81.25%) achieved complete remission and 4 (8.3%) partial remission. With a median follow-up of 98.5 months (13-246), the overall survival of the 48 patients was 62.6%. The cancer-specific survival (CSS) of the 39 patients with complete remission was 80.8%. Among the 39 patients with complete remission, 19 had invasive recurrence during follow-up with a CSS of 53.2%; by comparison, among patients with preserved bladders, CSS was 72.1% (p = 0.046). Predictive factors analysed were age, sex, tumour size >3 cm, grade, associated carcinoma in situ (CIS), number of tumours and number of previous recurrences. In multivariate analysis only tumour size and CIS were significant predictive factors for progression after preservation. Of the 6 patients with MIBC after NMIBC, 3 (50%) had no remission and underwent cystectomy and 15 patients (38.6%) had NMIBC recurrences during follow-up. CIS and high-grade tumours were treated with bacillus Calmette-Guérin. A bladder preservation rate of 81% and a CSS rate of 89% were obtained in the group with NMIBC recurrences. Conservative management of MIBC cancer is a feasible alternative to cystectomy in selected cases. Patients with MIBC after progression of primary NMIBC are not good candidates for a bladder preservation approach. NMIBC recurrences after bladder preservation in patients with MIBC respond to transurethral resection and bacillus Calmette-Guérin instillations.Urologia Internationalis 01/2010; 85(3):281-6. · 0.99 Impact Factor -
Article: Colorectal cancer metastasis resectability after treatment with the combination of oxaliplatin, irinotecan and 5-fluorouracil. Final results of a phase II study
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ABSTRACT: 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≥18 with MCRC, ECOG grade 0–2, and no prior treatment received L-OHP (85 mg/m2), CPT-11 (150 mg/m2) and 5-FU (2 250 mg/m2 in 48 h CI) on D1 every 15 days. Results. Forty-seven patients with initially non-resectable metastatic disease were included. Median age 62 years (38–76); 28 males; 26 patients with 0 performance status (ECOG) 40 patients had prior surgery and four adjuvant chemotherapy. All patients were evaluable for toxicity and 42 for response. Main grade 3–4 toxicities were neutropenia (40%), febrile neutropenia (4%), diarrhea (21%), nausea/vomiting (11%/15%), fatigue (11%), anemia and alopecia (9% each); grade 3–4 neurotoxicity was observed in 28% patients. Secondary surgery was possible in 15 of 47 (31.9%) patients and 12/30 (40%) patients with only LM: in this cohort, median OS has not been reached at 22 months median follow-up, with 2/12 patients having died. Overall response rate was 69% (95% CI, 53–82%); 13 (31%) had stable disease. Median time to progression and overall survival (OS) were 10.9 (95% CI, 9.9–13.2) and 19.9 (95% CI, 11.7-TBD) months, respectively. Conclusion. This combination has shown promising activity with manageable toxicity as front-line treatment in MCRC, and has allowed the resectability of LM in a considerable number of patients, offering them the possibility of long-term survival.07/2009; 47(2):286-292. -
Article: Methylenetetrahydrofolate reductase gene polymorphisms: genomic predictors of clinical response to fluoropyrimidine-based chemotherapy in females.
Journal of Clinical Oncology 08/2008; 26(20):3468; author reply 3468-9. · 18.37 Impact Factor -
Article: Irinotecan pharmacogenetics: influence of pharmacodynamic genes.
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ABSTRACT: 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. Polymorphisms in the drug target of camptothecins, topoisomerase I (TOP1), and downstream effectors may influence patient outcomes to irinotecan therapy. We undertook a retrospective candidate gene haplotype association study to investigate this hypothesis. Haplotype compositions of six candidate genes were constructed in European (n = 93), East Asian (n = 94), and West African (n = 95) populations. Haplotype-tagging single nucleotide polymorphisms (htSNP) were selected based on genealogic relationships between haplotypes. DNA samples from 107 European, advanced colorectal cancer patients treated with irinotecan-based regimens were genotyped for htSNPs as well as three coding region SNPs. Associations between genetic variants and toxicity (grade 3/4 diarrhea and neutropenia) or efficacy (objective response) were assessed. TOP1 and TDP1 htSNPs were related to grade 3/4 neutropenia (P = 0.04) and response (P = 0.04), respectively. Patients homozygous for an XRCC1 haplotype (GGCC-G) were more likely to show an objective response to therapy than other patients (83% versus 30%; P = 0.02). This effect was also seen in a multivariate analysis (odds ratio, 11.9; P = 0.04). No genetic variants were associated with diarrhea. This is the first comprehensive pharmacogenetic investigation of irinotecan pharmacodynamic factors, and our findings suggest that genetic variation in the pharmacodynamic genes may influence the efficacy of irinotecan-containing therapies in advanced colorectal cancer patients.Clinical Cancer Research 04/2008; 14(6):1788-96. · 7.74 Impact Factor -
Article: Colorectal cancer metastasis resectability after treatment with the combination of oxaliplatin, irinotecan and 5-fluorouracil. Final results of a phase II study.
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ABSTRACT: 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 > 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. Forty-seven patients with initially non-resectable metastatic disease were included. Median age 62 years (38-76); 28 males; 26 patients with 0 performance status (ECOG) 40 patients had prior surgery and four adjuvant chemotherapy. All patients were evaluable for toxicity and 42 for response. Main grade 3-4 toxicities were neutropenia (40%), febrile neutropenia (4%), diarrhea (21%), nausea/vomiting (11%/15%), fatigue (11%), anemia and alopecia (9% each); grade 3-4 neurotoxicity was observed in 28% patients. Secondary surgery was possible in 15 of 47 (31.9%) patients and 12/30 (40%) patients with only LM: in this cohort, median OS has not been reached at 22 months median follow-up, with 2/12 patients having died. Overall response rate was 69% (95% CI, 53-82%); 13 (31%) had stable disease. Median time to progression and overall survival (OS) were 10.9 (95% CI, 9.9-13.2) and 19.9 (95% CI, 11.7-TBD) months, respectively. This combination has shown promising activity with manageable toxicity as front-line treatment in MCRC, and has allowed the resectability of LM in a considerable number of patients, offering them the possibility of long-term survival.Acta Oncologica 02/2008; 47(2):286-92. · 3.33 Impact Factor -
Article: [Inversion of the sequence of surgery after neoadjuvant chemotherapy for synchronous liver metastases from colorectal cancer].
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ABSTRACT: 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. We report the case of a patient with advanced recto-colonic cancer, which responded well to chemotherapy given as neoadjuvant treatment prior to surgery, in which the hepatic metastases were resected before excision of the primary tumor.Cirugía Española 11/2007; 82(4):235-7. · 0.87 Impact Factor -
Article: [Surgical resection of liver metastases from colorectal carcinoma. Experience in Sant Pau Hospital].
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ABSTRACT: 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. We retrospectively analyzed a consecutive series of 116 patients who underwent 138 liver resections (65.4% minor and 35.5% major) for hepatic metastases from colorectal cancer between 1998 and 2004. In 34.5% of the patients, the lesions were synchronous. All patients were individually assessed by a multidisciplinary team. The mean number of metastases removed per patient was 2.43 (range: 1-10). The mean size of the largest tumor per patient was 40 mm (range: 12-90). In 67.3% of the patients, the primary tumor was at an advanced stage (III-IV). In 98% of the patients, the diagnosis was confirmed by helical computed tomography scans/magnetic resonance imaging and intraoperative ultrasonography. Postoperative morbidity was 31.2% and mortality was 2.2%. A mean of 2.7 units of blood was transfused per patient. Overall 5-year survival was 43.2% (median 50 months). Survival rates varied according to whether the patients had < 4 or > or = 4 colorectal liver metastases (50 and 43 months respectively), tumor size (more or less than 5 cm) (60 and 50.6 months respectively) and whether the site was monolobar or bilobar (60 and 43.11 months respectively). In 16 patients, recurrence of liver metastases led to 22 rehepatectomies. Overall 5-year survival was 36.7% (median 60 months) after the first rehepatectomy but was 36 and 12 months respectively after a second or third rehepatectomy. These results confirm that multidisciplinary decisions and interventions by specialist liver surgeons, as in our hospital, reduce postoperative morbidity and mortality and increase survival in patients requiring surgical removal of liver metastases from colorectal cancer.Cirugía Española 06/2007; 81(6):339-44. · 0.87 Impact Factor -
Article: K-ras Asp12 mutant neither interacts with Raf, nor signals through Erk and is less tumorigenic than K-ras Val12.
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ABSTRACT: 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. We studied tumor histology and growth, apoptotic and mitotic rates, activation of signal transduction pathways downstream of Ras and regulation of the cell cycle and apoptotic proteins in tumors derived from the implanted transformants. We found that the K12V oncogene induces a more aggressive tumorigenic phenotype than the K12D oncogene, whereas K12C does not induce tumors in this model. Thus, K12V mutant tumors proliferate about seven times faster, and have higher cellularity and mitotic rates than the K12D mutant tumors. A molecular analysis of the induced tumors shows that the K12V mutant protein interacts with Raf-1 and transduces signals mainly through the Erk pathway. Unexpectedly, in tumors induced by the K12D oncogene, the K-Ras mutant protein does not interact with Raf-1 nor activates the Erk canonical pathway. Instead, it transduces signals through the PI3K/Akt, JNK, p38 and FAK pathways. Finally, the higher growth rate of the K12V tumors associates with enhanced Rb phosphorylation, and PCNA and cyclin B upregulation, consistent with faster G1/S and G2/M transitions, without alteration of apoptotic regulation.Carcinogenesis 12/2006; 27(11):2190-200. · 5.70 Impact Factor -
Article: Description and management of cutaneous side effects during cetuximab or erlotinib treatments: a prospective study of 30 patients.
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ABSTRACT: 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. We sought to describe the cutaneous side effects and their management in patients with cancer treated with cetuximab or erlotinib. We clinically examined 30 patients determining type, frequency, treatment, and evolution of side effects. Most patients presented with a cutaneous reaction consisting of a follicular eruption, typically appearing in seborrheic areas within the first 15 days of treatment. Painful fissures in palms and soles and paronychia were the second most common cutaneous toxicities. We also noticed an alteration in hair growth at several months' follow-up. As these secondary effects responded well to treatment, few patients discontinued the antineoplastic therapy because of cutaneous toxicity. This was a prospective but uncontrolled study. Although these new targeted therapies have low systemic toxicity because of their high specificity, cutaneous side effects are common and may be serious.Journal of the American Academy of Dermatology 10/2006; 55(3):429-37. · 3.99 Impact Factor
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Top Journals
Institutions
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2012
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Hospital Regional Universitario Carlos Haya Malaga
Málaga, Andalusia, Spain
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2008–2012
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Hospital Universitari Germans Trias i Pujol
Badalona, Catalonia, Spain -
University of Washington Seattle
- Division of General Internal Medicine
Seattle, WA, USA
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2005–2012
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Hospital Clínico San Carlos
- Servicio de Oncología Médica
Madrid, Madrid, Spain
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2000–2011
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Hospital de la Santa Creu i Sant Pau
Barcelona, Catalonia, Spain
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2010
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University of Barcelona
Barcelona, Catalonia, Spain -
Autonomous University of Barcelona
Cerdanyola del Vallès, Catalonia, Spain -
Fundació Puigvert
- Department of Urology
Barcelona, Catalonia, Spain
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