Carlos Fernández-Martos

Hospital Casa de Salud

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Joan Maurel

Instituto de Salud Carlos III

Jaume Capdevila

Vall d'Hebron Institute of Oncology

Rocio García‐Carbonero

Hospital Universitario 12 De Octubre

Vicente Alonso

Hospital Universitario Miguel Servet

Carles Pericay

Corporació Sanitària Parc Taulí

Javier Gállego

Hospital General Universitario de Elche

Antonieta Salud

Hospital Universitari Arnau de Vilanova

Jorge Aparicio

Hospital Universitari i Politècnic La Fe

Jaime Feliú

Hospital Universitario La Paz

Barbara Sarholz

Merck (Germany)

Cooperative Institutions

Universitat de Barcelona

Hospital Clínic de Barcelona

Fundación Instituto Valenciano de Oncología

Centro de Investigación Biomédica en Red de Cáncer

Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

Hospital Arnau de Vilanova

Universitat Autònoma de Barcelona

Hospital Universitario La Paz

Instituto de Salud Carlos III

Institut Català d'Oncologia

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Incidence and patterns of phospho insulin growth factor receptor-1 (pIGF-1R) and matrilysin (MMP7) expression in metastatic colorectal cancer (mCRC), and correlation with KRAS status: A prospective evaluation in the PULSE trial—A GEMCAD study.

Journal of Clinical Oncology (2012)

Vicente Alonso Carlos Fernández-Martos Marta Martín Antonieta Salud José Carlos Méndez

e14041 Background: MMP7 can activate IGF-1R by IGF release due to IGFBP degradation. Activation of IGF-1R can contribute to EGFR resistance by transactivation. We previously described that concomitant expression of p-IGF-1R and MMP7 (Double positive; DP), correlates with poor prognosis, in KRAS WT patients (pts) treated with anti-EGFR compounds (Horndler el al, 2011). Therefore we designed a prospective clinical trial to validate DP as a marker of resistance in KRAS WT pts treated in first-line therapy with FOLFOX-6 plus panitumumab. Methods: mCRC pts in the ongoing prospective PULSE trial (NCT0128833) were prospectively evaluated for p-IGF-1R (p-1316), MMP7 expression and KRAS mutational status. Pts defined as DP should express MMP7 (++ or +++ intensity in >66% of tumor cells) and p-IGF-1R (++ or +++ intensity in >66% of tumor cells). KRAS pts with mutations at exon 2 were excluded. The study was designed to include 40 pts in the two groups (DP vs non-DP) to detect a Hazard ratio difference in PFS of <0.5 (DP vs non-DP) with 80% power. Results: From November 2010 to December 2011, 113 consecutive pts were screened from 24 Spanish Institutions. 54 KRAS WT (40 pts non-DP and 14 DP) have been included. The non-DP arm has being recently closed for inclusion, due to pre-planned complete accrual. Among DP pts, 27% were KRAS WT and 30% KRAS mutant; p=0.63. 48% of cases were positive for p-IGF-1R. Phospho-IGF-1R positive cases had different patterns of staining: peri-nuclear in 76%, 11% nuclear and only 13% membrane-apical staining. These patterns do not differ between KRAS WT; (n=70) and KRAS mutant pts (n=43) (p=0.60). Tumors with positive p-IGF-1R expression, independently of the pattern, have higher MMP7 co-expression (59%) compared with negative cases (13%) (p<0.0001). Conclusions: MMP7 contributes to activate IGF-1R pathway in pts with mCRC. Internalization of the activated IGF-1R, could explain in part, the lack of efficacy of IGF-1R inhibitors in mCRC clinical trials.

Panitumumab

Predictive marker

10.1200/jco.2012.30.15_suppl.e14041

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Should Upfront Chemotherapy Precede Preoperative Chemoradiation and Surgery?

Springer eBooks (2012)

Carlos Fernández-Martos Xabier García‐Albéniz

Systemic therapy

10.1007/978-3-642-25005-7_20

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Citations (1)

The Spanish experience with high-dose infusional 5-fluorouracil (5-FU) in colorectal cancer. The Spanish Cooperative Group For Gastrointestinal Tumor Therapy (TTD).

PubMed (1996)

Enrique Aranda Andrés Cervantes Alfredo Carrato Antonio Antón-Torres T. Massutí

Background In a previous phase I to II trial, we have shown that the maximum tolerable dose (MTD) of 5-Fluorouracil (5-FU) in 48-hour continuous infusion (CI) weekly was 3.5 gr/m2. In a subsequent confirmative phase II trial with 85 evaluable patients, a 38.5% response rate was obtained and the median survival reached was 12 months. These data were comparable to those achieved by biochemical modulation of 5-FU with Leucovorin. On this basis we tried to modulate high-dose 5-FU (3 gr/m2) with oral leucovorin (LV) but the regimen was too toxic and the dose had to be reduced. A new phase II trial with 2 g/m2/week plus oral leucovorin was planned. Patients received a median dose intensity of 5-FU of 1.6 g/m2/week (range 0.9-2). Three complete responses and 36 partial responses were observed. Overall response rate was 37.5% (95% CI, 28% to 46.8%). Median time to progression has been 7.4 months, and median survival 14.4 months. WHO grade 3 diarrhea was seen in 27 patients (24.5%). Grade 3 mucositis was also seen in 9 (8.1%) patients, and grade 4 was observed in one. Grade 3 nausea and vomiting was reported in 13 (11.7%) patients. Grade 3 hand-foot syndrome was detected in only 5 (4.5%) patients. Grade 4 leukopenia was observed in 1 case and grade 3 to 4 thrombocytopenia was observed in two cases, respectively. Oral leucovorin modulation of weekly 48-hour continuous infusion of 5-FU at 2 g/m2 is an active regimen, with diarrhea and mucositis as main limiting toxicities. Its antitumor activity does not seem superior to that obtained with a weekly 48 hour continuous infusion of 5-FU alone at a dose of 3.5 g/m2.

Mucositis

Leukopenia

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Supplementary Figure S1 from A Phase Ib Study of the DNA-PK Inhibitor Peposertib Combined with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer

Paul B. Romesser Jaume Capdevila Rocio García‐Carbonero Tony Philip Carlos Fernández-Martos

Study design

Neoadjuvant Therapy

10.1158/1078-0432.25232434

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Supplementary Figure S4 from A Phase Ib Study of the DNA-PK Inhibitor Peposertib Combined with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer

Paul B. Romesser Jaume Capdevila Rocio García‐Carbonero Tony Philip Carlos Fernández-Martos

. pDNA-PK/tDNA-PK ratios in PBMCs stimulated with bleomycin, pre- and post-dosing with peposertib.

10.1158/1078-0432.25232425.v1

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Supplementary Table S7 from A Phase Ib Study of the DNA-PK Inhibitor Peposertib Combined with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer

Paul B. Romesser Jaume Capdevila Rocio García‐Carbonero Tony Philip Carlos Fernández-Martos

Tumor mutational burden

Table (database)

10.1158/1078-0432.25232401.v1

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Preoperative Uracil, Tegafur, and Concomitant Radiotherapy in Operable Rectal Cancer: A Phase II Multicenter Study With 3 Years' Follow-Up

Journal of Clinical Oncology (2004)

Carlos Fernández-Martos Jorge Aparicio Carles Bosch Marilo Torregrosa Juan Campos

Purpose To assess tolerance and efficacy of preoperative treatment with uracil/tegafur and radiotherapy (RT) followed by surgery and postoperative flurouracil (FU)/leucovorin (LV) in patients with rectal cancer. Patients and Methods Patients (n = 94) with potentially resectable tumors, ultrasound at stages T2N+ (n = 4), T3 (n = 77), T4 (n = 13) were treated with UFT (400 mg/m 2 /d, 5 days a week for 5 weeks) and concomitant RT to the pelvis (45 Gy; 1.8 Gy/d over 5 weeks). Patients underwent surgery 5 to 6 weeks later followed by four cycles of FU/LV. Primary end points included downstaging, pathologic responses, and sphincter-preserving surgery. Secondary end points were recurrence-free survival and overall survival. Results All patients received the full RT dose. Fifteen patients (16%) needed UFT dose reduction. Preoperative G3+ toxicities included diarrhea (14%), leukopenia (1%), thrombocytopenia (1%), and nausea (4%). The downstaging rate was 54%, pathologic complete response (pCR) was 9% and, in an additional 23%, there were only residual microscopic foci. When cellular viability criteria were taken into account, the pCR was 15%. From 43 patients with abdominoperineal resection indication, 11 (25%) had sphincter-preserving surgery performed. Postoperative scheduled chemotherapy dose was not administered to 24% of patients because of G3+ toxicity (diarrhea, 8%; mucositis, 9%; and leukopenia, 7%). Patients with downstaging had significantly higher survival and recurrence-free survival rates than those without. At 3 years, actuarial patterns of failure were pelvic, 5% and distant, 11%. OS was 75%. Conclusion UFT combined with RT is safe and effective. In resectable rectal cancer, if preoperative treatment is considered, this approach can be an option.

Concomitant

Tegafur

10.1200/jco.2004.11.124

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Citations (69)

Total neoadjuvant therapy with or without aflibercept in rectal cancer: 3-year results of GEMCAD-1402

JNCI Journal of the National Cancer Institute (2023)

David Pesántez Sanne ten Hoorn Isidro Machado Xabier García‐Albéniz Nuria Rodrı́guez-Salas

Abstract Background The results of the Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD)-1402 phase II randomized trial suggested that adding aflibercept to modified fluorouracil, oxaliplatin, and leucovorin (mFOLFOX6) induction, followed by chemoradiation and surgery, could increase the pathological complete response (pCR) rate in patients with high-risk, locally advanced rectal cancer. Here we update results up to 3 years of follow-up and evaluate the predictive value of consensus molecular subtypes identified with immunohistochemistry (IHC). Methods Patients with magnetic resonance imaging–defined T3c-d and/or T4 and/or N2 rectal adenocarcinoma in the middle or distal third were randomly assigned to mFOLFOX6 induction, with aflibercept (mF+A; n = 115) or without aflibercept (mF; n = 65), followed by capecitabine plus radiotherapy and surgery. The risk local relapse, distant metastases, disease-free survival (DFS), and overall survival (OS) were estimated at 3 years. Selected samples were classified via IHC into immune-infiltrate, epithelial, or mesenchymal subtypes. Results mF+A and mF had 3-year DFS of 75.2% (95% confidence interval [CI] = 66.1% to 82.2%) and 81.5% (95% CI = 69.8% to 89.1%), respectively; 3-year OS of 89.3% (95% CI = 82.0% to 93.8%) and 90.7% (95% CI = 80.6% to 95.7%), respectively; 3-year cumulative local relapse incidences of 5.2% (95% CI = 1.9% to 11.0%) and 6.1% (95% CI = 1.7% to 15.0%), respectively; and 3-year cumulative distant metastases rates of 17.3% (95% CI = 10.9% to 25.5%) and 16.9% (95% CI = 8.7% to 28.2%), respectively. pCRs were achieved in 27.5% (n = 22 of 80) and 0% (n = 0 of 10) of patients with epithelial and mesenchymal subtypes, respectively. Conclusion Adding aflibercept to mFOLFOX6 induction was not associated with improved DFS or OS. Our findings suggested that consensus molecular subtypes identified with IHC subtypes could be predictive of pCR with this treatment.

Aflibercept

10.1093/jnci/djad120

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Biweekly alternating FOLFOX and FOLFIRI in patients with previously untreated, advanced colorectal cancer (ACC): Updated results

Journal of Clinical Oncology (2004)

Carlos Fernández-Martos Jorge Aparicio J. M. Vicent I. Maestu C. Llorca

3563 Background: Irinotecan (CPT-11) and oxaliplatin (L-OHP) are active agents in ACC. Combining each with continuous infusion (CI) 5-fluorouracil (5-FU) provides an objective response rate approaching 50%, with acceptable toxicity in first line treatment. The objective of this study was to assess the efficacy and tolerance of a protocol that alternates Gramont's LV5FU2 schedule plus L-OHP (FOLFOX-4) with the same 5-FU regimen plus CPT-11 (FOLFIRI) on a biweekly basis. Methods: Patients with previously untreated, histologically confirmed, unresectable ACC were included if they had measurable disease; adequate bone marrow, liver, and renal functions; PS (ECOG) 0–2; life expectancy > 3 months, and written informed consent. Treatment consisted of 2-hours CI Folinic acid (FA) 200 mg/m2, bolus 5-FU 400 mg/m2 and 22-hours CI 5-FU 600 mg/m2, all on days 1 and 2 every 14 days. CPT-11 (180 mg/m2) and L-OHP (85 mg/m2) were given on day 1 of alternating chemotherapy administrations. 1 chemotherapy cycle (FOLFOX-FOLFIRI) takes 28 days. Response evaluation was scheduled every 3 cycles. Results: 79 patients were enrolled (42 males, 37 females). Median age was 61 years (range 39–77). On PS, patients were distributed as follows: 0 (43.8%), 1 (47.5%), and 2 (8.8%). The number of metastatic sites was 1 (39.7%) or >1 (60.3%). 745 infusions were administered in 77 patiens who were evaluable for toxicity (median 5 cycles per patient, range 1–9 cycles). Response evaluation was performed in 45 patients. 8.9% of patients showed a complete response and 51.1% showed a partial response. Disease was stabilized in 15.6% of patients and in 24.4% of patients disease progression was observed. Of the 77 patients evaluated for toxicity, 47.5% had grade 3–4 toxicity. The most common grade 3–4 adverse events were: neutropenia 28.9%, diarrhea 21.1%, pain 6.6%, leucopenia 5.3%, anemia 5.3%, asthenia 3.9%, infection 2.6%, febrile neutropenia 2.6%, nausea/vomiting 2.6%, neurotoxicity 1.3% and transaminase increase 1.3%. Conclusions: The updated results of this study suggest that this regimen is effective and shows a good safety profile. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Prasfarma/Almirall

FOLFIRI

FOLFOX

Folinic acid

Regimen

10.1200/jco.2004.22.14_suppl.3563

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Role of Kras Status in Patients with Metastatic Colorectal Cancer Receiving First-Line Chemotherapy plus Bevacizumab: A TTD Group Cooperative Study

PLoS ONE (2012)

Eduardo Díaz‐Rubio Auxiliadora Gómez‐España Bartomeu Massutí Javier Sastre Margarita Reboredo

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.

10.1371/journal.pone.0047345

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Citations (40)