Cetuximab plus irinotecan after irinotecan failure in elderly metastatic colorectal cancer patients: Clinical outcome according

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1 Critical Reviews in Oncology/Hematology 78 (2011) Cetuximab plus irinotecan after irinotecan failure in elderly metastatic colorectal cancer patients: Clinical outcome according to KRAS and BRAF mutational status Contents Lorenzo Fornaro a, Giacomo Giulio Baldi a, Gianluca Masi a,, Giacomo Allegrini b, Fotios Loupakis a, Enrico Vasile a, Samanta Cupini c, Irene Stasi a, Lisa Salvatore a, Chiara Cremolini a, Bruno Vincenzi d, Daniele Santini d, Giuseppe Tonini d, Francesco Graziano e, Annamaria Ruzzo f, Emanuele Canestrari f, Mauro Magnani f, Alfredo Falcone a a U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Via Roma, Pisa, Italy b U.O. Oncologia Medica, Ospedale F. Lotti, Pontedera, Italy c U.O. Oncologia Medica, Azienda USL6 di Livorno, Livorno, Italy d U.O. Oncologia Medica, Università Campus Bio-Medico, Roma, Italy e U.O. Oncologia Medica, Ospedale di Pesaro, Pesaro, Italy f Dipartimento di Scienze Biomolecolari, Università di Urbino, Urbino, Italy Accepted 10 June Introduction Patients and methods Patient selection Treatment Assessments and statistical analysis EGFR immunohistochemistry and KRAS/BRAF mutational status evaluation Results Patient characteristics Treatment Safety Activity and efficacy KRAS and BRAF mutational status Discussion Conflict of interest statement Reviewers Acknowledgements References Biographies Abstract Background: Scarce data are available about safety and efficacy of cetuximab in elderly metastatic colorectal cancer (mcrc) patients. Patients and methods: We retrospectively analysed 54 irinotecan-refractory mcrc patients aged 70 years treated with cetuximab plus irinotecan and evaluated clinical outcome according to KRAS and BRAF mutational status. Corresponding author. Tel.: ; fax: address: gl.masi@tin.it (G. Masi) /$ see front matter 2010 Elsevier Ireland Ltd. All rights reserved. doi: /j.critrevonc

2 244 L. Fornaro et al. / Critical Reviews in Oncology/Hematology 78 (2011) Results: Median age was 73 years (70 82). Main grade 3 4 toxicities were skin rash (15%), diarrhea (19%) and neutropenia (13%). Irinotecan dose reduction was necessary in 39% of patients. Fifty-two (96%) patients were analysed for KRAS and BRAF status. The 29 KRAS wild-type patients achieved better RR (31% vs 4%; p = 0.030) and median PFS (4.21 months vs 3.95 months; p = 0.034; HR: 0.50, 95% CI: ) when compared with KRAS mutated ones. RR (41% vs 3%; p = 0.001) and mpfs (4.57 months vs 3.78 months, p = 0.001; HR: 0.35, 95% CI: ) were significantly higher among the 22 KRAS and BRAF wild-type patients compared to the 30 KRAS or BRAF mutated ones. Conclusion: Cetuximab plus irinotecan has a favourable safety profile in elderly mcrc patients, but a reduced dose of irinotecan should be considered. Such a combination can be a useful option for elderly KRAS and BRAF wild-type patients Elsevier Ireland Ltd. All rights reserved. Keywords: BRAF; Cetuximab; Chemotherapy; Elderly; KRAS; Metastatic colorectal cancer 1. Introduction More than 50% of colorectal cancer (CRC) cases arise in patients aged 70 years [1] and the prevalence of the disease is rising in the elderly population [2]. Notwithstanding, these patients are often underrepresented in clinical trials [3] and suboptimally treated in clinical practice [4 6]. Host factors (comorbidities, functional status and liver or kidney function) and, possibly, tumor biology differ between older and younger patients and among different elderly individuals: in such a heterogeneous population, individualized treatment strategies are needed in order to optimize efficacy and reduce the risk of toxicities [7]. Effective anti-vascular endothelial growth factor (VEGF) and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (moabs), such as bevacizumab and cetuximab or panitumumab, have extended the treatment options for metastatic CRC (mcrc) [8,9]. Observational and retrospective studies [10 12] have partly reassured about the safety profile of bevacizumab in the elderly population, while few data are available for anti-egfr agents. Since cetuximab plus irinotecan first reported increased response rate (RR) (22.9% vs 10.8%; p = 0.007) and median time to progression (TTP) (4.1 months vs 1.5 months; p < 0.001) over the moab alone after failure of an irinotecanbased treatment [13], numerous trials tested cetuximab either as single agent [14] or with different chemotherapy [15 17] in various lines of treatment. Patients up to 90 years old have been enrolled, with median age ranging from 58 to 63 years. Cetuximab demonstrated a favourable safety profile, skin rash and infusion-related reactions representing the main adverse effects reported. Despite the number of treated patients, the safety and efficacy of this agent in the elderly population remain suboptimally defined. The main published experience [18] among 56 elderly mcrc patients treated with cetuximab and chemotherapy suggested that increased age does not impair the safety nor the activity and efficacy of the anti- EGFR agent. Prospective trials in this setting tested first-line cetuximab both as single agent [19] and with chemotherapy [20], concluding that cutaneous toxicity and diarrhea are the most common adverse events and that cetuximab combined with chemotherapy results in superior activity than the moab alone. Since RR reported with anti-egfr moabs alone is approximately 10% and does not exceed 23% with cetuximab plus irinotecan, great efforts have been made in search of reliable predictive factors of resistance. The role of KRAS mutational status has been definitively established [21 23] and accepted by regulatory agencies. KRAS mutations occur in about 40% of CRCs (more often at codon 12 and 13) and lead to the synthesis of a constitutively activated Ras protein downstream the EGFR transduction pathway, which is accordingly unaffected by the binding of the moabs at the extracellular domain of the receptor. Recently, other factors have been explored in order to refine patient selection and BRAF exon 15 V600E mutation appears the most promising [24,25]. Interestingly, BRAF mutation is mutually exclusive with KRAS ones and occurs in approximately 10% of CRCs, thus representing an ideal factor for the selection of KRAS wildtype patients. However, none of the aforementioned trials evaluated KRAS and BRAF mutations in the elderly population. We conducted this retrospective analysis of 54 mcrc patients aged 70 years who received treatment with cetuximab plus irinotecan after irinotecan failure in order to better define the tolerability of this agent and its efficacy in a subgroup of elderly patients selected according to KRAS and BRAF mutational status. 2. Patients and methods 2.1. Patient selection We retrospectively identified elderly ( 70 years) patients with histologically confirmed mcrc who received cetuximab. Major selection criteria comprise positive EGFR status at immunohistochemistry (IHC), at least one previous line for metastatic disease with demonstrated resistance to an irinotecan-based regimen and measurable disease (RECIST criteria) [26] Treatment Cetuximab was delivered as a 1-h i.v. infusion at the dose of 250 mg/m 2 weekly (loading dose: 400 mg/m 2 over

3 L. Fornaro et al. / Critical Reviews in Oncology/Hematology 78 (2011) h on day 1, cycle 1) (standard schedule) or at the dose of 500 mg/m 2 over 1-h every 2 weeks (biweekly schedule). Chemotherapy consisted of irinotecan (180 mg/m 2 i.v. every 2 weeks) Assessments and statistical analysis Complete blood cell count was performed every 2 weeks and tumor response was evaluated every 8 weeks by CT scan. Toxicities were graded according to the National Cancer Institute-Common Toxicity Criteria Version 3.0. PFS (progression-free survival) and OS (overall survival) were estimated using the Kaplan Meier method. Correlation between KRAS/BRAF mutational status and response was assessed using two-tailed Fisher s exact test. PFS and OS were determined using the Kaplan Meier method and compared according to mutational status using the log-rank test. Statistical significance was set at p < 0.05 for a two-tailed test EGFR immunohistochemistry and KRAS/BRAF mutational status evaluation Paraffin-embedded tumor blocks representative of either primary tumor or metastatic lesion were collected and analysed for EGFR expression and KRAS/BRAF mutational status. EGFR IHC, KRAS codon 12 and 13 and BRAF V600E mutations detection was performed as reported elsewhere [25,27]. 3. Results 3.1. Patient characteristics Fifty-four patients treated between August 2004 and January 2009 were identified (Table 1). Median age was 73 (range 70 82) and 17 (31%) patients were 75 years old. Twenty-seven (50%) patients presented an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or 2. Forty-four (81%) patients had 2 sites of disease. Cetuximab was administered after failure of 1 (n = 13, 24%) or 2 (n = 41, 76%) lines of treatment. The majority (n = 51, 94%) had previously received all the three most active cytotoxic agents: fluoropyrimidines (either infusional 5-fluorouracil/leucovorin or capecitabine) (n = 53, 98%), oxaliplatin (n = 52, 96%) and irinotecan (n = 54, 100%). Ten (19%) patients had received first-line chemotherapy combined with bevacizumab Treatment A total of 653 doses of cetuximab were administered (range 2 72; median: 10). Thirty-three (61%) patients Table 1 Patient characteristics. Characteristic n % No. of patients Age, years Median (range) 73 (70 82) Gender Male Female ECOG performance status Primary tumor Colon Rectum Timing of metastases Synchronous Metachronous No. of involved organs Liver only metastases Yes 7 13 No No. of previous lines for advanced disease Previous drugs Fluoropyrimidine Irinotecan Oxaliplatin Bevacizumab No., number; ECOG, Eastern Cooperative Oncology Group. received the standard schedule, while 21 (39%) were treated with the biweekly schedule Safety All patients were evaluable for toxicities (Table 2). Most frequent grade 3 4 adverse events were skin rash and diarrhea. Skin rash occurred in almost all (47, 87%) patients but it was generally mild to moderate in severity (grade 1 2: 39, 72%; grade 3 4: 8, 15%). Diarrhea occurred in 42 (78%) patients and was grade 3 4 in 10 (19%) and grade 1 2 in 32 (59%) patients. Seven (13%) patients developed grade 3 4 neutropenia and 4 (7%) febrile neutropenia. Dose delays were necessary in 23 patients (43%), mainly due to skin or gastrointestinal toxicity. Cetuximab dose adjustment was made in 5 (9%) patients because of skin toxicity. Twentyone (39%) patients required reduction of irinotecan dose, mainly because of grade 2 diarrhea. No patient was hos-

4 246 L. Fornaro et al. / Critical Reviews in Oncology/Hematology 78 (2011) Table 2 Maximum toxicities per patient (n = 54). Toxicity G1 (%) G2 (%) G3 (%) G4 (%) Diarrhea 18 (33) 14 (26) 9 (17) 1 (2) Nausea/vomiting 19/5 (35/9) 5/4 (9/7) 2/1 (4/2) 0/0 (0/0) Stomatitis 15 (28) 12 (22) 0 (0) 0 (0) Skin rash 24 (44) 15 (28) 8 (15) 0 (0) Leucopenia 14 (26) 6 (11) 3 (6) 1 (2) Neutropenia a 10 (19) 6 (11) 5 (9) 2 (4) Anaemia 22 (41) 4 (7) 1 (2) 0 (0) Thrombocytopenia 6 (11) 4 (7) 1 (2) 0 (0) a Four (7%) patients developed febrile neutropenia. pitalized due to toxicities and no toxic death or cardiac and thromboembolic event occurred. Forty-four (81%) patients discontinued treatment due to disease progression, 1 (2%) due to toxicity and 2 (4%) because of refusal to continue; in 2 (4%) patients treatment was discontinued because local procedures on liver metastases were performed Activity and efficacy All patients were evaluable for response and efficacy. Ten patients achieved a partial response (PR), for an objective RR of 19%. Disease stabilization was reported in 24 (44%) patients, while 20 (37%) progressed during treatment. Among patients who achieved disease stabilization as best response, 3 had a PFS 6 months. Two responding patients underwent local procedures on hepatic metastases, which consisted in a radical surgical resection plus radiofrequency ablation (RFA) and in a RFA alone. Patients with grade 2 3 skin toxicity achieved higher RR (24% vs 10%; p = 0.073) and longer median PFS (4.80 months vs 3.78 months; p = 0.027; HR: 0.53, 95% CI: ) compared with patients with grade 0 1 reactions. At a median follow-up of 29.0 months, 51 (94%) patients have progressed and 44 (81%) have died. The median PFS and the median OS were 4.0 and 11.5 months, respectively (Fig. 1A and B). Median OS calculated from the date of diagnosis of mcrc and death was 33.6 months KRAS and BRAF mutational status Fifty-two (96%) patients were evaluated for KRAS and BRAF mutational status. KRAS and BRAF mutations were identified in 23 (44%) and 7 (13%) of the examined samples, respectively, and were mutually exclusive. Response according to KRAS and BRAF status are listed in Table 3. KRAS wild-type patients reported significantly higher RR (31% vs 4%; p = 0.030) and median PFS (4.21 months vs 3.95 months; p = 0.034; HR: 0.50, 95% CI: ) (Fig. 1C) compared to mutated ones, while no statistically significant difference in median OS was observed (15.82 vs 10.56; p = 0.200; HR: 0.66, 95% CI: ) (Fig. 1 D). When only KRAS wild-type patients are considered, there is not a significant correlation between the onset and intensity of skin rash and median PFS (grade 2 3 vs grade 0 1: 4.00 vs 4.21 months; p = 0.335; HR: 0.67, 95% CI: ), despite a trend for higher RR in patients with grade 2 3 vs grade 0 1 toxicity (46% vs 19%; p = 0.226). None of the BRAF mutated patients responded to treatment, in comparison with 10 (22%) of 45 patients with BRAF wild-type disease (p = 0.173). BRAF mutation was associated with shorter PFS (median PFS: 2.60 months vs 4.34 months in BRAF wild-type; p = 0.027; HR: 0.27, 95% CI: ) (Fig. 1 E) and a trend toward shorter OS (median OS: 2.99 months vs months in BRAF wild-type; p = 0.349; HR: 0.63, 95% CI: ) (Fig. 1 F). Patients with either KRAS or BRAF mutations reported significantly worse outcome compared to KRAS and BRAF wild-type patients both in terms of RR (3% vs 41%; p = 0.001) and median PFS (3.78 months vs 4.57 months, p = 0.001; HR: 0.35, 95% CI: ) (Fig. 1G) with a trend toward decreased median OS (10.0 months vs 16.5 months, p = 0.066; HR: 0.27, 95% CI: ) (Fig. 1H). When patients are selected for both KRAS and BRAF wild-type status, cutaneous toxicity is associated with a trend toward higher RR (grade 2 3 vs grade 0 1: 55% vs 27%; p = 0.387) and longer median PFS (grade 2 3 vs grade 0 1: 6.84 months vs 4.57 months; p = 0.603; HR: 0.78, 95% CI: ). 4. Discussion Scarce data are available on the safety and efficacy and the predictive role of molecular markers of anti-egfr moabs in the elderly mcrc population [18 20]. In our series, we did not report any unexpected adverse events: cutaneous rash and diarrhea were the main grade 3 4 toxicities and occurred at rates comparable to those reported by Bouchahda et al. [18]. Notably, treatment delays or chemotherapy dose reductions were necessary in approximately 40% of patients due to long-lasting grade 2 toxicities (mainly diarrhea), suggesting that a slightly reduced dose of irinotecan ( mg/m 2 ) should be considered as initial treatment in this subset. As regards efficacy, our data indicate that the outcome of unselected elderly patients treated with cetuximab [18 20] is similar to that achieved in general mcrc population [13], both in terms of RR and median PFS. Interestingly, as reported by previously

5 L. Fornaro et al. / Critical Reviews in Oncology/Hematology 78 (2011) Table 3 Best response according to KRAS and BRAF mutational status (52 patients evaluated). Overall KRAS BRAF KRAS and BRAF KRAS or BRAF n =52 WT n =29 Mut n =23 p WT n =45 Mut n =7 PR 19% 31% 4% % 0% % 3% SD 44% 34% 52% 42% 43% 32% 50% PD 37% 35% 44% 36% 57% 27% 47% PR, partial response; SD, stable disease; PD, progressive disease; WT, wild-type; Mut, mutated; n, number; p, p-value (comparison between PR and SD + PD). p WT n =22 Mut n =30 p published series, development and severity of cutaneous toxicity identify patients who benefit more from treatment and, despite statistics is limited by the small number of patients, this clinical factor seems to retain its significance also when molecular selection by means of mutational analyses is performed. Personalizing patient s care is an intriguing challenge for oncologists, since the benefit conferred by anti-egfr moabs Fig. 1. PFS and OS curves. (A) PFS in all patients. (B) OS in all patients. (C) PFS according to KRAS mutational status. (D) OS according to KRAS mutational status. (E) PFS according to BRAF mutational status. (F) OS according to BRAF mutational status. (G) PFS according to KRAS and BRAF mutational status. (H) OS according to KRAS and BRAF mutational status. n, number; pts, patients; wt, wild-type; mut, mutated.

6 248 L. Fornaro et al. / Critical Reviews in Oncology/Hematology 78 (2011) is restricted to a subset of cases only, while the majority of treated patients is nevertheless exposed to potentially severe adverse events. In agreement with literature data, 44% of the tested specimens in our series harbored a KRAS mutation, which is confirmed as predictive of resistance to cetuximab treatment: only one mutated patient achieved an objective response and median PFS reported in the mutated subgroup was significantly shorter compared to that reported in wildtype patients. Recently published data have demonstrated that BRAF V600E mutation is a strong negative prognostic factor [28,29] and seems to be associated with lack of benefit from anti- EGFR moabs in retrospective analyses on small series of mcrc patients receiving salvage treatment with these agents [24,25], bringing out the role of BRAF status as a promising candidate predictive factor. In line with previous reports, we identified the V600E mutation in 13% of analysed samples, all of which were KRAS wild-type. Presence of this mutation was associated with lack of response and predicted for worse median PFS. Of note, comparing KRAS and BRAF wild-type with KRAS or BRAF mutated patients, a subgroup with higher chances of benefit from treatment, both in terms of RR and PFS, can be identified. Due to the lack of a control arm and sample size limitations, our series cannot definitively clarify the negative predictive impact of BRAF mutation in mcrc patients receiving treatment with cetuximab, while its prognostic role appears to be confirmed by the poor OS results reported among BRAF mutated patients. However, in our opinion these and already reported retrospective data suggest that BRAF mutated patients should not be treated with anti-egfr agents and further stress the need for a definitive answer which should come from BRAF analysis in phase III trials comparing anti-egfr moabs and best supportive care. We are conscious that the retrospective nature of our analysis is a major limitation: even though the 70 years cut-off can be considered adequate to define elderly patients, our series is not fully representative of the elderly population. Obviously, a certain grade of selection occurred (as proved by the fact that 11 patients had received an intense chemotherapy regimen such as FOLFOXIRI in first-line) and the reported results are probably not valid for frail patients with multiple comorbidities. However, the majority (81%) of patients we analysed had 2 sites of disease and 50% had a deterioration of PS, suggesting that selected elderly patients (by means of a comprehensive multidisciplinary assessment) with significant tumor burden or cancer-related symptoms are not exposed to excessively increased risk of toxicities when treated with cetuximab. As regards efficacy, all patients had previously received irinotecan and most of them had been exposed to all the most active cytotoxics: even if heavily pretreated, these patients achieved RR and PFS results which compare well with those reported in the literature. Moreover, refining patient selection on the basis of molecular data (such as KRAS and BRAF mutational status), the therapeutic index of this agent can be further optimized. These data confirm that age per se should not be a deterrent to offer effective treatments such as anti-egfr moabs to mcrc patients. The magnitude of benefit appears in line with those achieved in younger patients and it can be reached at the price of acceptable toxicity, even though a reduced dose of irinotecan appears necessary. Combining the evaluation of BRAF V600E mutation to KRAS codon 12 and 13 mutations could help to refine patient selection. Therefore, personalized chemotherapy and targeted use of an anti-egfr agent can be a promising treatment strategy for selected elderly mcrc patients. Conflict of interest statement Authors have no financial and/or personal relationships to disclose. Reviewers Professor Hans-Joachim Schmoll, M.D. Ph.D., Martin- Luther-Universitat Halle-Wittenberg, Klinik U Poliklinik fur Innere Medizin Hematologie/Onkologie Halle (Saale), Ernst- Gruber Strasse 40, D Halle, Germany. Dr. Giordano Domenico Beretta, M.D., Ospedale Sant Orsola-Fatebenefratelli, Deparment of General Medicine, Brescia, Italy. Dr. Mario Scartozzi, M.D., AO Ospedali Riuniti, Università Politecnica delle Marche, Clinica di Oncologia Medica, via Conca, I Ancona, Italy. Acknowledgements We thank Michele Andreuccetti and Simona Giannace for data management and technical assistance. References [1] Merlin F, Prochilo T, Tondulli L, et al. Colorectal cancer treatment in elderly patients: an update on recent clinical studies. Clin Colorectal Cancer 2008;7: [2] Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin 2006;56: [3] Hutchins LF, Unger JM, Crowley JJ, et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999;341: [4] McKibbin T, Frei CR, Greene RE, et al. Disparities in the use of chemotherapy and monoclonal antibody therapy for elderly advanced colorectal cancer patients in the community oncology setting. Oncologist 2008;13: [5] Raftery L, Sanoff HK, Goldberg R. Colon cancer in older adults. Semin Oncol 2008;35: [6] Papamichael D, Audisio R, Horiot JC, et al. Treatment of the elderly colorectal cancer patient: SIOG expert recommendations. Ann Oncol 2009;20:5 16.

7 L. Fornaro et al. / Critical Reviews in Oncology/Hematology 78 (2011) [7] Repetto L, Fratino L, Audisio RA, et al. Comprehensive geriatric assessment adds information to ECOG performance status in elderly cancer patients: an Italian Group for Geriatric Oncology Study. J Clin Oncol 2002;20: [8] Chau I, Cunningham D. Treatment in advanced colorectal cancer: what, when and how? Br J Cancer 2009;100: [9] Köhne CH, Lenz HJ. Chemotherapy with targeted agents for the treatment of metastatic colorectal cancer. Oncologist 2009;14: [10] Kabbinavar FF, Hurwitz HI, Yi J, et al. Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: pooled analysis of cohorts of older patients from two randomized clinical trials. J Clin Oncol 2008;27: [11] Kozloff MF, Sugrue MM, Purdie DM, et al. Safety and effectiveness of bevacizumab (BV) and chemotherapy (CT) in elderly patients (pts) with metastatic colorectal cancer (mcrc): results from the BRiTE observational cohort study. J Clin Oncol 2008;26(May 20 Suppl.), abs [12] Van Cutsem E, Rivera F, Berry S, et al. Safety and efficacy of bevacizumab (BEV) and chemotherapy in elderly patients with metastatic colorectal cancer (mcrc): results from the BEAT observational cohort study. Eur J Cancer Suppl 2009;7(2), abs [13] Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan refractory colorectal cancer. N Engl J Med 2004;351: [14] Jonker DJ, O Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007;357: [15] Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. 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Cetuximab and capecitabine as first line treatment for elderly patients with metastatic colorectal cancer: preliminary results of TTD trial. Eur J Cancer Suppl 2009;7(2), abs [21] Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006;66: [22] Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359: [23] Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008;26: [24] Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008;26: [25] Loupakis F, Ruzzo A, Cremolini C, et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer 2009;101: [26] Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. EORTC, NCI USA, NCI Canada. J Natl Cancer Inst 2000;92: [27] Loupakis F, Pollina L, Stasi I, et al. PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol 2009;27: [28] Van Cutsem E, Lang I, Folprecht G, et al. Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer (mcrc): The influence of KRAS and BRAF biomarkers on outcome: updated data from the CRYSTAL trial Gastrointestinal Cancers Symposium, abs 281. [29] Bokemeyer C, Bondarenko I, Hartmann JT, et al. Biomarkers predictive for outcome in patients with metastatic colorectal cancer (mcrc) treated with first-line FOLFOX4 plus or minus cetuximab: updated data from the OPUS study Gastrointestinal Cancers Symposium, abs 428. Biographies Lorenzo Fornaro gained his medical degree from the University of Pisa in 2006 and completed specialist training in Medical Sciences at Sant Anna School of Advanced Studies in Pisa in Since 2007, he has been a fellow in Oncology at the Department of Oncology, University of Pisa, Italy. His major areas of interests lie in the fields of gastrointestinal oncology and translational research on the cytotoxic drugs and biologic agents used in colorectal cancer treatment. He is a member of the Associazione Italiana di Oncologia Medica (AIOM), the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO). Giacomo Giulio Baldi is a medical oncologist who received his medical degree in 2005 from the University of Florence. Dr. Baldi is currently working at the U.O. Oncologia 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Italy. He is a member of the Associazione Italiana di Oncologia Medica (AIOM), the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO). He is involved in the care of patients with gastrointestinal cancers and in clinical research in metastatic colorectal cancer treatment (particularly, in the multidisciplinary management of hepatic metastases) and neuroendocrine tumors. Gianxluca Masi is a medical oncologist who gained his medical degree from the University of Pisa in 1997 and completed specialty training in Oncology in From 2003 to 2009, he held the position of Deputy Head at the Department of Oncology Azienda USL 6 of Livorno, Italy. Since 2009, he has held the positions of Deputy Head at the Department of Oncology Azienda Ospedaliero-Universitaria Pisana, and Assistant Professor in Clinical Oncology at the University of Pisa, Italy. Dr. Masi has published about 50 papers in international and national journals, book chapters and abstracts of presentations for national and international conferences. The majority of papers involve experimental therapeutic agents, preclinical and clinical trials in gastrointestinal tumors.

8 250 L. Fornaro et al. / Critical Reviews in Oncology/Hematology 78 (2011) Giacomo Allegrini is a medical oncologist and a pharmacologist. He has received his medical degree and specialties at the University of Genoa and Pisa (Italy). He was trained in basic and clinical research on cancer also at the Brown University, Providence (RI), USA. He is involved in the care of patients with different kind of tumors and clinical research. In particularly, he is implicated in the development of genomics markers predictive of response to antiangiogenetic drugs. He has published more than 35 articles in peer-reviewed international scientific or medical journals or books. He has made several oral presentations at medical congresses. He is the director of the Division of Medical Oncology at the Pontedera s Hospital, Pisa (Italy). He is member of scientific or medical societies including the American Society of Clinical Oncology (ASCO). Fotios Loupakis is a medical oncologist who received his medical degree from the University of Pisa in 2003 and completed specialty training in Oncology in He attended the Master s program in clinical development of new drugs at the University of Pisa, and is currently a Ph.D. student at the University of Pisa. He holds the position of Deputy Head at the Department of Oncology Azienda Ospedaliero-Universitaria Pisana, Italy. His scientific activity is principally focused on pharmacology, translational and clinical research in gastrointestinal tumors, particularly in the field of targeted agents approved for colorectal cancer treatment. He is a member of the Associazione Italiana di Oncologia Medica (AIOM), the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO). Enrico Vasile is a medical oncologist who gained his medical degree from the University of Pisa in 2002 and completed his specialty training in Oncology in He attended the Master s program in clinical development of new drugs at the University of Pisa, and is currently a Ph.D. student at the University of Pisa, Italy. He holds the position of Deputy Head of the Department of Oncology Azienda Ospedaliero-Universitaria Pisana, Italy. His scientific activity focuses principally on pharmacology, translational and clinical research in pancreatic cancer and lung tumors. Samanta Cupini is a medical oncologist who received her medical degree from the University of Pisa in 2000 and completed specialty training in Oncology in Since 2008, she has held the position of Deputy Head at the Department of Oncology Azienda USL 6 of Livorno, Italy. Dr. Cupini has focused her activity in clinical trials in gastrointestinal tumors, with peculiar attention to the role of chemotherapy and new targeted agents in the multidisciplinary treatment of liver metastases from colorectal cancer. Irene Stasi gained her medical degree in 2006 from the University of Pisa. She has been a fellow in Oncology at the University of Pisa, Department of Oncology. Her work centers on the role of molecular factors as markers of the efficacy of anti-egfr agents in metastatic colorectal cancer. She is a member of the Associazione Italiana di Oncologia Medica (AIOM), the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO). Lisa Salvatore gained her medical degree in 2007 from the University of Pisa. Since 2008, she has been a fellow in Oncology at the Department of Oncology, University of Pisa, Italy. Her work focuses on clinical research in colorectal cancer and on the identification of markers that predict the efficacy of antiangiogenic agents in this setting. She is a member of the Associazione Italiana di Oncologia Medica (AIOM), the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO). Chiara Cremolini gained her medical degree in 2008 from the University of Pisa and completed specialist training in Medical Sciences at Sant Anna School of Advanced Studies in Pisa in Since 2009, she has been a fellow in Oncology at the Department of Oncology, University of Pisa, Italy. Her areas of interest focus on the identification of predictive markers of benefit and toxicities from biologic agents approved for the use in advance colorectal cancer. Bruno Vincenzi was born in Velletri on July 16th, He is a medical oncologist in the Medical Oncology Department of Campus Bio-Medico University of Rome. He is the author of about 180 papers published in international journals. He is actively involved in clinical and translational research. Current fields of investigation are addressed to the clinical and molecular aspects of solid tumors, to the study of angiogenesis in cancer and to the development of antiangiogenetic drugs. Moreover he is active in both clinical and translational study in soft tissue sarcoma, gastrointestinal cancer and bone metastases. Daniele Santini is a medical oncologist working at the Division of Medical Oncology, Campus Bio-Medico University of Rome, Italy. He teaches oncology and immunology and performs research activities at the Campus Bio-Medico University of Rome. He is the author of about 200 regular papers in international journals of clinical oncology, cancer research and molecular pathology. Current fields of investigation are addressed to the clinical and molecular aspects of gastrointestinal carcinomas (phases II and III studies, and predictive/prognostic molecular markers in gastrointestinal cancer), the study of angiogenesis in cancer and the pathophysiology and treatment of bone metastases. Giuseppe Tonini was born on August He is a medical oncologist and he acts as chief of the Division of Medical Oncology of the Campus Bio-Medico University in Rome. He teaches oncology to the students of this university. He is an active member of the American Society of Clinical Oncology (ASCO) and of the Associazione Italiana di Oncologia Medica (AIOM). He is conducting clinical research in the treatment of cancer and specifically lung and breast cancer for

9 L. Fornaro et al. / Critical Reviews in Oncology/Hematology 78 (2011) several years. To date, he has published about 220 full papers in international journals. Current fields of investigation: clinical and molecular aspects of solid cancer (gastrointestinal, lung and breast cancer), supportive care in cancer and angiogenesis. Francesco Graziano is a medical oncologist who received his medical degree at the University of Palermo, Italy. He was trained in clinical oncology at the University of Ancona, Italy. His current position is of senior oncologist at the Department of Onco-Hematology, Azienda Ospedaliera San Salvatore, Pesaro, Italy. His primary interest in cancer research is in translation investigations in gastrointestinal cancer. For this activity, he cooperates with the Department of Biomolecular Sciences, University of Urbino, Italy. Main fields of research are cancer pharmacogenetics and molecular predictive/prognostic marker in gastrointestinal cancer. He is member of the Associazione Italiana di Oncologia Medica (AIOM), the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO). He is author and co-author of more than 100 peerreviewed paper in referenced journals. Annamaria Ruzzo is a Ph.D. in Biochemical and Pharmacological methodologies. As a researcher she was first trained in genetics and molecular biology of inherited diseases and than in oncology and pharmacogenomics at the University of Urbino, Italy. Her research has been addressed mainly to the field of translational studies in colorectal and gastric cancer. She has published more than 48 papers in internationally referred journals. Emanuele Canestrari is a Ph.D. in Biochemical and Pharmacological methodologies. His post-doctoral interests are addressed to the field of pharmacogenomics and translational studies in gastrointestinal oncology. He has published more than 15 papers in internationally referred journals. Mauro Magnani, Ph.D., is full professor of Biochemistry at the University of Urbino, Italy. He had been visiting researcher at the University of Birmingham and Visiting Professor at the Department of Biology in Haifa, Israel. His interests are addressed to the development of new drug delivery and drug targeting systems, protein turnover ubiquitination and regulation of gene expression, mechanisms of drug resistance and drug toxicity and modulation of NF-kB and gene expression by oligonucleotide decoys. Moreover, he has conducted translational studies in oncology and pharmacogenomics in the field of colorectal and gastric cancer research. He has published three books and more than 350 papers in international journals and he is inventor in 9 patents. Alfredo Falcone gained his medical degree from the University of Pisa in 1984 and completed specialty training in Oncology at the University of Genoa in He was a fellow at the Roger Williams Cancer Center in Providence, RI, USA, and in the National Institute for Cancer Research in Genoa. Currently, he is Professor of Clinical Oncology at the University of Pisa and Head of the Department of Oncology Azienda Ospedaliero-Universitaria Pisana, Italy. Prof. Falcone is a member of the Associazione Italiana di Oncologia Medica (AIOM), the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) and has published over 300 publications in peer-reviewed international and national journals, book chapters and abstracts of presentations to international and national conferences. The majority of these papers relate to experimental therapeutics, pharmacology and clinical trials in gastrointestinal tumors.