First-line single-agent cetuximab in elderly patients with metastatic colorectal cancer. A phase II clinical and molecular study of the Spanish group for digestive tumor therapy (TTD)

Critical Reviews in Oncology/Hematology 77 (2011) 78–84

First-line single-agent cetuximab in elderly patients with metastatic colorectal cancer. A phase II clinical and molecular study of the Spanish group for digestive tumor therapy (TTD)夽 J. Sastre a,∗ , E. Aranda b , C. Grávalos c , B. Massutí d , M. Varella-Garcia e , F. Rivera f , G. Soler g , A. Carrato h , J.L. Manzano i , E. Díaz-Rubio a , M. Hidalgo j a

h

HC San Carlos, Madrid, Center affíliated to the Red Temática de Investigación Cooperativa (RD06/0020/0021), Instituto Carlos III, Spanish Ministry of Science and Innovation, Spain b Hospital Reina Sofía de Córdoba, Spain c Hospital 12 de Octubre de Madrid, Spain d Hospital General de Alicante, Spain e University of Colorado Cancer Center, Aurora, CO, USA f Hospital Marqués de Valdecilla, Santander, Spain g Instituto Catalán de Oncología, Barcelona, Spain Hospital General de Elche, Center affíliated to the Red Temática de Investigación Cooperativa (RD06/0020/0021), Instituto Carlos III, Spanish Ministry of Science and Innovation, Spain i Hospital German Trias I Pujol, Instituto Catalán de Oncología, Badalona, Spain j Centro Oncológico Clara Campal, Madrid, Spain Accepted 26 November 2009

Contents 1. 2.

3.

4.

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Patient selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Treatment schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Evaluations during the study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Evaluation of efficacy and toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Biological studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Treatment compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Activity and survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Molecular studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79 79 79 80 80 80 80 80 81 81 81 81 82 82 83 83 83 83 84 84

夽 The article was presented as Oral Presentation at 31st ESMO Congress, 29 September–3 October 2006 at Istanbul, Turkey and under abstract ID 33486 at ASCO 2007 Annual Meeting, 1–5 June 2007. ∗ Corresponding author at: Servicio de Oncología Médica, HC San Carlos, c/ Martín Lagos s/n, 28040 Madrid, Spain. Tel.: +34 91 330 35 46; fax: +34 91 330 35 44. E-mail address: [email protected] (J. Sastre).

1040-8428/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2009.11.005

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Abstract Purpose: To evaluate the efficacy and safety of first-line single-agent cetuximab in fit elderly patients with metastatic colorectal cancer, as well as potential molecular predictive factors for efficacy. Patients and methods: Patients aged 70 or older with metastatic CRC without criteria for frailty and no prior treatment for advanced disease were treated with single-agent cetuximab 400 mg/m2 followed by weekly 250 mg/m2 until disease progression or unacceptable toxicity. Results: Forty-one patients were included. Two patients achieved a complete response and 4 patients had a partial response for an overall response rate of 14.6%. Fifteen patients (36.6%) remained stable. Median time to progression was 2.9 months and median overall survival 11.1 months despite two-third of patients received chemotherapy at progression. Forty-five percent of EGFR gene copy number positive patients by FISH were progression-free at 12 weeks, in contrast with 12% of FISH negative patients (p = 0.04). Grade 3 skin toxicity was reported in 5 patients (12.2%). Hypersensitivity infusion reactions were not reported and there were no toxic deaths. Conclusion: Cetuximab is a safe monoclonal antibody with moderate activity in first-line metastatic colorectal cancer, but the present study does not support the use of cetuximab as single-agent in first-line fit elderly patients with metastatic CRC. © 2009 Elsevier Ireland Ltd. All rights reserved. Keywords: Cetuximab; Monotherapy; Elderly patients; Colorectal cancer; EGFR

1. Introduction Colorectal cancer (CRC) is one of the most common malignancies in the elderly population. In the European Union, 40% of patients diagnosed with CRC are older than 74 years, and its incidence is expected to increase in the future [1]. The best treatment option for elderly patients with metastatic colorectal cancer remains controversial, because they represent a minority in the clinical trials that defined the modern treatment of this disease [2]. The majority of trials specifically designed for elderly patients with advanced disease were phase II studies employing single-agent fluoropyrimidines or raltitrexed. The overall response rate (RR) in these studies ranged from 13 to 29% [3–5]. Several prospective studies with polychemotherapy have recently been conducted in fit elderly patients. Response rates of 35–36% were reported [6,7], which is consistent with pooled and subgroup analysis of elderly patients in studies that were not specifically designed for this group of patients, and suggest a similar benefit to younger patients treated with combination therapy [8,9]. Nevertheless, no phase III studies have been conducted to confirm the superiority of combination therapy over single-agent in terms of overall survival. In fact, the median survival results reported with polychemotherapy in prospective clinical trials (13.2–15.3 months) are only slightly higher than those achieved with monotherapy [6,7]. Some authors have indeed advocate that treatment of elderly patients should be decided by a comprehensive geriatric assessment and a risk-adapted individual therapy [10,11]. The lack of solid survival benefit of combined chemotherapy in this group of patients opens the opportunity to conduct single-agent studies with active drugs with close clinical and radiological monitoring. Cetuximab is a chimeric G1 immunoglobulin monoclonal antibody that targets the extracellular domain of epidermal growth factor receptor (EGFR). EGFR is commonly expressed in many human tumors including CRC, and is involved in signalling pathways affecting cell proliferation, differentiation and angiogenesis [12]. Single-agent cetuximab has been shown to be active in pretreated patients with

advanced colorectal cancer (CRC) (9–10.8% RR) [13,14]. In the cetuximab single-agent arm of the BOND study, a subgroup analysis suggested that the activity of cetuximab might be higher than the earlier it was introduced (data not published). Furthermore, RR was 15% for patients older than 65 years in second-line therapy (data not published) [14]. Other monoclonal antibody binding HER-family receptors such as trastuzumab, obtained 11.5% RR in pretreated breast cancer patients and its activity rose up to 26% in first-line [15]. Toxicity profile of cetuximab compares favourably with chemotherapy. Furthermore, biological studies have shown that patients with amplified EGFR derived higher benefit from these treatments opening the opportunity to patient selection [16]. Recently, it has become clear that cetuximab does not benefit patients with KRAS mutated tumors further supporting the notion that patient selection based on biological factors identifies a group of patients likely to benefit from these agents [17]. The objective of this phase II study was to determine the activity of single-agent cetuximab in the first-line treatment of patients with advanced CRC. Close clinical and radiological monitoring were mandatory with chemotherapy treatment for patients on disease progression. Blood and tumor tissue samples were collected to investigate predictive factors for efficacy of cetuximab treatment.

2. Materials and methods Local Ethics Committee approval was obtained before enrollment of any patient into the study, which was performed in accordance with the Declaration of Helsinki and its subsequent amendments as well as Good Clinical Practice Guidelines. Signed informed consent was obtained from all patients before study entry. 2.1. Patient selection Inclusion criteria included: signed informed consent; metastatic non-resectable colorectal adenocarcinoma his-

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tologically confirmed; age ≥ 70; positive tumor tissue immunohistochemistry for EGFR (substituted during the study by tumor tissue sample available for immunohistochemistry EGFR analysis); absence of previous treatment for advanced disease; at least one measurable lesion by WHO criteria; Karnofsky performance status 80–100; interval of more than 12 months after conclusion of adjuvant chemotherapy; life expectancy greater than 3 months; adequate bone marrow, renal and hepatic functions (neutrophils ≥ 1.5 × 109 /l, haemoglobin ≥ 9 g/dl, platelets ≥ 100 × 109 /l, total bilirubin < 1.5× upper limit of normal (ULN), AST and ALT ≤2.5 × ULN or 5 × ULN in the case of liver metastases and serum creatinine <1.5 × ULN. Exclusion criteria were: brain or leptomeningeal metastases; other malignancy except basal cell skin carcinoma or in situ carcinoma of the cervix; previous administration of anti-EGFR therapy; serious concomitant disease such as unstable heart disease, acute myocardial infarction in the last 12 months, uncontrolled active infection, severe neurologic or psychiatric disorders; presence of one or more criteria for “frailty”: (1) dependent for daily living activities; (2) presence of three or more comorbid conditions including congestive heart failure, other chronic heart disease, obstructive pulmonary disease, cerebrovascular disease, peripheral neuropathy, chronic renal failure, hypertension, diabetes, systemic vasculitis, and severe arthritis; and (3) presence of geriatric syndromes such as dementia, delirium in stressful situations, fecal or urinary incontinence in absence of infections, diuretic, laxatives or benign prostate hyperplasia, severe depression, frequent falls, spontaneous bone fractures, and neglected patients. 2.2. Treatment schedule Cetuximab was administered intravenously (iv) at an initial dose of 400 mg/m2 as a 2-h iv infusion followed by weekly iv 250 mg/m2 . Premedication with iv antihistaminic drug was mandatory. Cetuximab was maintained until disease progression, unacceptable toxicity or patient consent withdrawal. Cetuximab dose was reduced to 200 mg/m2 in the case of a 2nd episode of grade 3 cutaneous toxicity and 150 mg/m2 if repeated. Cetuximab was delayed until recovery to grade 0–1 toxicity was observed. 2.3. Evaluations during the study In the 14 days before the first infusion, patients underwent a clinical history and physical examination, Independent Daily Activities Katz Scale, comorbidity, blood counts, liver and renal function tests, CEA level and evaluation of prothrombine time and electrolytes. Abdominal CT scan together with chest-X-ray or chest-CT scan were performed within 28 days before treatment commencement. The study was designed with a close CT-scan monitoring every 6 weeks, in order to start with chemotherapy in the case of early radiological disease progression. As the patients

were clinically monitored weekly, the evidence of symptoms or signs of rapid disease progression constituted a criterion to stop cetuximab and initiate chemotherapy. During the period of treatment, blood counts and biochemical parameters were performed every 3 weeks, and CEA levels every 6 weeks for 6 months and thereafter every 3 months. 2.4. Evaluation of efficacy and toxicity Tumor response was evaluated by the investigators using the radiologic WHO criteria at 6-week interval for 6 months and thereafter every 3 months, until the disease progressed or the patient died. No independent radiological review committee was established. Patients were considered assessable for efficacy if they had received at least 6 weeks of treatment. All patients were included in the intent-to-treat analysis. Time to tumor progression and overall survival were calculated from the inclusion in the study until documentation of progression or death, respectively. Toxicity was evaluated weekly and graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. 2.5. Biological studies Genomic DNA was collected at baseline to determine the number of CA repeats in the intron 1 of the EGFR. Plasma levels of circulating EGFR were measured on day 0 and day 15. Pretreatment tumor samples were obtained and tested for expression of the EGFR and PTEN by immunohistochemistry. The EGFR gene copy number was assessed by FISH. The mutation status of KRAS was also determined. Detailed laboratory methods for these studies have been previously published [18–21]. Based on gene copy number, the patients were classified into two groups: (i) FISH+ patients with tumors having high level of polysomy (four or more copies of the gene in ≥40% of cells) or gene amplification and (ii) FISH− patients with tumors with no or low genomic gain (four or more copies of the gene in <40% of the cells) [22]. 2.6. Statistical analysis Primary end-point was RR assessment. Secondary objectives were safety profile, time to progression (TTP) and overall survival (OS). Survival was estimated using the Kaplan–Meier method. Sample size was calculated using the Simon’s optimal two-staged design to detect a minimum expected response rate of 15%. Patients were accrued in two stages. If no objectives responses were observed in the first 19 patients, a response rate ≥15% could be excluded at a level of significance of 95% and accrual would stop. If there were at least one complete or partial response, then a total of 40 patients would be included to validate the response rate more accurately. For the analysis of biomarkers, patients with objective response or stable disease at 12 weeks

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81

Table 1 Patient characteristics (n = 41). n (%) Median age (range)

76 (70–88)

Sex Men Women

24 (58.5) 17 (41.5)

Karnofsky 80 90 100

16 (39) 9 (22) 16 (39)

Prior chemotherapy Adjuvant chemotherapy Concurrent chemoradiation Number of metastatic locations 1 2 >2

9 (22) 1 (2.4) Fig. 1. Time to progression curve by Kaplan–Meier method. 29 (70.7) 10 (24.4) 2 (4.9)

were grouped together and considered as the clinical benefit group.

3. Results Table 1 summarizes the main characteristics of the 41 patients recruited in the study between February and October 2005. Median age was 76 years. Ten patients (24.4%) had previously received adjuvant or neoadjuvant chemotherapy. The most relevant concomitant comorbid conditions were vascular disorders, mainly hypertension (48.8%), metabolism abnormalities such as diabetes (46.3%), musculoskeletal and connective tissue disorders (17%) and ocular diseases (14.6%). 3.1. Treatment compliance Median duration of treatment with cetuximab was 57 days (range 1–309). In only 2 patients (4.8%), the dose of cetuximab had to be reduced due to toxicity. Administration was delayed because of cutaneous toxicity in 11 patients (26.8%). Median absolute and relative dose–intensity values of cetuximab were 245.5 mg/m2 /week and 100%, respectively.

3.3. Activity and survival All patients were included for efficacy assessment in an intent-to-treat analysis. Two patients achieved a complete response and 4 patients had a partial response for an overall response rate of 14.6% (95% CI 5.6–29.2%). Fifteen patients (36.6%) remained stable after treatment. A total disease control of 51.2% (95% CI 35.1–67.1%) was achieved. Four out of 15 patients (26.7%) who developed grade 2 or 3 acne-like rash responded, in contrast with 2 of 26 patients (7.7%) who did not experience cutaneous toxicity greater than grade 1. This difference, however, did not reach statistical significance (p = 0.163). Median time to progression was 2.9 months and median overall survival 11.1 months (Figs. 1 and 2). A subgroup of 9 patients was free of progression at 12 weeks. For this subgroup of patients, median time to progression was 8.3 months (Fig. 3). Twenty-seven of the 41 patients (65.9%) received chemotherapy (26) or radiotherapy (1) after progression on cetuximab. Single-agent capecitabine and irinotecan or oxaliplatin-based combinations were the most common regimens employed. Ten patients (24.3%) received more than one chemotherapy regimen.

3.2. Safety Different patterns of cutaneous toxicity such as acneiform rash or folliculitis constituted the most common adverse event and were observed in 29 patients (70.7%). Grade 3 skin toxicity was reported in 5 patients (12.2%). Other related adverse events were asthenia, diarrhea, nausea and anorexia that were serious (grade 3 or 4) in less than 5% of the patients. Serum levels of magnesium were not routinely measured. Hypersensitivity infusion reactions were not reported and there were no toxic deaths.

Fig. 2. Overall survival curve by Kaplan–Meier method.

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that time point. These differences are not statistically significant likely due to the small number of patients analyzed. The only patient with mutant KRAS who had not suffered disease progression at 12 weeks time point had a FISH+ tumor.

4. Discussion Cetuximab is an active monoclonal anti-EGFR antibody in patients previously treated with irinotecan-based chemotherapy. Overall RR is approximately 10% [13,14]. The response rate of 15% in the older than 65 years patient subgroup of the BOND study (data not published), and the previous experience with trastuzumab, with a reported RR in first-line metastatic breast cancer which was higher than double than in second-line [15], prompted us to test the activity and safety profile of first-line cetuximab in the subgroup of fit elderly patients with metastatic CRC. In our study, cetuximab has shown to be active with a RR of 14.6% that seems to be higher than in chemo-refractory patients, but not as high as we expected. Disappointing results have also recently been published with single-agent first-line cetuximab in unselected patients with metastatic colorectal cancer, achieving 10% RR [23]. In contrast, the TTP we observed in first-line with cetuximab has been double than that reported in irinotecanrefractory patients (2.9 months versus 1.4 months). These results raise question about the best end-point to evaluate the true contribution of the new biologic targeted therapies in CRC. Recently, two randomized studies in which single-agent anti-EGFR monoclonal antibodies were compared with best supportive care in chemotherapy-refractory patients, have shown an advantage in progression-free survival [24] and OS [25] for the treated group, and the RR were only 8% and 10% for cetuximab and panitumumab, respectively. Another interesting subject of research is how to improve efficacy by patient selection. EGFR analysis by immunohistochemistry does not seem to have predictive value for response [26]. Recently, KRAS status in tumor cells has been established as a useful predictive factor for response to cetuximab. Patients with mutant KRAS obtained 0% RR when treated with single-agent cetuximab in chemo-refractory patients [27]. Progression-free survival was significantly longer for patients with wild-type KRAS tumors compared with those with mutant KRAS. In contrast, EGFR increased gene copy number measured by fluores-

Fig. 3. Time to progression curve for the subgroup of patients free of progression at 12 weeks, by Kaplan–Meier method.

3.4. Molecular studies Baseline and day 15 plasma samples to determine circulating levels of the shed EGFR were obtained in 27 patients. The circulating levels of the EGFR shed domain were increased in all patients by day 15 compared to day 1 with an average increment of 31.2% (range 4.2–86.2). No differences in outcome, however, were observed as a function of variation in EGFR levels. Likewise, germline DNA was obtained in 28 patients to determine the number of CA repeats in the EGFR intron 1. No significant differences in outcome were observed as a function of this parameter (data not shown). Table 2 summarizes the results of the biomarker analysis. The number of EGFR copy numbers by FISH was determined in 36 patients. Eleven patients were FISH+. Forty-five percent of FISH+ patients were progression-free at 12 weeks including 3 patients with an objective response. In contrast, only 3 out of 25 FISH negative patients (12%) were progression-free at 12 weeks (p = 0.04). However, 2 patients with FISH− tumors responded, both wild-type KRAS. The median TTP in FISH+ patients was 147 days versus 77 days for FISH− patients (p = 0.03). PTEN status was determined in 30 patients and was low or absent in 24 patients. No differences were noted in RR or tumor progression as a function of PTEN levels. Twenty-three tumors had enough quality of DNA to sequence the KRAS. Five patients had mutant KRAS and 4 of them progressed at 12 weeks. In contrast, 7 of 18 patients with wild-type KRAS were progression-free at Table 2 Biomarker analysis. Best response

n

KRAS

EGFR copy number

PTEN expression

WT

Mutant

UK

Low

High

UK

Low

Normal

UK

PR or CR SD or PD

6 35

5 13

0 5

1 17

2 23

3 8

1 4

4 20

0 6

2 9

PF at 12 weeks PD at 12 weeks

9 32

7 11

1 4

1 17

3 22

5 6

1 4

5 19

1 5

3 8

CR: complete response; PR: partial response, SD: stable disease, PD: progressive disease; PF: progression-free; UK: unknown.

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cence in situ hybridization (FISH) has been suggested as a positive predictive factor for response and time to progression [28]. Nevertheless, some authors have pointed out the important heterogeneity of repeated measures of mean EGFR gene copy number by FISH, leading to potential misclassifications of FISH status in up to 38% of patients [29]. Our “window of opportunity” trial probably represents the best scenario to test a predictive factor for anti-EGFR therapy, since cancer cells were not previously exposed to chemotherapy and no cytotoxic agents were used in combination with the antiEGFR drug. The number of EGFR gene copies by FISH was determined in 36 of the 41 patients. Forty-five percent of FISH+ patients were progression-free at 12 weeks including 3 patients with objective response, while only 12% of FISH− patients were progression-free at 12 weeks. Unfortunately, tumor tissue for KRAS status was only available in 23 patients. Four out of 5 patients with mutant KRAS had progressed at 12 weeks. In contrast, 7 of 18 patients with wild-type KRAS were progression-free at 12 weeks. Both, EGFR copies by FISH and KRAS status results were available in 8 of the 9 patients who remained free of progression at 12 weeks. Seven out of 8 had wild-type KRAS and the only mutant KRAS was FISH+. Patients with KRAS mutated tumors who benefited from cetuximab therapy have already been reported, and all of them were FISH+ [30]. The authors pointed out the possibility that, in presence of an overexpressed target, occasionally tumor shrinkage could occur also in individuals harbouring the KRAS mutation. In our study, strong conclusions cannot be drawn due to the small sample size, but a clear tendency to worse results in KRAS mutant patients are consistent with the results reported by other authors. Other analyzed predictive factors such as PTEN expression, and number of CA repeats in the intron 1 of the EGFR did not predict response to cetuximab. All the results of our exploratory analysis on molecular predictive factors should be interpret with caution due to the small sample of this phase II study. From a clinical point of view, in accordance with the study reported by Pessino, cetuximab monotherapy should not be an alternative to chemotherapy in first-line for fit elderly patients with advanced colorectal cancer. Our trial was initiated in 2005 when few data had been reported about combination chemotherapy in elderly patients with metastatic colorectal cancer, and the data with single-agent therapy were in the range of that expected for cetuximab. Nowadays, several studies suggest that polychemotherapy may be as useful for elderly patients as for the younger population but no phase III studies have been reported confirming it. Toxicity was really mild, skin rash being the most relevant adverse event. In our trial, skin rash was a surrogate marker for activity as well as in other publications, but due to the small simple size and the low number of patients who responded, the difference did not reach statistical significance. Median overall survival in our study is in the range of that reported in other studies with single-agent chemotherapy in the elderly population. The inclusion of patients whose tumors had KRAS muta-

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tions, the absence of any chemotherapy in 34% of patients and the treatment with single-agent fluoropyrimidines in a substantial number of them may have contributed to the relative short median survival compared with historical data from phase II studies with irinotecan or oxaliplatin-based chemotherapy as first-line treatment. Many patients refused to receive chemotherapy and in other cases their physicians did not consider them as candidates for toxic approaches. In conclusion, cetuximab is a safe monoclonal antibody with moderate activity in first-line metastatic CRC, achieving a response rate of 14%. The present study does not support the use of cetuximab as single-agent in first-line fit elderly patients with metastatic CRC. KRAS mutations may be useful to identify those patients who will not respond to cetuximab, and perhaps FISH for EGFR might have predictive value for efficacy, but more studies with a bigger sample size are needed.

Conflicts of interest J. Sastre, E. Aranda, B. Massutí, E. Díaz-Rubio, consultant or advisory role Merck; F. Rivera, Research Funding Merck; C. Grávalos, M. Varella-Garcia, G. Soler, A. Carrato, J.L. Manzano, M. Hidalgo, no potential conflicts of interest.

Reviewers Claus Henning Koehne, Professor, Department of Oncology/Hematology, Städl. Klinikum Oldenburg GmbH, Dr.-Eden-Str. 10, D-26133 Oldenburg, Germany. Alberto Sobrero, Professor, Head, Medical Oncology Unit, University Hospital San Martino, Medical Oncology Department, Largo Benzi 10, I-16132 Genova, Italy.

Contributions Conception and design: J. Sastre, C. Grávalos, M. Hidalgo and E. Díaz-Rubio. Provision of study materials or patients: J. Sastre, E. Aranda, C. Grávalos, B. Massutí, M. VarellaGarcia, F. Rivera, G. Soler, A. Carrato, J.L. Manzano, E. Díaz-Rubio, M. Hidalgo. Collection and assembly of data: J. Sastre, E. Aranda, C. Grávalos, B. Massutí, M. VarellaGarcia, F. Rivera, G. Soler, A. Carrato, J.L. Manzano, E. Díaz-Rubio, M. Hidalgo. Data analysis and interpretation: J. Sastre and M. Hidalgo. Manuscript writing: J. Sastre and M. Hidalgo. Final approval of manuscript: J. Sastre, E. Aranda, C. Grávalos, B. Massutí, M. Varella-Garcia, F. Rivera, G. Soler, A. Carrato, J.L. Manzano, E. Díaz-Rubio, M. Hidalgo.

Acknowledgement Supported by the TTD, Madrid, Spain.

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Biography Dr. J. Sastre, Ph.D., is a medical oncology staff working at San Carlos. Hospital in Madrid. He earned a medical degree from the Faculty of Medicine of the Universidad Autónoma de Madrid. Dr. Sastre completed the Medical Oncology Speciality in the Universidad Complutense de Madrid where he obtained the Ph.D. degree by its contributions to the knowledge of cisplatin nephroprotective effect of glutathione. Now, he is an active member of the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD), leading and collaborating with research in Gastrointestinal Tumors, specially in the context of the elderly population. Dr. Sastre clinical activity is also focused in the treatment and research of Neuroendocrine tumors, being member of the European Neuroendocrine Tumor Society (ENETS) and the Spanish Group for Neuroendocrine Tumors (GETNE). He is a member of various professional organizations such as The Spanish Society of Medical Oncology (SEOM), Germinal Oncology Group (GG) and collaborates with several editorial boards for peer-reviewed journals. He has authored or coauthored numerous articles, book chapters and monographs on various aspects related to cancer diagnosis and treatment.