Annals of Oncology Advance Access originally published online on November 6, 2007
Annals of Oncology 2008 19(2):332-339; doi:10.1093/annonc/mdm452
gastrointestinal tumors |
A phase Ib dose-escalation study of erlotinib, capecitabine and oxaliplatin in metastatic colorectal cancer patients
1 University Hospital Gasthuisberg, Leuven, Belgium
2 Sydney Cancer Centre, Sydney, Australia
3 Institut Claudius Regaud, Toulouse, France
4 F. Hoffmann-La Roche, Nutley, NJ, USA
5 F. Hoffmann-La Roche Ltd, Basel, Switzerland
* Correspondence to: Prof. E. Van Cutsem, University Hospital Gasthuisberg, Herestraat 49, BE-3000 Leuven, Belgium. Tel: +32-16-34-42-25; Fax: +32-16-34-44-19; E-mail: eric.vancutsem{at}uz.kuleuven.ac.be
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Abstract |
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Background: Dysregulation of the epidermal growth factor receptor (HER1/EGFR) has been reported in colorectal cancer (CRC). Erlotinib is a potent inhibitor of HER1/EGFR-mediated signaling. This trial of patients with metastatic CRC (MCRC) examined the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of erlotinib in combination with capecitabine and oxaliplatin (XELOX), a regimen with established efficacy.
Patients and methods: Patients previously untreated or treated with one line of 5-fluorouracil and/or irinotecan received escalating oral doses of erlotinib (daily), capecitabine (days 1–14) and i.v. oxaliplatin (day 1 of a 21-day cycle).
Results: The first six patients in cohort 1 (erlotinib 100 mg/day, capecitabine 825 mg/m2 twice daily, oxaliplatin 130 mg/m2) had no dose-limiting toxicities (DLTs). In cohort 2 (capecitabine increased to 1000 mg/m2 twice daily), two of six patients had DLTs. When cohort 2 was expanded to 11 patients two further DLTs occurred, exceeding the definition of MTD. Cohort 1 was expanded to 12 patients, and no DLTs occurred. The most common adverse events (AEs) were diarrhea and rash. There was a trend for reduced capecitabine concentrations in the presence of erlotinib. While this was not statistically significant, the possibility of an interaction affecting capecitabine PK cannot be excluded. Antitumor activity was observed in both cohorts (one complete and four partial responses, and stable disease in 11 patients).
Conclusion: The MTD for this combination in MCRC is capecitabine 825 mg/m2 twice daily days 1–14, oxaliplatin 130 mg/m2 day 1 and erlotinib 100 mg/day of a 21-day cycle. The combination was well tolerated at the MTD, with no unexpected AEs. The use of this combination in MCRC warrants further investigation.
Key words: capecitabine, erlotinib, metastatic colorectal cancer, oxaliplatin, XELOX
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Colorectal cancer (CRC) is one of the most common forms of cancer, with approximately one million new cases of CRC reported worldwide in 2002 (9% of new cancer cases) and deaths estimated at more than half a million [1]. In patients with advanced (metastatic) disease, median survival when untreated is 6 months or less [2].
The treatment of metastatic CRC (MCRC) has evolved rapidly over the last 10 years to include combinations of agents such as capecitabine, oxaliplatin, irinotecan and/or bevacizumab [3–10] that are more convenient and effective [with respect to overall survival (OS)] than traditional therapies.
The third generation platinum analog, oxaliplatin (Eloxatin®) has demonstrated activity against a range of solid tumors, including colon carcinomas [11], and has been combined successfully with both infused/bolus 5-fluorouracil (5-FU)/LV and oral capecitabine in the treatment of MCRC. The combination of oxaliplatin and 5-FU/leucovorin (LV) (FOLFOX) significantly increased efficacy in the first-line, second-line and adjuvant settings [4, 12, 13].
Capecitabine (Xeloda®) is an oral fluoropyrimidine that generates 5-FU preferentially in tumor tissue compared with healthy tissue. In MCRC, capecitabine monotherapy has achieved significantly higher response rates than 5-FU/LV [3]. In phase III studies, combination therapy using capecitabine was highly effective, providing similar efficacy and improved safety compared with 5-FU-based combination therapy [6, 7]. Moreover, as the capecitabine plus oxaliplatin (XELOX) regimen requires only one clinic visit per 3-week cycle, this is a substantial advantage compared with 5-FU/LV regimens, in terms of convenience for patients and caregivers [14].
Importantly, XELOX represents a well-tolerated, active and simple chemotherapy backbone that can act as the starting point for incorporating other agents with novel mechanisms of action and specific molecular targets. One such therapeutic target is the epidermal growth factor receptor (HER1/EGFR). HER1/EGFR-activated signal transduction pathways regulate a variety of cellular processes [15] controlling tumor cell proliferation, apoptosis, angiogenesis and metastatic spread in many human epithelial cancers [15]. Overexpression of HER1/EGFR occurs in many tumor types [16], including colorectal carcinoma [17], and (in some cancers) confers a poor prognosis [16, 17]. Proof of concept for targeting HER1/EGFR in CRC has been demonstrated with cetuximab, a monoclonal antibody directed against the extracellular domain of the HER1/EGFR. Phase II studies indicated that cetuximab has antitumor activity in refractory CRC, either as a single agent or in combination with chemotherapy [18].
Erlotinib (Tarceva®) is a highly potent, orally active, reversible HER1/EGFR inhibitor. Preclinical studies provided encouraging evidence of antitumor activity in human xenograft models [19–21], and in phase I and II clinical trials, erlotinib demonstrated efficacy against a range of solid tumor types, including non-small-cell lung cancer (NSCLC) and head and neck cancer [22, 23], with more modest effects in ovarian, colorectal and metastatic breast cancer [24]. In a phase III trial in pancreatic cancer, erlotinib plus gemcitabine significantly prolonged OS compared with gemcitabine alone [25]. In a phase III trial in patients with relapsed NSCLC, single-agent erlotinib was superior to placebo in terms of overall and progression-free survival and quality of life measures [26, 27].
Erlotinib, capecitabine and oxaliplatin have different modes of action and there is little overlap between their toxicity profiles. Combining such agents could therefore lead to improved therapeutic strategies for patients with CRC. The current study was carried out to assess whether erlotinib can be used in combination with capecitabine and oxaliplatin in patients with MCRC. The primary objectives were to determine the maximum tolerated dose (MTD) of the triplet combination, and to evaluate the safety of this regimen. Other objectives were to determine the pharmacokinetics (PK) of erlotinib, capecitabine and oxaliplatin when used together, and to assess preliminary antitumor efficacy of the combination.
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patients
Patients with histologically confirmed MCRC, at least one measurable lesion according to the response evaluation criteria in solid tumors (RECIST) [30], Eastern Cooperative Oncology Group performance status zero to one,
18 years of age and a life expectancy 12 weeks were eligible for the trial. Patients could be chemotherapy naive or had one previous treatment with 5-FU and/or irinotecan for MCRC. Exclusion criteria included: prior chemotherapy/radiotherapy <4 weeks before trial entry (or adjuvant chemotherapy <6 months before), hypersensitivity to fluoropyrimidines, peripheral neuropathy with functional impairment, inadequate renal, hepatic, cardiopulmonary or hematologic function. All patients gave informed consent. The trial conformed to the latest version of the Declaration of Helsinki and the Guideline for Good Clinical Practice ICH Tripartite Guideline (January 1997), and/or local laws and regulations. The protocol and amendments were reviewed by independent Ethics Committees.
drugs
Erlotinib hydrochloride (25 mg, 100 mg and 125 mg tablets) and capecitabine (150 mg and 500 mg tablets) were supplied by F. Hoffmann-La Roche Limited; a standard, commercially available i.v. preparation of oxaliplatin was used. Each treatment cycle was 21 days (3 weeks). Figure 1 shows the dosing schedule during the first 42 days of the study.
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Low doses of erlotinib and capecitabine were used initially to minimize potential side-effects. The starting dose of capecitabine (825 mg/m2 twice daily) was just below the recommended dose (1000 mg/m2 twice daily) in combination with oxaliplatin [14, 28]. Similarly, the starting dose for erlotinib (100 mg/day) was less than the MTD (150 mg/day [29]).
No other tumor therapy was permitted. Hematopoietic growth factors were allowed to treat symptomatic neutropenia. Concomitant coumadin (warfarin) was strongly discouraged; if anticoagulation therapy was needed, heparin was recommended.
treatment schema
This phase Ib trial used an open-label, nonrandomized, dose-escalation design, conducted in three centers. At least six patients were to be enrolled sequentially into each of three dosage cohorts. The planned dose levels, dosing schedule and dose-escalation scheme are summarized in Figure 1. Patients received up to eight cycles (24 weeks) of combined treatment, and thereafter could remain on erlotinib until disease progression. Specified dose modifications and interruptions were permitted for management of particular adverse events (AEs).
dose-limiting toxicities and determination of MTD
Dose escalation was continued until more than a third of patients in any cohort had dose-limiting toxicities (DLTs) during the first two cycles, meaning that the dose had exceeded the MTD. Dose escalation was therefore stopped. The preceding cohort was then expanded to 12 patients to confirm tolerability (see Figure 1). Thus, the MTD was the dose immediately below that causing DLTs in more than a third of patients.
DLTs were: grade 4 neutropenia for >5 days, or febrile neutropenia (absolute neutrophil count <1.0 x 109/l and temperature 38.5°C); grade 4 thrombocytopenia (platelets 
25.0 x 109/l) or grade 3 thrombocytopenia with bleeding or requiring platelet transfusion; any non-hematologic toxicity grade 3 (except alopecia and inadequately treated nausea and diarrhea).
assessments
At screening (up to a month before the trial), informed consent, demographic information and full medical histories were obtained from all patients. For women of childbearing age, a negative pregnancy test was required. In the week before the start of treatment, and before each cycle of chemotherapy, patients had full clinical evaluations and laboratory tests (including blood chemistry and urinalysis). Hematology was assessed at baseline and weekly during treatment. A 12-lead electrocardiogram was carried out at baseline, at the start of cycle 2 and at completion of or withdrawal from, the trial.
Clinical and laboratory safety assessments were carried out weekly throughout the trial. The severity of AEs and abnormal laboratory parameters were rated using the National Cancer Institute–Common Toxicity Criteria (NCT-CTC), version 2.0. All patients who received at least one dose of the trial medication and a safety follow-up were included in the analysis.
tumor response
Assessments for the secondary endpoint of tumor response were carried out at baseline (up to a month before treatment began), and repeated every two cycles (6 weeks), or as required if progression was suspected. Responses were assessed and confirmed according to RECIST [30]. The best response achieved (from start of treatment until progression was identified) was evaluated. A complete response (CR) was defined as the disappearance of all target lesions (lasting for at least 4 weeks), and a partial response (PR) as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as a reference the baseline sum longest diameter.
PK analyses
Venous blood samples were obtained from the noninfusion arm on days 1 and 21 of cycle 1 and day 1 of cycle 2 (see Figure 1). Two milliliter, 3 ml or 5 ml blood samples (for PK assessment of capecitabine, erlotinib and oxaliplatin, respectively) were collected into tubes containing EDTA (capecitabine) or lithium heparin (erlotinib and oxaliplatin) and immediately placed on ice and processed within an hour. Plasma samples were prepared by centrifugation for 10 min at 4°C, and stored at –20°C or –70°C until analysis.
Measurements of erlotinib and the major metabolite OSI-420 were carried out with a validated, specific LC-MS/MS assay. Oxaliplatin (total and free platinum) was measured using an atomic absorption method (MDS Pharma Services Inc., St Laurent, Quebec, Canada). Capecitabine and its metabolites, 5-FU and 5'-DFUR, were measured using LC-MS/MS (Advion Biosciences Inc., Ithaca, NY).
Using a noncompartmental (model-independent) analysis, the following PK parameters were calculated from erlotinib and metabolite plasma concentration–time profiles on cycle 1, day 21 and cycle 2, day 1: area under the concentration–time curve (AUC0–12 h and AUC0–24 h), peak concentration (Cmax) and time to peak concentration (tmax). For free and total oxaliplatin, and for capecitabine and metabolites (5-FU and 5'-DFUR), the following parameters were calculated from the resulting plasma concentration–time profiles on day 1 of cycles 1 and 2: Cmax, tmax, AUC0–last and terminal half-life (t
). For each parameter, descriptive statistics were calculated (for erlotinib when given alone and with capecitabine plus oxaliplatin, and for capecitabine and oxaliplatin given in combination, with or without erlotinib).
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patient characteristics and treatment
From November 2002 to August 2003 a total of 23 patients were enrolled into the trial, 12 in cohort 1 and 11 in cohort 2. The baseline demographic and clinical characteristics of the patients are shown in Table 1. All tumors were adenocarcinomas.
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All patients completed at least one cycle of treatment; 10/12 of cohort 1 and 9/11 of cohort 2 completed at least two cycles of treatment. The median number of cycles received was seven for cohort 1 (range 3–12) and six for cohort 2 (range 1–17). Six patients in cohort 1 and three in cohort 2 received greater than or equal to eight cycles of combination therapy.
DLTs and determination of MTD
No DLTs were reported for the first six patients in cohort 1, so six patients were enrolled into cohort 2. Of these six, one experienced grade 3 diarrhea and grade 2 intolerable rash, hyperbilirubinemia and thrombocytopenia. A second patient had grade 3 diarrhea and rash. Five more patients were enrolled into cohort 2, and of these, two had DLTs (one grade 3 rash and one grade 4 diarrhea). In total, 4 of 11 patients in cohort 2 had DLTs, so the dosing regimen had exceeded the MTD. Dose escalation was stopped, and cohort 1 was expanded to 12 patients. There were no DLTs in the additional six patients, thus confirming the MTD as 100 mg/day erlotinib, 130 mg/m2 oxaliplatin on day 1 and 825 mg/m2 twice daily capecitabine on days 1–14 of a 21-day cycle.
safety and tolerability
Treatment related AEs are summarized in Table 2 (most were grade 1 or 2). One patient died, due to multiorgan failure, which was not considered treatment related. Two patients in cohort 1 withdrew due to AEs; one with Henoch-Schonlein purpura (possibly treatment related), and one with dysesthesia (probably treatment related) and obstruction (unrelated). In cohort 2, two patients withdrew due to AEs; one due to diarrhea (probably treatment related) and one due to intestinal ischemia (unrelated).
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PKs
The PK analysis was conducted for patients in cohorts 1 and 2. The results for the two cohorts were comparable; the data for cohort 1 are presented in full here. Figure 1 shows the sampling schedule in relation to the dosing schedule for the three drugs. Changes in the mean plasma concentrations over time are shown in Figure 2, and the derived PK parameters are shown in Table 3.
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Several patients had implausibly high erlotinib and OSI-420 concentrations at 24 h on cycle 2, day 1, indicating that samples had been taken after the erlotinib dose on cycle 2, day 2. The high concentrations at 24 h influenced the mean concentration time profiles for erlotinib and OSI-420. Because the time of erlotinib dosing on cycle 2, day 2 was not recorded, the sequence of dosing and blood sampling could not be confirmed. However, an additional PK parameter (AUC0–12 h) was calculated to account for this potential anomaly.
No marked differences were seen between the PK profile of erlotinib when patients were receiving erlotinib as monotherapy (cycle 1, day 21) compared with receiving concomitant capecitabine and oxaliplatin (cycle 2, day 1). Plasma concentrations of OSI-420 after combination therapy were also comparable to those observed after monotherapy. Although tmax for both erlotinib and OSI-420 was somewhat greater during combination treatment, given the large variability in tmax on cycle 2, day 1, the differences were not considered to be important (medians: 1.5 versus 1.98 h; no formal statistical tests carried out). Similarly, there were no notable differences between the PK profile of oxaliplatin when patients were receiving capecitabine and oxaliplatin alone (cycle 1, day 1) compared with receiving concomitant erlotinib (cycle 2, day 1).
Plasma concentrations and corresponding PK parameters for capecitabine and its metabolites 5-FU and 5'-DFUR were highly variable. In the presence of erlotinib, the mean Cmax for capecitabine was 
27% lower and mean AUC was 12% lower. To a lesser degree, reduced concentrations of 5-FU and 5'-DFUR were also noted when capecitabine and erlotinib were administered concurrently. A paired t-test carried out on capecitabine Cmax data (cycle 1, day 1; cycle 2, day 1) indicated that the difference in mean values was not statistically significant (P = 0.133). The high variability and the relatively small patient numbers in each group make it difficult to assess the clinical relevance of the differences observed between the PK profiles of capecitabine, 5-FU and 5'-DFUR when patients received capecitabine and oxaliplatin only (cycle 1, day 1) or with concomitant erlotinib (cycle 2, day 1).
Possible correlations between the level of erlotinib exposure and laboratory abnormalities (bilirubin/transaminases) or intensity of AEs (diarrhea and rash) were evaluated during the first three cycles. No relationships were found (data not shown).
tumor response
Ten patients in cohort 1 and eight in cohort 2 were assessable for assessment of tumor response. Table 4 summarizes the best response to treatment obtained in each cohort. The majority of patients had stable disease Standard deviation, (SD) (duration 7 weeks to >47 weeks), a PR (duration 9 weeks to >53 weeks) or a CR. Five second-line patients were assessable for response, two in cohort 1 (one PR, one SD) and three in cohort 2 (one PR, two SD). The remainder received the study drugs as first-line therapy.
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XELOX is an important new regimen for the treatment of CRC. The present results indicated that erlotinib may be usefully combined with the XELOX regimen in patients with MCRC.
The primary objective of this study was to determine the MTD for this combination of drugs (the dose immediately below that at which more than a third of patients had DLTs). Using this definition, the MTD was shown to be dose level 1 (erlotinib 100 mg/day, capecitabine 825 mg/m2 twice daily and oxaliplatin 130 mg/m2) (Figure 1). At the second dose level, DLTs (diarrhea and rash) were reported at a frequency precluding further escalation.
At the recommended dose, the triplet combination was well tolerated, and all AEs were mild to moderate, predictable and consistent with the known toxic effects of the component drugs. Three patients withdrew due to AEs (which may have been treatment related). Two other patients withdrew due to obstruction and intestinal ischemia. Although, in the investigators’ judgment, these events were not related to the use of the study drugs, a relationship cannot be excluded, as both patients also had diarrhea and one had vomiting. In previous phase Ib trials, erlotinib was well tolerated when given in combination with various chemotherapeutic drugs, including taxanes and platinum-derived compounds [31–33].
The most common treatment-related AEs were diarrhea, rash, nausea and neurotoxicity. As expected, the severity of AEs was greater at dose level 2. Rash and diarrhea are associated with HER1/EGFR inhibition [29], and both have been observed in trials of erlotinib monotherapy [26, 29] and combination therapy [24, 25], and other HER1/EGFR-targeted agents [34]. As diarrhea has also been reported with capecitabine [35], the starting doses of both drugs were lower than normally recommended. While the rate of diarrhea and rash meant that it was not possible to escalate to the MTD for erlotinib or the recommended dose for capecitabine, most reports of rash and diarrhea were only mild to moderate in severity. Previously, the tolerability of an oxaliplatin plus capecitabine ± bevacizumab regimen in patients with MCRC (TREE study) was found to improve when the capecitabine dose was reduced from 1000 mg/m2 to 825 mg/m2 twice daily [10]. Reports of nervous system disorders (paresthesia, dysesthesia, trismus, headache or polyneuropathy) with the combination were probably related to oxaliplatin. Neuropathy was observed in phase I/II trials with XELOX in patients with advanced CRC [14, 36].
No notable difference was observed between the PK profiles of erlotinib alone and in combination with capecitabine and oxaliplatin, indicating that there was no relevant interaction affecting erlotinib PK. The PK of oxaliplatin was also not affected by the presence of erlotinib. There was a trend for reduced capecitabine concentrations in the presence of erlotinib. Although this difference was not found to be statistically significant, peak values and AUC's for capecitabine (and, to a lesser extent, its two measured metabolites) were all somewhat lower in the presence of erlotinib. Thus, the possibility of an interaction effecting capecitabine PK cannot be excluded. There was no apparent relationship between erlotinib exposure and laboratory abnormalities or AEs (diarrhea and rash) during the first three cycles.
This trial provides preliminary evidence of the antitumor efficacy of the triple drug combination in patients with MCRC. Of the 18 assessable patients, 16 achieved either a PR or had SD as best response; only two had progressive disease. The overall response rate was 33% in cohort 1 and 25% in cohort 2. Other erlotinib-based regimens have shown promise in other tumor types, with advantages for OS recently demonstrated in phase III trials. In patients with pancreatic cancer, erlotinib plus gemcitabine significantly prolonged OS compared with gemcitabine alone [25]. Erlotinib monotherapy also improved overall- and progression-free survival (as well as quality of life) in patients with advanced NSCLC who had failed first- and second-line chemotherapy [26, 27].
Newer therapies, such as cetuximab and bevacizumab, are beginning to play a role in the treatment of CRC, and their integration with chemotherapy regimens is an area of intense research activity. Indeed, combination treatments using bevacizumab [8] or cetuximab [18] have demonstrated improved survival and response, respectively. In NSCLC, encouraging preliminary results have been reported for the combination of erlotinib and bevacizumab [37].
In the present study, addition of a targeted therapy, erlotinib, to the established chemotherapy regimen of XELOX achieved encouraging antitumor activity in patients with MCRC. The recommended dose, for use in further studies, is erlotinib 100 mg/day; oxaliplatin 130 mg/m2 on day 1 and capecitabine 825 mg/m2 twice daily on days 1–14 of a 21-day cycle. These results, although preliminary, confirm the feasibility of adding erlotinib to the XELOX regimen and are worthy of further investigation.
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F. Hoffmann-La Roche Ltd.
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The authors would like to thank M Simpson, of Gardiner-Caldwell Communications for his assistance in drafting the manuscript.
Received for publication July 24, 2007. Accepted for publication August 13, 2007.
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1. Ferlay J, Bray F, Pisani P, et al. GLOBOCAN 2002. In: Cancer Incidence, Mortality and Prevalence Worldwide. Version 2.0. IARC CancerBase No. 5 (2004) Lyon, France: IARC Press, http://www-depdb.iarc.fr/globocan2002.htm.
2. Ragnhammer P, Halfstroem L, Nygren P, et al. A systematic overview of chemotherapy effects in colorectal cancer. Acta Oncol (2001) 40:282–308.[Web of Science][Medline]
3. Van Cutsem E, Hoff P, Harper P, et al. Oral capecitabine versus intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised controlled trials. Br J Cancer (2004) 90:1190–1197.[CrossRef][Web of Science][Medline]
4. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol (2004) 22:23–30.
5. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med (2000) 343:905–914.
6. Sastre J, Massuti B, Tabernero JM, et al. Preliminary results of a randomized phase III trial of the TTD Group comparing capecitabine and oxaliplatin (CapeOx) vs. oxaliplatin and 5-fluorouracil in continuous infusion (5-FU CI) as first line treatment in advanced or metastatic colorectal cancer (CRC). Proc Am Soc Clin Oncol (2005) 23:252s. (Abstr 3524).
7. Arkenau H, Schmoll H, Kubicka S, et al. Infusional 5-fluorouracil/folinic acid plus oxaliplatin (FUFOX) versus capecitabine plus oxaliplatin (CAPOX) as first line treatment of metastatic colorectal cancer (MCRC): results of the safety and efficacy analysis. Proc Am Soc Clin Oncol (2005) 23:247s. (Abstr 3507).
8. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med (2004) 350:2335–2342.
9. Fernando N, Yu D, Morse M, et al. A phase II study of oxaliplatin, capecitabine and bevacizumab in the treatment of metastatic colorectal cancer. Proc Am Soc Clin Oncol (2005) 23:260s. (Abstr 3556).
10. Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin/fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC): final analysis of the TREE-Study. J Clin Oncol (2006) 24(Suppl):148s. (Abstr 3510).
11. O'Dwyer PJ, Johnson SW. Current status of oxaliplatin in colorectal cancer. Semin Oncol (2003) 30:S78–S87.
12. Simpson D, Dunn C, Curran M, Goa KL. Oxaliplatin: a review of its use in combination therapy for advanced metastatic colorectal cancer. Drugs (2003) 63:2127–2156.[CrossRef][Web of Science][Medline]
13. André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med (2004) 350:2343–2351.
14. Cassidy J, Tabernero J, Twelves C, et al. XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol (2004) 22:2084–2091.
15. Arteaga C. Targeting HER1/EGFR: a molecular approach to cancer therapy. Semin Oncol (2003) 30(3 Suppl 7):3–14.[Medline]
16. Nicholson R, Gee J, Harper M. EGFR and cancer prognosis. Eur J Cancer (2001) 37:S9–S15.[Web of Science][Medline]
17. Amador ML, Hidalgo M. Epidermal growth factor receptor as a therapeutic target for the treatment of colorectal cancer. Clin Colorectal Cancer (2004) 4:51–62.[Medline]
18. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med (2004) 351:337–345.
19. Kunkel MW, Hook KE, Howard CT, et al. Inhibition of the epidermal growth factor receptor tyrosine kinase by PD153035 in human A431 tumors in athymic nude mice. Invest New Drugs (1996) 13:295–302.[Web of Science][Medline]
20. Pollack VA, Savage DM, Baker DA, et al. Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinoma with CP 358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther (1999) 291:739–748.
21. Higgins B, Kolinsky K, Smith M, et al. Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small-cell lung cancer tumor xenograft models. Anticancer Drugs (2004) 15:503–512.[CrossRef][Medline]
22. Pérez-Soler R, Chachoua A, Hammond LA, et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol (2004) 22:3238–3247.
23. Soulieres D, Senzer NN, Vokes EE, et al. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol (2004) 22:77–85.
24. Tang PA, Tsao MS, Moore MJ. A review of erlotinib and its clinical use. Expert Opin Pharmacother (2006) 7:177–193.[CrossRef][Web of Science][Medline]
25. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical Trials Group [NCIC-CTG]. J Clin Oncol (2007) 25:1960–1966.
26. Shepherd FA, Pereira JR, Ciuleanu T, et al. Erlotinib in previously treated non-small cell lung cancer. N Engl J Med (2005) 353:123–132.
27. Bezjak A, Tu D, Seymour L, et al. Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol (2006) 24:3831–3837.
28. Díaz-Rubio E, Evans TR, Tabemero J, et al. Capecitabine (Xeloda) in combination with oxaliplatin: a phase I, dose-escalation study in patients with advanced or metastatic solid tumors. Ann Oncol (2002) 13:558–565.
29. Hidalgo M, Siu LL, Nemunaitis J, et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol (2001) 19:3267–3279.
30. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumours. J Natl Cancer Inst (2000) 92:205–216.
31. Jones R, Hanauske A, Díaz-Rubio E, et al. Final evaluation of Tarceva (erlotinib) in combination with FOLFOX4 in patients with solid tumors. Clin Cancer Res (2003) 9:6095s. (Abstr A108).
32. Prados MD, Lamborn KR, Chang S, et al. : Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. Neuro-oncol (2006) 8:67–78.
33. Trigo J, Baselga J, De Rosa F, et al. A phase Ib study of TarcevaTM plus capecitabine and docetaxel in metastatic breast cancer. Clin Cancer Res (2003) 9:6096s. (Abstr A74).
34. Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial—INTACT 2. J Clin Oncol (2004) 22:785–794.
35. Cassidy J, Twelves C, Van Cutsem E, et al. First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol (2002) 13:566–575.
36. Pfeiffer P, Hahn P, Jensen HA. Short-time infusion of oxaliplatin (Eloxatin) in combination with capecitabine (Xeloda) in patients with advanced colorectal cancer. Acta Oncol (2003) 42:832–836.[CrossRef][Web of Science][Medline]
37. Herbst RS, Johnson DH, Mininberg E, et al. Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. J Clin Oncol (2005) 23:2544–2555.
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