Annals of Oncology Advance Access originally published online on May 4, 2007
Annals of Oncology 2007 18(7):1185-1189; doi:10.1093/annonc/mdm124
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2007 European Society for Medical Oncology
gastrointestinal tumors |
Phase II study of FOLFOX, bevacizumab and erlotinib as first-line therapy for patients with metastastic colorectal cancer
1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2 Division of Medical Oncology, Beth-Israel Deaconess Medical Center, Boston, MA
3 Division of Medical Oncology, Massachusetts General Hospital, Boston, MA, USA
* Correspondence to: Dr J. A. Meyerhardt, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Tel: +1 617-632-6855; Fax: +1 617-632-5370; E-mail: jmeyerhardt{at}partners.org
 |
Abstract |
|---|
 Top Abstract introductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
Background: Targeting the epidermal growth factor receptor and angiogenesis have proven useful strategies against metastatic colorectal cancer. The benefit of combining inhibitors of both pathways is unknown.
Patients and methods: Patients with previously untreated metastatic colorectal cancer were enrolled in a phase II trial of infusional 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX), bevacizumab and erlotinib. The primary end point was progression-free survival.
Results: Thirty-five patients were enrolled and all came off trial for reasons other than progression; 18 (51%) had protocol-defined adverse events requiring removal, nine (26%) withdrew consent due to toxicity, six pursued surgery or localized therapies and two requested a treatment holiday. Principal toxic effects included rash, neuropathy and diarrhea. Seven patients came off trial before first restaging. By intention-to-treat analysis, one patient had a confirmed complete response, 10 had confirmed partial responses and one had an unconfirmed partial response (response rate = 34%). One patient had progressive disease at time of withdrawal from the trial, thus progression-free survival could not be calculated.
Conclusion: The combination of FOLFOX, bevacizumab and erlotinib led to higher than expected early withdrawal due to toxicity, limiting conclusions regarding efficacy. These findings raise concern regarding the tolerability of adding more agents to already complex combination regimens for metastatic colorectal cancer.
Key words: bevacizumab, colorectal cancer, erlotinib, FOLFOX
|
introduction |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
Colorectal cancer is the fourth most common malignancy and second most frequent cause of cancer-related death in the United States, with 153 760 new cases and 52 180 deaths anticipated in 2007 [1]. Nineteen percentage of patients with colorectal cancer have metastatic disease at the time of diagnosis [2] and
50% of patients who are initially diagnosed with localized disease ultimately develop metastases [3]. While there have been substantive advances in the treatment of metastatic colorectal cancer over the past 5 years [4], median survival for these patients remains <2 years and <8% survive for >5 years. New treatment strategies need to be explored. The last decade has led to the rapid introduction of multiple new cytotoxic and molecularly targeted therapies that are active against colorectal cancer. Increasingly, standard first-line chemotherapy for good performance status (PS) patients with metastatic disease include a fluoropyrimidine with either oxaliplatin or irinotecan and bevacizumab. These regimens appear to be equally efficacious. The benefit of adding other agents to these regimens has yet to be determined in randomized trials. Any potential benefit will also need to be weighed against the additional toxicity of adding therapies to already aggressive combinations of agents.
The epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target in a variety of human cancers [5]. In colorectal cancer, between 25% and 77% of tumors overexpress EGFR [6–8] and overexpression has been associated with a poorer prognosis [6, 8]. Monoclonal antibodies against EGFR have proven to be efficacious as monotherapy and in combination with chemotherapy in patients with metastatic disease [9–11]. While the oral inhibitors of the EGFR intracellular domain, such as erlotinib and gefitinib, do not appear to have measurable activity against metastatic colorectal cancer as single agents [12, 13], they may enhance the activity of combination chemotherapy [14–16]. Erlotinib is an attractive option for EGFR inhibition due to ease of administration and potentially decreased visits to the infusion unit. Furthermore, there may be potential synergistic activity when combining an anti-EGFR inhibitor with bevacizumab [17–20].
We therefore conducted a multicenter phase II study to assess the efficacy and toxicity of a combination of infusional 5-fluorouracil (5-FU), leucovorin, oxaliplatin, bevacizumab and erlotinib for the first-line treatment of patients with metastatic colorectal cancer.
|
patients and methods |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
patients
Patients were eligible if they had metastatic colorectal adenocarcinoma and had not received prior chemotherapy for metastatic disease. Patients who had recurred after adjuvant therapy were eligible if >12 months had elapsed between the date of the last dose of chemotherapy and the date of recurrence. Patients had to have measurable disease by Response Evaluation Criteria in Solid Tumors Group (RECIST) [21], an Eastern Cooperative Oncology Group PS of zero to two, and adequate hematological, hepatic and renal function. Patients could not have been previously treated with prior oxaliplatin, irinotecan, an EGFR inhibitor, or bevacizumab. Exclusion criteria included peripheral neuropathy of grade 2 or greater severity, major surgery within the past 4 weeks, uncontrolled serious medical or psychiatric illness, other malignancy within the past 5 years (except limited basal cell or squamous cell carcinoma of the skin or in situ cervix carcinoma), inadequately controlled hypertension (blood pressure >150/100 mmHg on antihypertensive medications), unstable angina, history of myocardial infarction or stroke within 6 months, clinically significant peripheral vascular disease, bleeding diathesis or coagulopathy, history of abdominal fistula or abscess within the past 6 months, history of gastrointestinal perforation, nonhealing wound or ulcer and lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome. Patients were accrued from three hospitals in Boston. The study was approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board. All patients signed informed consent.
treatment
Treatment cycles were repeated every 14 days. Erlotinib was administered orally at 150 mg per day continuously. On day 1 of each cycle, patients received i.v. bevacizumab 5 mg/kg (>90 min for the first dose, 60 min for the second dose and 30 min for each dose thereafter) followed by concurrent i.v. oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 >2 h followed by bolus 5-FU 400 mg/m2 and then initiation of 46-h infusion of 5-FU 2.4 g/m2 (modified FOLFOX-6).
All toxic effects were graded according to the National Cancer Institute (NCI)–Common Toxicity Criteria (CTC) version 3.0, except for neurotoxicity (which was graded based on an NCI-accepted grading and dose modification schema specific for oxaliplatin). Initiation of a cycle of cytotoxic chemotherapy required an absolute neutrophil count at least 1500/µl, platelets at least 75 000/µl and resolution of other toxic effects to at least CTC grade 1. Resolution of toxicity was required within 3 weeks of the intended start of a cycle or patients were withdrawn from the study. Bevacizumab could not be administered until toxic effects from 5-FU resolved to allowable levels. However, oxaliplatin could be held (with continuation of 5-FU, leucovorin and bevacizumab) for grade 3 neurotoxicity for up to 4 weeks from the first scheduled dose that was missed until resolution to grade 1 or better. Similarly, bevacizumab could be held for up to 4 weeks (with continuation of 5-FU, leucovorin and oxaliplatin) for grade 3 hemorrhage, grade 3 or asymptomatic grade 4 venous thrombosis and grade 3 proteinuria.
Erlotinib was held for up to 14 days for grade 3 or 4 skin toxic effects, grade 3 or 4 nausea, grade 3 vomiting, grade 2 or greater diarrhea and other unanticipated, drug-related side-effects. Erlotinib was restarted when toxic effects resolved to no greater than grade 1 (or skin toxicity was tolerable to patient). For rash, nausea, vomiting or grade 2 diarrhea, erlotinib could be resumed at the same dose, though a dose reduction was permitted at the clinician's discretion. For grade 3 or 4 diarrhea, a dose reduction was required. Erlotinib could be continued even if other medications required a treatment delay if side-effects were deemed not attributable to erlotinib. Erlotinib dose reductions were in 50 mg decrements, with the lowest dose being 50 mg daily.
Oxaliplatin and 5-FU dose reductions were required for grade 3 or 4 neutropenia, thrombocytopenia, or anemia; grade 2 or greater stomatitis (5-FU only) or grade 4 mucositis (5-FU and oxaliplatin); grade 3 or greater diarrhea (despite optimal antidiarrheal therapy); grade 3 (oxaliplatin only) or 4 nausea/emesis (5-FU and oxaliplatin) or other grade 3 or 4 toxic effects by NCI-CTC criteria. Oxaliplatin dose reductions were required for grade 2 neurotoxicity that persisted between cycles or grade 3 neurotoxicity.
Bevacizumab dose reductions were not permitted. However, bevacizumab could be held for resolution of grade 3 or asymptomatic grade 4 venous thrombosis, grade 3 proteinuria or grade 3 hemorrhage. Permanent discontinuation of study medications was required for grade 4 hypertension, hemorrhage or proteinuria; symptomatic grade 4 venous thrombosis or any wound dehiscence or gastrointestinal tract perforation.
Treatment was continued until development of progressive disease by RECIST, unacceptable toxicity, withdrawal of consent, intercurrent illness that prevented continuation of therapy, or changes in the patient's condition that rendered him or her unable to continue study drugs (as judged by the treating clinician).
evaluation
Baseline tumor measurements by computed tomography were obtained within 28 days before treatment was initiated. Physical examination, toxicity assessment and laboratory studies were conducted at the start of each 2-week cycle. Patients were asked to keep a diary of their self-administration of erlotinib as well as record daily side-effects.
Repeat imaging was required after three cycles (week 7) and every four cycles thereafter. Evaluation of response (at least 30% reduction in sum of longest diameters of target lesions), stable disease (less than 30% reduction and less than 20% increase in sum of longest diameters of target lesions) and disease progression was based on RECIST [21]. Confirmation scans for responders were carried out at least 4 weeks after the initial scan documenting the reduction.
statistical analysis
The primary end point of this study was to determine the progression-free survival (PFS) of the combination of bevacizumab, FOLFOX and erlotinib as first-line therapy for patients with metastatic colorectal cancer. Secondary objectives included assessment of response rate, median duration of response, overall survival (OS) as well as characterization of toxic effects.
Responses were determined by RECIST with an intention-to-treat analysis [21]. PFS was defined as the time between study enrollment and progression of disease or death while on protocol; patients who were withdrawn from the study for other reasons were censored at the discontinuation of study therapy. OS was defined as the time between study enrollment and death and estimated by the Kaplan–Meier method [22].
The original power calculations were based on a phase II single-stage design. As PFS was the primary objective, a landmark time point of 1 year PFS was utilized with the assumption that a true 1 year PFS of 50% or better would be considered promising, whereas <30% will not be of further interest. With a sample size of 35 patients, the probability of concluding the regimen promising was 0.84 if a true but unknown 12-month PFS rate was 50% and was 0.07 if a true but unknown 12-month PFS rate was 30%. If 15 of 35 eligible patients were alive and progression free at 12 months, the 90% exact binomial confidence interval (CI) would be 29%–58%. These probabilities were calculated based on an exact binomial distribution.
|
results |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
baseline characteristics
From January 2005 to March 2006, 35 patients were enrolled onto this study. For the entire cohort, patients completed a median of six cycles (defined as 2 weeks of therapy) with a range of 1–22 cycles. Primary analyses were based on intent-to-treat; thus, all 35 patients enrolled were included in efficacy and toxicity analyses. The baseline characteristics of the enrolled patients are shown in Table 1. The study cohort was composed of 60% males, had a median age of 58, and had an approximately even distribution of baseline PS of 0 and 1 patients. Eighty-six percentage of patients had not received prior adjuvant chemotherapy, thus the vast majority of the cohort was truly chemotherapy naive.
|
toxicity
While the primary objective of the trial was to study PFS, the toxic effects of the regimen limited any conclusions regarding efficacy. Seven patients came off trial before first restaging. Of these seven patients, four patients withdrew consent since they were uncomfortable with the toxic effects (one due to grade 3 rash, one due to hospitalization for febrile neutropenia but was eligible for dose reduction and resumption of protocol therapy, one due to grade 3 nausea and emesis, and one due to grade 2 taste disturbance and diarrhea). Two of the other three patients off trial within two cycles were removed for toxicity (microperforation in one patient and grade 3 diarrhea not resolved to grade 1 within 3 weeks) and one patient came off trial due to a Port-A-Cath thrombosis requiring removal of the device.
In total, 77% of patients came off trial either for protocol-defined toxicity reasons or for withdrawal of consent attributed to side-effects of the medications (Table 2). Six patients were removed from trial due to neurological toxic effects (one for ataxia and five for grade 3 peripheral neuropathy) after therapy for 6–17 cycles. Two patients had a small bowel obstruction after four and six cycles, both with at least grade 2 vomiting, diarrhea and dehydration.
|
Adverse events for the entire cohort are shown in Table 3. Eighty-three percentage of patients experienced treatment-related diarrhea (43% were grade 3 or 4). Nearly all patients developed a rash with 26% being classified as grade 3. Other prominent toxic effects included neuropathy, nausea and/or emesis, anorexia, fatigue and bone marrow suppression. No patients experienced an arterial embolic event. Eighty-six percentage of patients experienced at least one grade 3 or 4 toxicity.
|
Seventy-one percentage of patients required a dose reduction of one or more agents while on trial. Of the 10 patients who did not have a dose reduction, all but one came off trial for toxicity-related reasons (either protocol defined requiring removal or withdrawal of consent) after a median of two cycles (range 1–6 cycles); the remaining patients not dose reduced underwent resection of liver metastases after six cycles. A total of 19 patients (54% of entire cohort) required at least one dose reduction of erlotinib, of whom four required two dose reductions (initial dose 150 mg daily, dose level 1 was 100 mg daily and dose level 2 was 50 mg daily). Most reductions were due to diarrhea (48%) and/or dermatitis (39%). Eighteen patients (51%) required at least one dose reduction of oxaliplatin; seven required two or more reductions (initial dose 85 mg/m2, dose level 1 was 65 mg/m2, dose level 2 was 50 mg/m2 and dose level 3 was 40 mg/m2). The most common reasons for dose reductions of oxaliplatin were neutropenia (38%), diarrhea (29%), neuropathy (17%), fatigue (13%) and/or thrombocytopenia (4%). Fourteen patients (40%) required a dose reduction of 5-FU with six requiring at least two reductions. Dose reductions of 5-FU including both the bolus dose (initial dose 400 mg/m2, dose level 1 was 320 mg/m2, dose level 2 was 250 mg/m2 and dose level 3 was 200 mg/m2) and the 46-h continuous infusion (initial dose 2400 mg/m2, dose level 1 was 1920 mg/m2, dose level 2 was 1600 mg/m2 and dose level 3 was 1360 mg/m2). The most common reasons for dose reductions of 5-FU were neutropenia (42%), diarrhea (37%), fatigue (11%), stomatitis (5%) and/or thrombocytopenia (5%). Leucovorin and bevacizumab were not dose reduced and both were held if at least the 5-FU was held. Bevacizumab was held in two patients temporarily for wound healing and grade 1 hemorrhage.
efficacy
The primary end point for this study was PFS. No patients came off trial for progression of disease though one patient had documented progression 1 week after being removed for grade 3 neuropathy. Since the study did not specify to follow patients for progression after cessation of protocol therapy, neither median nor 1-year PFS could be calculated. By intention-to-treat analyses, one patient had a confirmed complete response, 10 had confirmed partial responses and 1 had an unconfirmed partial response (patient pursued resection of liver metastases and refused a confirmation scan). Thus, the overall response rate (including the unconfirmed partial response) was 34% (95% CI, 18%–50%). Median duration of response could not be calculated since no patient came off trial for progression of disease, however, following a response, patients were on trial for a median of 5 months (range 0.2–10 months). Ten patients received four cycles or less of therapy (<2 months). Of the remaining 25 patients that received at least 2 months of therapy, the response rate was 48% (95% CI, 27%–68%). The one patient who had a complete response initially had at least five measurable lesions in his liver (largest 3.5 cm in greater diameter) and continues to have no detectable disease nearly 1 year after discontinuing all chemotherapy.
The median follow-up for patients still alive is 14 months. Seven of the patients have died. Eighty percentage of the patients were alive at 1 year. Figure 1 demonstrates the OS of the cohort as of December 31, 2006. Median OS has not yet been reached.
|
|
discussion |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
In this multi-institution, phase II study of the combination of FOLFOX, bevacizumab and erlotinib as first-line therapy for patients with metastatic colorectal cancer, we observed an 86% grade 3/4 toxicity rate which led to a higher than anticipated drop-out rate before progressive disease. The toxic effects and drop-out rate limit any conclusions regarding the efficacy of the regimen. The response rate of 34% appears lower than anticipated with FOLFOX and bevacizumab alone [23]. Even after exclusion of patients that did not remain on trial for at least 2 months, a response rate of 48% does not appear appreciably different than such a regimen without erlotinib.
Targeting multiple pathways involved in cancer development and progression is an attractive clinical research model. For patients with colorectal cancer, bevacizumab has potentiated the efficacy of standard cytotoxic chemotherapies, though the exact mechanism is unknown [24, 25]. EGFR appears to play an important role in the progression of colorectal cancer, and inhibition of receptor activity has proven beneficial in some patients [9–11]. Combining these multiple strategies (traditional cytotoxic chemotherapies, antiangiogenesis and EGFR inhibitors) is a logical step in clinical investigations.
It is becoming increasingly clear that toxicity is the main drawback of these combination strategies. Spigel et al. [26] tested FOLFOX, bevacizumab and erlotinib in a cohort of 30 patients and also found higher than expected toxic effects leading to premature closure of their trial. Similarly, the DREAM-OPTIMOX3 study by the Groupe Cooperateur Multidisciplinaire en Oncologie was redesigned after pilot data indicated that combining oxaliplatin, bevacizumab, erlotinib and either capecitabine (XELOX) or infusional 5-FU was too toxic. Investigators were unable to deliver more than six cycles of combination chemotherapy, and patients are now receiving the combination of bevacizumab and erlotinib as maintenance after six cycles of either XELOX or FOLFOX and bevacizumab (Tournigand, personal communication).
It is unclear whether targeting the EGFR with monoclonal antibodies will be more tolerable. Cetuximab and panitumumab are monoclonal antibodies against EGFR that are active against metastatic colorectal cancer as monotherapy [9–11, 27] and cetuximab enhances the activity of irinotecan [9]. The Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) trial recently completed accrual. In this trial, patients were randomized to receive fluoropyrimdine, oxaliplatin and bevacizumab combination therapy with or without panitumumab. The CALGB/SWOG 80405 trial is continuing enrollment of patients treated with FOLFOX or infusional 5-FU, and leucovorin and irinotecan and randomized to either bevacizumab, cetuximab, or the combination of bevacizumab and cetuximab. Given the findings of this and other trials' attempt to add erlotinib to standard combination chemotherapy and bevacizumab, the results of the PACCE and CALGB/SWOG 80405 trials will need to be interpreted both from potential added efficacy, as well as the risks of added toxic effects.
The number of available chemotherapy regimens against metastatic colorectal cancer is rapidly growing. While the increasing options have clearly improved survival for patients with metastatic colorectal cancer [4], the combination and sequencing of agents remains to be understood. While adding more agents to existing regimens is attractive both in theory and in preclinical models, enthusiasm must be tempered by the need to conduct properly designed trials that truly balance efficacy with toxicity, resulting in both a prolongation in survival and maintenance of quality of life.
|
Acknowledgements |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
This work was supported by Sanofi-Synthelabo, a member of the Sanofi-Aventis group, and Genentech, Inc.
|
Footnotes |
|---|
Present address: Lahey Clinic, Burlington, MA, USA. 
Received for publication March 8, 2007. Accepted for publication March 13, 2007.
|
References |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
|---|
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin (2007) 57:436–446.
2. Ries L, Eisner M, Kosary C, et al. SEER cancer statistics review, 1975–2000. (2003) Bethesda, MD: Institute NC. http://seer.cancer.gov/csr/1975_2000/. (14 February 2007, date last accessed).
3. Midgley R, Kerr D. Conventional cytotoxic and novel therapeutic concepts in colorectal cancer. Expert Opin Investig Drugs (2001) 10:1011–1019.[CrossRef][Web of Science][Medline]
4. Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med (2005) 352:476–487.
5. Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol (2002) 20:1S–13S.[Web of Science][Medline]
6. Mayer A, Takimoto M, Fritz E, et al. The prognostic significance of proliferating cell nuclear antigen, epidermal growth factor receptor, and mdr gene expression in colorectal cancer. Cancer (1993) 71:2454–2460.[CrossRef][Web of Science][Medline]
7. Salomon DS, Brandt R, Ciardiello F, et al. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol (1995) 19:183–232.[Web of Science][Medline]
8. Hemming AW, Davis NL, Kluftinger A, et al. Prognostic markers of colorectal cancer: an evaluation of DNA content, epidermal growth factor receptor, and Ki-67. J Surg Oncol (1992) 51:147–152.[Web of Science][Medline]
9. Cunningham D, Humblet Y, Siena S, et al. Cetuximab (C225) alone or in combination with irinotecan (CPT-11) in patients with epidermal growth factor receptor (EGFR)-positive, irinotecan-refractory metastatic colorectal cancer (MCRC). N Engl J Med (2004) 351:337–345.
10. Hecht JR, Patnaik A, Malik I, et al. ABX-EGF monotherapy in patients (pts) with metastatic colorectal cancer (mCRC): an updated analysis. Proc Am Soc Clin Oncol (2004) 23:248.
11. Saltz LB, Meropol NJ, Loehrer PJ Sr, et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol (2004) 22:1201–1208.
12. Townsley C, Major P, Siu LL, et al. Phase II study of OSI-774 in patients with metastatic colorectal cancer. GI Cancer Symposium American Society of Clinical Oncology (2004).
13. Rothenberg ML, Lafleur B, Levy DE, et al. Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma. J Clin Oncol (2005) 23:9265–9274.
14. Cho CD, Fisher GA, Halsey J, et al. Phase I study of gefitinib, oxaliplatin, 5-fluorouracil, and leucovorin (IFOX) in patients with advanced solid malignancies. Invest New Drugs (2006) 24:117–123.[CrossRef][Web of Science][Medline]
15. Meyerhardt JA, Clark JW, Supko JG, et al. Phase I study of gefitinib, irinotecan, 5-fluorouracil and leucovorin in patients with metastatic colorectal cancer. Cancer Chemother Pharmacol (2007).
16. Meyerhardt JA, Zhu AX, Enzinger PC, et al. Phase II study of capecitabine, oxaliplatin, and erlotinib in previously treated patients with metastastic colorectal cancer. J Clin Oncol (2006) 24:1892–1897.
17. Bozec A, Fischel JL, Milano G. Epidermal growth factor receptor/angiogenesis dual targeting: preclinical experience. Curr Opin Oncol (2006) 18:330–334.[Web of Science][Medline]
18. Lindsey H. Bevacizumab and erlotinib show promise for kidney cancer. Lancet Oncol (2006) 7:15.[Web of Science][Medline]
19. Sandler A, Herbst R. Combining targeted agents: blocking the epidermal growth factor and vascular endothelial growth factor pathways. Clin Cancer Res (2006) 12:4421s–4425s.
20. Takeyama K, Jung B, Shim JJ, et al. Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke. Am J Physiol Lung Cell Mol Physiol (2001) 280:L165–L172.
21. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst (2000) 92:205–216.
22. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc (1958) 53:457–481.[CrossRef][Web of Science]
23. Hochster HS. Bevacizumab in combination with chemotherapy: first-line treatment of patients with metastatic colorectal cancer. Semin Oncol (2006) 33:S8–S14.[Web of Science][Medline]
24. 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.
25. Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol (2005) 23:3697–3705.
26. Spigel DR, Hainsworth JD, Burris HA, et al. Phase II study of FOLFOX4, bevacizumab, and erlotinib as first-line therapy in patients with advanced colorectal cancer. Gastrointestinal Cancers Symposium American Society of Clinical Oncology (2006) (Abstr 238).
27. Chung KY, Shia J, Kemeny NE, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol (2005) 23:1803–1810.
CiteULike 
Connotea 
Del.icio.us What's this?
Related articles in Ann Oncol:
- In this issue
Ann Oncol 2007 18: 1127.[Extract] [FREE Full Text]
This article has been cited by other articles:
|
|
 |
|
  A. Bozec, A. Sudaka, N. Toussan, J.-L. Fischel, M.-C. Etienne-Grimaldi, and G. Milano Combination of sunitinib, cetuximab and irradiation in an orthotopic head and neck cancer model Ann. Onc., June 19, 2009; (2009) mdp070v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Hecht, E. Mitchell, T. Chidiac, C. Scroggin, C. Hagenstad, D. Spigel, J. Marshall, A. Cohn, D. McCollum, P. Stella, et al. A Randomized Phase IIIB Trial of Chemotherapy, Bevacizumab, and Panitumumab Compared With Chemotherapy and Bevacizumab Alone for Metastatic Colorectal Cancer J. Clin. Oncol., February 10, 2009; 27(5): 672 - 680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Folprecht, J. Tabernero, C.-H. Kohne, C. Zacharchuk, L. Paz-Ares, F. Rojo, S. Quinn, E. Casado, R. Salazar, R. Abbas, et al. Phase I Pharmacokinetic/Pharmacodynamic Study of EKB-569, an Irreversible Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in Combination with Irinotecan, 5-Fluorouracil, and Leucovorin (FOLFIRI) in First-Line Treatment of Patients with Metastatic Colorectal Cancer Clin. Cancer Res., January 1, 2008; 14(1): 215 - 223. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||