This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Van Cutsem, E. Search for Related Content PubMed PubMed Citation Articles by Van Cutsem, E.

Special Section on Colorectal Cancer

Challenges in the Use of Epidermal Growth Factor Receptor Inhibitors in Colorectal Cancer

Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium

Key Words. Epidermal growth factor receptor • Monoclonal antibody • Cetuximab • Panitumumab • Rash • Tyrosine kinase inhibitors

Correspondence: Eric Van Cutsem, M.D., Ph.D., Digestive Oncology Unit, University Hospital Gasthuisberg/Leuven, Herestraat 49, 3000 Leuven, Belgium. Telephone: +32 16 34 4218; Fax: +32 16 34 4419; e-mail: Eric.VanCutsem{at}uz.kuleuven.ac.be

Received November 14, 2005; accepted for publication August 18, 2006.

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Activity in Advanced Disease Ongoing Studies Challenges of Scheduling and... Patient Selection EGFR Tyrosine Kinase Inhibitors... Conclusion Disclosure of Potential... References

 
After completing this course, the reader will be able to:

1. Describe the activity of EGFR inhibitors in metastatic colorectal cancer.
   
2. Discuss planned studies.
   
3. Discuss adverse events of EGFR inhibitors.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Activity in Advanced Disease Ongoing Studies Challenges of Scheduling and... Patient Selection EGFR Tyrosine Kinase Inhibitors... Conclusion Disclosure of Potential... References

 
Novel targeted agents increase the therapeutic armamentarium in metastatic colorectal cancer (mCRC). Monoclonal antibodies against the epidermal growth factor receptor (EGFR) are active against EGFR-expressing mCRC that is refractory to irinotecan. EGFR monoclonal antibodies also have promise in less advanced stages of CRC. Cetuximab and panitumumab are clearly active agents. It has been shown that cetuximab is more active when administered in combination with irinotecan. Phase II studies also report promising activity when monoclonal antibodies against the EGFR are combined with classic chemotherapeutic regimens in the first-line treatment of mCRC. However, the best means of scheduling such agents and integrating them with each other and with chemotherapy have yet to be established. The management of toxicity (particularly rash) and finding appropriate means of selecting patients pose additional challenges. While the occurrence of rash is associated with greater likelihood of response, EGFR staining by immunohistochemistry at baseline is not. For reasons that are not yet clear, the tyrosine kinase inhibitors of EGFR seem less effective than their monoclonal antibody counterparts in the therapy of mCRC.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Activity in Advanced Disease Ongoing Studies Challenges of Scheduling and... Patient Selection EGFR Tyrosine Kinase Inhibitors... Conclusion Disclosure of Potential... References

 
Grothey et al. demonstrate that median overall survival (OS) in clinical trials correlates highly (p = .0008) with the percentage of patients who receive all three of the cytotoxic agents 5-fluorouracil (5-FU), oxaliplatin, and irinotecan in the course of their disease [1]. When 80%–90% of patients have had all three drugs, a median OS of more than 20 months can be expected. It is reasonable to suggest (and indeed there is already preliminary evidence) that this relationship will continue to hold with the incorporation into therapy of agents targeted against epidermal and vascular endothelial growth factors or their receptors.

	ACTIVITY IN ADVANCED DISEASE

Top Learning Objectives Abstract Introduction Activity in Advanced Disease Ongoing Studies Challenges of Scheduling and... Patient Selection EGFR Tyrosine Kinase Inhibitors... Conclusion Disclosure of Potential... References

 
In Chemoresistant Disease
The activity of epidermal growth factor receptor (EGFR) inhibitors, particularly the monoclonal antibodies (MoABs), has been established in patients with chemore-fractory colorectal cancer (CRC). Figure 1 shows a simplified mechanism of action of the MoABs and tyrosine kinase inhibition of EGFR [2–5].

View larger version (24K): [in this window] [in a new window]   Figure 1. Anti-EGFR therapies [2–5]. Abbreviations: EGFR, epidermal growth factor receptor; K, kinase; R, receptor.

The consistent RR of 10% (or slightly greater) and the 30%–40% rate of SD achieved by EGFR inhibitors in these refractory patients are impressive.

The original work by Saltz et al. justified the BOND study, a large (329 patients) randomized phase II study of cetuximab plus irinotecan (218 patients) versus cetuximab alone (111 patients) in irinotecan-refractory CRC [10]. The RR with the combination was significantly higher, i.e., 23% versus 11% with cetuximab alone (p = .007), and the disease control rates were 56% versus 32%, respectively. The median time to progression (TTP) was also significantly greater for the combination arm (4.1 vs. 1.5 months, p < .001), and the median survival time was 8.6 months for cetuximab plus irinotecan and 6.9 months in the cetuximab arm (p = .48). The combination arm had more frequent adverse events, but the severity and incidence were similar to those anticipated with irinotecan alone.

A large phase III trial (study 408) has randomized almost 500 patients with oxaliplatin- and irinotecan-refractory EGFR-expressing metastatic CRC (mCRC) between Best Supportive Care (BSC) and BSC plus panitumumab. The aim of this pivotal trial is to show a significant difference in PFS. The results will be reported in 2006.

First-Line Therapy
In first-line therapy, there are only relatively small phase II studies, but data from five trials (none yet published in full) suggest promising activity when cetuximab is combined with either irinotecan- or oxaliplatin-based chemotherapy (Table 1) [11–15].

Turning to oxaliplatin-containing regimens, Van Cut-sem et al. found an 81% RR (74% confirmed responses) in 42 patients given cetuximab with oxaliplatin/5-FU/leucovorin (FOLFOX) in the ACROBAT study [14]. Of these patients, 23% subsequently had their liver metastases resected. Hoehler et al. reported a 55% RR and SD rate of 24% in 38 patients given cetuximab plus 5-fluorouracil/leucovorin/oxaliplatin (FUFOX) [15].

There are also data showing good activity first line when panitumumab (ABX-EGF) is added to IFL (Table 2) [16]. Of 19 patients, 47% had an RR and disease was stable in 32% [16]. As with the other studies cited, the rate of early disease progression, which happened in only one patient in this small trial, was low. All patients who responded to the panitumumab combination developed a skin rash.

There is therefore good preclinical rationale for the BOND2 study of cetuximab plus bevacizumab with or without irinotecan in irinotecan-refractory CRC patients not tested for the presence of the EGFR [10, 19, 20]. In a randomized phase II study, irinotecan-refractory CRC patients received irinotecan (same dose and schedule as per their last treatment administration prior to study) plus cetuximab (400 mg/m² loading dose, then weekly at 250 mg/m²) plus bevacizumab (5 mg/kg given every other week) versus cetuximab (400 mg/m² loading dose, then weekly at 250 mg/m²) plus bevacizumab (5 mg/kg given every other week) [19]. Use of the two antibodies plus irinotecan (n = 41) is associated with a 37% RR and 7.9-month TTP, compared with an RR of 20% and 5.6-month TTP in patients treated with cetuximab plus bevacizumab alone (n = 40). In the BOND study, the cetuximab/irinotecan arm achieved an RR of 23% and the TTP was 4.1 months, while the cetuximab alone arm had an RR of 11% and a TTP of 1.5 months [10]. In the Saltz et al. study [19], no unexpected toxicities were encountered. Grade 3 rash and grade 2 rash were observed in 7 (17%) and 25 patients (60%), respectively, on the cetuximab/bevacizumab/irinotecan arm and in 8 (20%) and 26 patients (65%), respectively, on the cetuximab/bevacizumab arm. Grade 3–4 diarrhea was observed in 24% of patients on the cetuximab/bevacizumab/irinotecan arm and 0% of patients on the cetuximab/bevacizumab arm. The combination of cetuximab/bevacizumab, alone or with irinotecan, appeared tolerable and active and warrants the investigation of this combination in front-line combination chemotherapy regimens.

	ONGOING STUDIES

Top Learning Objectives Abstract Introduction Activity in Advanced Disease Ongoing Studies Challenges of Scheduling and... Patient Selection EGFR Tyrosine Kinase Inhibitors... Conclusion Disclosure of Potential... References

 
The CRYSTAL study is a large multicenter study in which 1,212 patients with previously untreated mCRC that expresses EGFR have been randomized to FOLFIRI with or without the addition of cetuximab (Fig. 2). This should provide important information on the role of EGFR inhibition first line.

View larger version (34K): [in this window] [in a new window]   Figure 2. Phase III study of FOLFIRI ± cetuximab in metastatic CRC:CRYSTAL study design. Abbreviations: 5-FU, 5-fluorouracil; CRC, colorectal cancer; EGFR, epidermal growth factor receptor; FOLFIRI, irinotecan/5-fluorouracil/leucovorin; LV, leucovorin.

View larger version (19K): [in this window] [in a new window]   Figure 3. ‘COIN’ phase III study in first-line metastatic colorectal cancer: study design. Abbreviations: CT, chemotherpy; EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer.

View larger version (16K): [in this window] [in a new window]   Figure 4. Schema of the Cancer and Leukemia Group B 80405 phase III study in advanced CRC. Abbreviations: CRC, colorectal cancer; FOLFIRI, irinotecan/5-fluorouracil/leucovorin; FOLFOX, oxaliplatin/5-fluorouracil/leucovorin.

The BOS study of the European Organization for Research and Treatment of Cancer will randomize patients with resectable liver metastases of CRC preoperatively to FOLFOX4 plus cetuximab versus FOLFOX4 plus cetuximab and bevacizumab. The outcome of this trial should provide a basis for the strategy of developing a neoadjuvant and adjuvant treatment.

The CALGB has another strategically important trial. In this study, patients who have received FOLFOX or FOL-FIRI first line are being randomized to cetuximab alone, bevacizumab alone, or their combination (Fig. 4).

Studies in the adjuvant setting, and of novel agents combined with radiotherapy in rectal cancer, have also started, and many are being planned.

	CHALLENGES OF SCHEDULING AND TOXICITY

Top Learning Objectives Abstract Introduction Activity in Advanced Disease Ongoing Studies Challenges of Scheduling and... Patient Selection EGFR Tyrosine Kinase Inhibitors... Conclusion Disclosure of Potential... References

 
The optimal dose of EGFR inhibitors is not clear: in particular, we do not yet know whether the best option is to dose until the appearance of rash. The possibility of twice weekly, rather than once weekly, dosing needs to be explored with cetuximab.

The Incidence and Significance of Rash
Figure 5 shows a typical EGFR inhibitor–induced skin rash. The BOND study showed that the most frequent adverse events related to cetuximab are allergic reaction and skin toxicity [10]. However, cetuximab did not increase the incidence of those side effects typically seen with irinotecan.

View larger version (68K): [in this window] [in a new window]   Figure 5. Epidermal growth factor receptor (EGFR) inhibitor–induced rash [25].

The association between rash and efficacy is proving intriguing. Retrospective analysis of the BOND data showed a clear association between higher grades of skin reaction and RR and median TTP [10]. This was true also for OS, the median value rising from 3 months in patients with no rash to 14 months in those with rash of grade 3 severity. The same relationship was seen in the panitumumab study [9]. The association between rash severity and survival seems to hold true across the range of clinical trials of cetuximab in CRC, and indeed in the treatment of tumors at other disease sites (Fig. 6) [7, 10, 21–24]. Figure 7 describes severe EGFR inhibitor–induced skin reactions and provides therapy suggestions [25].

View larger version (28K): [in this window] [in a new window]   Figure 6. Correlation of rash and survival after treatment with cetuximab [7, 10, 21–24]. Abbreviations: CRC, colorectal cancer; SCCHN, squamous cell carcinoma of the head and neck.

View larger version (35K): [in this window] [in a new window]   Figure 7. Epidermal growth factor receptor (EGFR) inhibitor–induced skin reactions and therapy suggestions. (Picture kindly provided by S. Segaert.)

In this context, the current EVEREST study will provide food for thought. In the trial, patients with irinotecan-refractory EGFR-expressing CRC receive 3 weeks of classic treatment with cetuximab and irinotecan (Fig. 8). At 3 weeks, those who do not have grade 2 or greater rash are randomized to continue with the standard regimen or to a dose escalation of cetuximab until severe rash occurs. Serial skin and tumor biopsies for expression of EGFR and markers of downstream signaling should help elucidate the link between rash and antitumor activity.

View larger version (28K): [in this window] [in a new window]   Figure 8. Dose escalation until rash: EVEREST study. Abbreviations: EGFR, epidermal growth factor receptor; mCRC, meta-static colorectal cancer; PK, pharmacokinetics; RR, response rate; TTP, time to progression.

	PATIENT SELECTION

Top Learning Objectives Abstract Introduction Activity in Advanced Disease Ongoing Studies Challenges of Scheduling and... Patient Selection EGFR Tyrosine Kinase Inhibitors... Conclusion Disclosure of Potential... References

 
While EGFR expression is evident on immunohistochemistry in 70%–80% of CRCs, data from the BOND study show that intensity of staining does not correlate with RR [10]. The panitumumab study involved an initial cohort of patients who were EGFR ++ or EGFR +++ in 10% or more of evaluated cells, and a later cohort of patients with less intense staining. The two cohorts seem not to differ appreciably in rates of response or stable disease [9].

These findings may relate to the absence of a correlation between the EGFR status of the primary tumor and that of metastases [26]. More recently, Chung et al. have reported a 25% rate of response in 16 patients retrospectively identified as negative by immunohistochemistry for EGFR [27].

No one has yet established a marker that is genuinely valuable in predicting response to EGFR inhibitors in patients with CRC. For example, there appears to be no equivalent of the EGFR mutation that seems to mediate response to gefitinib in patients with lung cancer.

	EGFR TYROSINE KINASE INHIBITORS IN CRC

Top Learning Objectives Abstract Introduction Activity in Advanced Disease Ongoing Studies Challenges of Scheduling and... Patient Selection EGFR Tyrosine Kinase Inhibitors... Conclusion Disclosure of Potential... References

 
Compared with the anti-EGFR MoABs, the role of tyrosine kinase inhibitors of EGFR has not been extensively investigated in mCRC. However, it seems clear that gefitinib as a single agent is not active in chemorefractory CRC [28, 29]. In combination with FOLFOX, gefitinib does have a high RR (78% first line), but toxicity is also high, with grade 3–4 diarrhea occurring in 49% of patients [30]. The combination of erlotinib with capecitabine and oxaliplatin is more feasible but less active [31]; and FOLFOX plus the EGFR tyrosine kinase inhibitor EKB-569 also seems feasible [32].

	CONCLUSION

Top Learning Objectives Abstract Introduction Activity in Advanced Disease Ongoing Studies Challenges of Scheduling and... Patient Selection EGFR Tyrosine Kinase Inhibitors... Conclusion Disclosure of Potential... References

 
The novel targeted agents increase the therapeutic armamentarium in mCRC. The MoABs cetuximab and panitumumab against EGFR have proven activity against EGFR-expressing irinotecan-refractory mCRC. Furthermore, EGFR MoABs have promising activity in less advanced stages of CRC. Cetuximab and bevacizumab have appealing activity when combined.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Top Learning Objectives Abstract Introduction Activity in Advanced Disease Ongoing Studies Challenges of Scheduling and... Patient Selection EGFR Tyrosine Kinase Inhibitors... Conclusion Disclosure of Potential... References

 
The author indicates no potential conflicts of interest.

	REFERENCES

Top Learning Objectives Abstract Introduction Activity in Advanced Disease Ongoing Studies Challenges of Scheduling and... Patient Selection EGFR Tyrosine Kinase Inhibitors... Conclusion Disclosure of Potential... References

 

1. Grothey A, Sargent D, Goldberg RM et al. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004;22:1209–1214.[Abstract/Free Full Text]
2. Rini BI. VEGF-targeted therapy in metastatic renal cell carcinoma. The Oncologist 2005;10:191–197.[Abstract/Free Full Text]
3. Harari PM. Epidermal growth factor receptor inhibitor strategies in oncology. Endocr Relat Cancer 2004;11:689–708.[Abstract/Free Full Text]
4. Mendelsohn J, Baselga J. Status of epidermal growth factor antagonists in the biology and treatment of cancer. J Clin Oncol 2003;21:2787–2799.[Abstract/Free Full Text]
5. Wells A. Molecules in focus EGF receptor. Int J Biochem Cell Biol 1999;31:637–643.[CrossRef][Medline]
6. Saltz L, Kies M, Abbruzzese JL et al. The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies. Proc Am Soc Clin Oncol 2003;22:204. [Abstract 817].
7. 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.[Abstract/Free Full Text]
8. Lenz HJ, Mayer RJ, Gold PJ et al. Activity of cetuximab in patients with colorectal cancer refractory to both irinotecan and oxaliplatin. J Clin Oncol 2004;22(suppl 14):3510. [Abstract, ASCO Annual Meeting Proceedings (Post-Meeting Ed.)].
9. Hecht JR, Patnaik A, Malik I et al. ABX-EGF monotherapy in patients (pts) with metastatic colorectal cancer (mCRC): an updated analysis. J Clin Oncol 2004;22(suppl 14):3511. [Abstract, ASCO Annual Meeting Proceedings (Post-Meeting Ed.)].
10. 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.[Abstract/Free Full Text]
11. Rosenberg AH, Loehrer PJ, Needle MN et al. Erbitux (IMC-C225) plus weekly irinotecan (CPT-11), fluorouracil (5FU) and leucovorin (LV) in colorectal cancer (CRC) that expresses the epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol 2002;21:536a.
12. Folprecht G, Lutz M, Schoeffski P et al. Cetuximab/irinotecan/high-dose-5-fluorouracil/leucovorin (HD-5-FU/LV) in the first-line therapy of metastatic colorectal cancer (CRC). 2004 Gastrointestinal Cancers Symposium. 283a.
13. Rougier P, Raoul J-L, Van Laethem J-L et al. Cetuximab+FOLFIRI as first-line treatment for metastatic colorectal CA. J Clin Oncol 2004;22(suppl 14):3513. [Abstract. ASCO Annual Meeting Proceedings (Post-Meeting Ed.)].
14. Van Cutsem E, Tabernero J, Diaz-Rubio E et al. An international phase II study of cetuximab in combination with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FOLFOX-4) in the first-line treatment of patients with metastatic colorectal cancer (CRC) expressing Epidermal Growth Factor Receptor (EGFR). Ann Oncol 2004;15(suppl 3):iii91. 339a.
15. Höhler T, Dittrich C, Lordick F, et al. A phase I/II study of cetuximab in combination with 5-fluorouracil (5-FU)/folinic acid (FA) plus weekly oxaliplatin (L-OHP) (FUFOX) in the first-line treatment of patients with metastatic colorectal cancer (mCRC) expressing epidermal growth factor receptor (EGFR): preliminary results. Ann Oncol 2004; 15(suppl 3):2620a.
16. Berlin J, Malik I, Picus J et al. Panitumumab therapy with irinotecan, 5-fluorouracil, and leucovorin (IFL) in patients (pts) with metastatic colorectal cancer (mCRC). Ann Oncol 2004;15 suppl 3:Abstract 265PD.
17. Jung YD, Mansfield PF, Akagi M et al. Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model. Eur J Cancer 2002;38:1133–1140.[CrossRef][Medline]
18. Ciardiello F, Bianco R, Damiano V et al. Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res 2000;6:3739–3747.[Abstract/Free Full Text]
19. Saltz LB, Lenz H, Kindler H et al. Interim report of randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer. 2005 Gastrointestinal Cancers Symposium. Abstract 169b.
20. Saltz LB, Lenz H, Hochster H et al. Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer. 2005 ASCO Annual Meeting. 3508a.
21. Saltz L, Rubin M, Hochster H et al. Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol 2002;21:7a.
22. Xiong HQ, Rosenberg A, LoBuglio A et al. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II trial. J Clin Oncol 2004;22:2610–2616.[Abstract/Free Full Text]
23. Kies MS, Arquette MA, Nabell L et al. Final report of the efficacy and safety of the anti-epidermal growth factor antibody Erbitux (IMC-C225), in combination with cisplatin in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) refractory to cisplatin containing chemotherapy. Proc Am Soc Clin Oncol 2002;21:925a.
24. Van Cutsem E, Mayer R, Gold P et al. Correlation of acne rash and tumor response with cetuximab monotherapy in patients with colorectal cancer refractory to both irinotecan and oxaliplatin. Eur J Cancer 2004;(suppl 2):85–86. 279a.
25. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005;16:1425–1433.[Abstract/Free Full Text]
26. Scartozzi M, Bearzi I, Berardi R et al. Epidermal growth factor receptor (EGFR) status in primary colorectal tumors does not correlate with EGFR expression in related metastatic sites: implications for treatment with EGFR-targeted monoclonal antibodies. J Clin Oncol 2004;22:4772–4778.[Abstract/Free Full Text]
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.[Abstract/Free Full Text]
28. Mackenzie MJ, Hirte HW, Glenwood G et al. A phase II trial of ZD1839 (Iressa) 750 mg per day, an oral epidermal growth factor receptor-tyrosine kinase inhibitor, in patients with metastatic colorectal cancer. Invest New Drugs 2005;23:165–170.[CrossRef][Medline]
29. Rothenberg M, Lafleur B, Washington MK et al. Changes in epidermal growth factor receptor signaling in serum and tumor biopsies obtained from patients with progressive metastatic colorectal cancer (MCRC) treated with gefitinib (ZD1839): An Eastern Cooperative Oncology Group study. J Clin Oncol 2004;22(suppl 14):3000. [Abstract, ASCO Annual Meeting Proceedings (Post-Meeting Ed.)].
30. 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 2005;Jul 18:[Epub ahead of print].
31. Van Cutsem E, Beale P, Delord J et al. Tarceva (erlotinib) in combination with Xeloda and oxaliplatin in patients with metastatic colorectal cancer (CRC). A phase I dose escalation trial. Clin Cancer Res 2003;9:109a.
32. Tejpar S, Van Cutsem E, Gamelin E et al. Phase 1/2a study of EKB-569, an irreversible inhibitor of epidermal growth factor receptor, in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) in patients with advanced colorectal cancer (CRC). J Clin Oncol 2004;22(suppl 14):3579. [Abstract, ASCO Annual Meeting Proceedings (Post-Meeting Ed.)].

This article has been cited by other articles:

				R. M. Giusti, K. A. Shastri, M. H. Cohen, P. Keegan, and R. Pazdur FDA Drug Approval Summary: Panitumumab (VectibixTM) Oncologist, May 1, 2007; 12(5): 577 - 583. [Abstract] [Full Text] [PDF]

				P. G. Johnston The Colorectal Cancer Coalition: Reflections on the Future Oncologist, October 1, 2006; 11(9): 970 - 972. [Full Text] [PDF]

This Article Abstract Full Text (PDF) eLetters: Submit a response to this article Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Van Cutsem, E. Search for Related Content PubMed PubMed Citation Articles by Van Cutsem, E.