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Journal of Clinical Oncology, Vol 24, No 4 (February 1), 2006: pp. 656-662 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.1749 Increased Toxicity With Gefitinib, Capecitabine, and Radiation Therapy in Pancreatic and Rectal Cancer: Phase I Trial ResultsFrom the Duke University Medical Center, Durham, NC Address reprint requests to Brian G. Czito, Department of Radiation Oncology, Box 3085, Duke University Medical Center, Durham, NC 27710; e-mail: czito001{at}mc.duke.edu
PURPOSE: Overexpression of epidermal growth factor receptor (EGFR) has been associated with aggressive tumor phenotypes, chemotherapy, and radiation resistance, as well as poor survival in preclinical and clinical models. The EGFR inhibitor gefitinib potentiates chemotherapy and radiation tumor cytotoxicity in preclinical models, including pancreatic and colorectal cancer. We initiated two phase I trials assessing the combination of gefitinib, capecitabine, and radiation in patients with localized pancreatic and rectal cancer. PATIENTS AND METHODS: Patients with pathologically confirmed adenocarcinoma of the pancreas and rectum were eligible. Pretreatment staging included computed tomography, endoscopic ultrasound, and surgical evaluation. Patients received 50.4 Gy of external-beam radiation therapy to the tumor in 28 fractions. Capecitabine and gefitinib were administered throughout the radiation course. Following completion, patients were restaged and considered for resection. Primary end points included determination of dose-limiting toxicity (DLT) and a phase II dose; secondary end points included determination of non-DLTs and preliminary radiographic and pathologic response rates. RESULTS: Ten patients were entered in the pancreatic study and six in the rectal study. DLT was seen in six of 10 patients in the pancreatic study and two of six patients in the rectal study. The primary DLT in both studies was diarrhea. Two patients developed arterial thrombi. CONCLUSION: The combination of gefitinib, capecitabine, and radiation in pancreatic and rectal cancer patients resulted in significant toxicity. A recommended phase II dose was not determined in either of our studies. Further investigation with this combination should be approached with caution.
The epidermal growth factor receptor (EGFR) is a transmembrane protein that, when activated, initiates intracellular signaling pathways leading to cell division, migration, and differentiation. EGFR overexpression has been observed in many human cancers, including pancreatic1 and colorectal carcinomas.2 Importantly, EGFR overexpression has been associated with more aggressive tumor phenotypes and poor prognosis.3-5 Additionally, radiation resistance has been observed in cancers exhibiting high levels of EGFR expression in vivo.6,7 Gefitinib (Iressa; AstraZeneca, Wilmington, DE) is a selective inhibitor of the EGFR tyrosine kinase. Preclinical studies in colorectal and pancreatic cancer have shown enhanced cytotoxicity by combining gefitinib with both radiation therapy and chemotherapy, including capecitabine.8-12 Clinically, EGFR inhibition has shown promise for the treatment of colorectal and pancreatic cancers, particularly in combination with chemotherapy.13-20 For patients with metastatic pancreatic cancer, the combination of gemcitabine plus erlotinib has shown a modest survival benefit compared with gemcitabine alone.21 In head and neck cancers, antibody EGFR inhibitors with radiation therapy have demonstrated significant improvements in local control and survival compared with radiation therapy alone.22 These and other clinical data support the rationale for assessing combinations of conventional chemotherapy agents and radiation therapy with EGFR inhibitors. For both rectal and pancreatic cancer, radiation therapy plus fluoropyrimidines provides improved local control and survival compared with radiation alone.23,24 Capecitabine (Xeloda; Hoffman-La Roche Inc, Nutley, NJ), an oral fluorouracil (FU) analog, has theoretical advantages as a radiosensitizer and has demonstrated activity as a radiosensitizer in rectal and pancreatic cancers.25-27 On the basis of the potential for gefitinib to augment the activity of both radiation and capecitabine and the need for more active, better-tolerated, and more convenient regimens, we hypothesized that the combination of gefitinib with radiation therapy plus capecitabine would be well-tolerated and potentially active. To address these questions, two concurrent phase I/II studies were initiated: one in locally advanced rectal cancer and the other in pancreatic cancer.
Both protocols were approved by the Duke University institutional review board (Durham, NC) and studies performed according to the Declaration of Helsinki as amended in Somerset West (1996). All patients provided written informed consent before trial entry.
Eligibility Criteria
Pretreatment Assessment
Radiotherapy
Chemotherapy
Adverse events assessment was performed at least weekly during the radiation course using the National Cancer Institute Common Toxicity Criteria (version 3.0). Adverse effects, including diarrhea, were managed aggressively with standard supportive measures. Dose modifications for grade 3/4 hematologic and nonhematologic toxicities related to radiation therapy, capecitabine, and gefitinib toxicities were in the protocol. For grade 3 diarrhea/nonhematologic toxicity, grade 3/4 hand-foot syndrome, and grade 4 neutropenia/thrombocytopenia, all treatment was held until resolution to grade 1 with the option of restarting all treatment with capecitabine at 75% of original dose; for grade 4 diarrhea/nonhematologic toxicity, all treatment was held until resolution to grade 1 with the option of restarting all treatment with capecitabine at 50% of original dose. There were no dose reductions for radiation or gefitinib.
Surgery/Histologic Review
Study Design, Definition, and End Points
DLT was defined as any of the following: grade 4 neutropenia, neutropenic fever/sepsis,
Sixteen patients were enrolled onto these two phase I studies between November 2003 and January 2005 (pancreatic cancer trial: 10 patients; rectal cancer trial: six patients). Patient characteristics are summarized in Table 1.
Dose Escalation and Toxicity Pancreatic cancer. Seven patients were enrolled at dose level 1 and three patients at dose level 2. Initially, three patients were enrolled at dose level 1 (gefitinib 250 mg/d, capecitabine 650 mg/m2/bid). After study entry and receiving 34.2 Gy, one patient withdrew in part because of grade 2 diarrhea, fatigue, and anorexia but without experiencing DLT. Therefore, one additional patient was accrued to complete this cohort. No DLT was observed in these three patients. Subsequently, three patients were enrolled on dose level 2. Of these, one patient experienced grade 3 nausea, vomiting, diarrhea, and dehydration during week 4 of treatment, requiring hospital admission. This patient was unable to complete therapy. Another patient developed grade 3 dehydration, requiring hospital admission, and completed radiation therapy without chemotherapy following a 10-day treatment interruption. The third patient, with a history of peripheral vascular disease, developed an arterial thrombus of the left external iliac, common femoral and distal superficial femoral artery during week 4 of treatment, requiring emergent femoral bypass and, ultimately, distal amputation. He completed his radiation course following a 4-week break. Since dose level 2 was associated with unacceptable toxicity, additional patients were accrued to dose level 1 to better define tolerability. In this expanded cohort, all three accrued patients experienced DLT. One patient developed grade 3 nausea, vomiting, dehydration, and anorexia during week 3 of treatment, requiring hospital admission. This patient was unable to complete treatment. The second patient experienced grade 3 diarrhea, requiring capecitabine dose modification (75% of original dose), such that less than 85% of the planned drug administration was completed (a protocol-defined DLT). The third patient suffered grade 4 diarrhea and grade 3 cardiac toxicity (syncope) during week 4 of treatment and was admitted with complaints of dizziness, nausea, and diarrhea. Repeat abdominal CT revealed diffuse small bowel dilation with potential obstruction. At laparotomy, no significant findings (bowel obstruction or ischemia) were observed and the patient recovered uneventfully. This patient was unable to complete his radiation course. Table 2 lists cumulative incidence of toxicities for this study. In both studies, DLTs occurred despite optimal medical management.
No patient received adjuvant gefitinib-based chemotherapy following completion of radiation therapy and/or surgery. Further dose de-escalation was not pursued for gefitinib since this agent was not available in tablet sizes smaller than 250 mg; capecitabine was not de-escalated because of theoretical concerns for efficacy at doses lower than 650 mg/m2 bid. Rectal cancer. Six patients were enrolled at dose level 1. Two patients with locally recurrent disease had previously received adjuvant FU/leucovorin chemotherapy 1 and 4 years prior, respectively. Three patients were enrolled initially. One patient required hydration and later hospital admission for medication-refractory grade 4 diarrhea (DLT) week 4 of treatment. He completed radiation treatments without chemotherapy following a 2-week treatment interruption. Two other patients experienced grade 1/2 diarrhea but did not reach DLT. Three additional patients were enrolled at dose level 1. One patient developed progressive pain in the left leg/foot during week 3 of treatment. Arteriogram demonstrated thrombosis of the left superficial femoral artery, requiring tissue plasminogen activating factor, heparin, angioplasty, and stent therapy. This event was conservatively attributed to study treatment. Despite clinical improvement, the patient subsequently developed tachycardia and tachypnea, with chest radiograph demonstrating an infiltrate. His clinical condition deteriorated and he expired. Autopsy demonstrated pulmonary findings suggestive of aspiration pneumonia and residual rectal adenocarcinoma with multiple subclinical liver metastases. Two other patients experienced grade 1/2 diarrhea. Accrual to dose level 1 was halted because of DLT and lower dose levels were not explored as in the pancreatic cancer study. Safety data for both studies are listed in Table 2.
Efficacy Measures
Rectal cancer. Five patients were assessable for efficacy (details in all patients are presented in Table 4). One patient developed multiple hepatic metastases. Laparotomy was undertaken in four patients. One patient treated for a local recurrence underwent repeat low anterior resection (R0) with coloanal anastomosis; the other patient underwent R2 (gross residual) resection with end colostomy. Both patients had gross residual disease without nodal involvement in the surgical specimen. Both patients with primary cancer underwent R0 resection (one, abdominoperineal resection; one, low anterior resection). In the surgical specimens, gross residual disease without nodal involvement was observed.
While combined modality toxicity delayed surgery from 2 to 4 weeks in two of nine patients across both studies, no patient was deemed medically inoperable as a result of complications of chemoradiotherapy. No wound healing or perioperative complications were attributed to combined modality treatment in either study.
Radiation therapy with FU-based chemotherapy results in improved local control and survival rates in many gastrointestinal malignancies as well as providing palliation in noncurative cases.23,24,28 In addition to clinical activity for several cancers (colorectal, breast, gastric), capecitabine is active as a radiosensitizer for pancreatic and rectal cancers.25,26,29 Our studies attempted to build on this platform by assessing an all-oral regimen combining both a fluoropyrimidine and an EGFR inhibitor. EGFR inhibitors have strong preclinical rational as potent chemosensitizers and radiosensitizers.30 When combined with chemotherapy, EGFR inhibition has also been shown to confer clinical benefit in colorectal cancer13 and in pancreatic cancer.21 Phase III data in head and neck cancer with radiation and cetuximab have confirmed that EGFR inhibitors are clinically active radiosensitizers.22 However, the efficacy and tolerability of radiation plus EGFR inhibition has not yet been confirmed in gastrointestinal cancers, where tumor sensitivity and local tissue tolerances may differ. In both of our studies, DLT was reached with gefitinib doses of 250 mg/d despite dose reduction of capecitabine to 650 mg/m2/bid when given during the course of radiation. Others have reported that capecitabine is well-tolerated in combination with radiation at doses of 800 mg/m2 to 1,000 mg/m2/bid on 5- and 7-day per week schedules in both rectal25,29,31 and pancreatic cancers.26 Our results suggest the addition of gefitinib to neoadjuvant therapy with capecitabine and radiation results in significant enhancement of this regimen's toxicity. The predominant toxicity observed in our studies was diarrhea, a known toxicity for gefitinib, capecitabine, and radiation. Similar toxicity has been observed with gefitinib and other small molecule EGFR inhibitors given in combination with FU/capecitabine-based chemotherapy without radiation in metastatic colorectal cancer patients.14,20,32,33 The finding of arterial thrombosis in two of 16 patients enrolled in these trials was unexpected. This event may be related to chance alone given our small study size and the lack of similar events reported for gefitinib and other EGFR inhibitors. The reported incidence of all thrombotic events in patients receiving capecitabine-based chemotherapy ranges from 1.5% to 8%,34,35 and reported thrombotic events during gefitinib therapy are also relatively uncommon.36-39 Recent reports describing results of small molecule EGFR inhibitors alone or in combination with conventional chemotherapeutic agents without radiation in colorectal and pancreatic cancer have indicated that these combinations yield modest response rates with diarrhea as the predominant toxicity.20,40-43 Fisher et al14 described 56 patients with metastatic colorectal cancer treated with FOLFOX-4 (FU, leucovorin, oxaliplatin) concurrent with gefitinib 500 mg/d. Grade 3/4 toxicities of neutropenia (53%), diarrhea (49%), and nausea (20%) were observed. In previously untreated patients and treated patients, partial responses were observed in 78% and 36%, respectively. Moore et al21 described the results of a phase III trial comparing 569 patients with advanced pancreatic cancer receiving gemcitabine versus gemcitabine plus erlotinib. Significant improvements in 1-year (24% v 17%) and progression-free survival were observed in patients receiving erlotinib therapy. Grade 3/4 toxicity was comparable in both arms. Of the 10 patients enrolled on the pancreatic cancer trial, six patients had stable disease, three patients had progression, and one patient was not assessable. No locally advanced patients were downstaged to resectable. Of six patients enrolled on the rectal cancer trial, two patients had a partial response, two patients had stable disease, one patient had progression, and one patient was not assessable. Of the three pancreatic and four rectal cancer patients who underwent resection, only one patient (pancreatic cancer) had microscopic residual disease alone. All other patients had macroscopic residual disease. While too small to draw firm conclusions regarding the potential efficacy of combining gefitinib with capecitabine plus radiation in gastrointestinal cancers, the activity seen in this study was not encouraging. The reasons for the significant toxicity and limited activity from adding an EGFR inhibitor to radiation therapy and capecitabine may have many explanations, including the limited number of patients studied. The lack of robust radiographic and pathologic responses in our studies may also be partially a result of a failure to complete radiation and/or systemic therapy as planned (seven patients) as well as prolonged delays in radiation therapy (three patients). In summary, the combination of capecitabine, gefitinib, and radiation in pancreatic and rectal cancers as given in our studies results in significant toxicity. A recommended phase II dose was not reached in either study given DLTs at the lowest dose level. Treatment at lower dose levels was not pursued given significant toxicities encountered, concerns about effectiveness associated with dose reductions of capecitabine, and the lack of availability of gefitinib at a lower standard dose. Given the strong preclinical rationale for combining EGFR inhibitors with radiation, additional study of this class of drugs as radiosensitizers in gastrointestinal cancers is warranted. However, our data suggest combined modality studies with EGFR inhibitors, particularly gefitinib, should be approached with caution.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required
We thank the patients who participated in these studies and their families; Amy Franklin (study coordinator); and Wanda Lawrence for her assistance in manuscript preparation.
Supported by AstraZeneca Pharmaceuticals and Roche Pharmaceuticals. Presented in part at the American Society for Therapeutic Radiology and Oncology Translational Research in Radiation Oncology Symposium, San Francisco, CA, August 5-6, 2005. All work contained within this manuscript is original. Authors' disclosures of potential conflicts of interest and authors contribution are found at the end of this article.
1. Korc M, Chandrasekar B, Yamana Y, et al: Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth and transforming growth factor alpha. J Clin Invest 90:1352-1360, 1992[Medline] 2. Saeki T, Salomon D, Johnson G, et al: Association of epidermal growth factor-related peptides and type I receptor tyrosine kinase receptors with prognosis of human colorectal carcinomas. Jpn J Clin Oncol 25:240-249, 1995 3. Khorana A, Ryan C, Eberly S, et al: EGFR expression and survival in stage II, III and IV colon cancer. Proc Am Soc Clin Oncol 22:317, 2003 (abstr 1272) 4. Raymond E, Faivre S, Armand J: Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs 60:15-23, 2000[CrossRef][Medline] 5. Nicholson RI, Gee JM, Harper ME, et al: EGFR and cancer prognosis. Eur J Cancer 37:S9–S15, 2001[Medline] 6. Akimoto T, Hunter N, Buchmiller L, et al: Inverse relationship between epidermal growth factor receptor expression and radio curability of murine carcinomas. Clin Cancer Res 5:2884-2890, 1999 7. Barker FG 2nd, Simmons ML, Chang SM, et al: EGFR overexpression and radiation response in glioblastoma multiforme. Int J Radiat Oncol Biol Phys 51:410-418, 2001[Medline] 8. Williams K, Telfer B, Stratford I, et al: ZD1839, a specific oral epidermal growth factor receptor-tyrosine kinase inhibitor, potentiates radiotherapy in a human colorectal cancers xenograft model. Br J Cancer 86:1157-1161, 2002[CrossRef][Medline] 9. Raben D, Helfrich B, Chans D, et al: ZD1839, a selective epidermal growth factor tyrosine kinase inhibitor, alone and in combination with radiation and chemotherapy as a new therapeutic strategy in non-small cell lung cancer. Semin Oncol 29:37-46, 2002[CrossRef][Medline] 10. Raben D, Phistery M, Helfrich B, et al: ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor enhances radiation induced cytotoxicity in human pancreatic and cholangiocarcinoma cell lines in vitro. Presented at the Gastrointestinal Cancer Research Conference, Orlando, FL, November, 2000 11. Ciardiello F, Caputo R, Bianco R, et al: Anti-tumor effect in potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839, an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 6:2053-2063, 2000 12. Magne N, Fisheo J, Dubreuil A, et al: ZD1839 (Iressa) modifies the activity of key enzymes linked to fluoropyrimidine activity. Clin Cancer Res 9:4735-4742, 2003 13. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and Cetuximab plus Irinotecan in Irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 14. Fisher G, Kuo T, Cho C, et al: A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer. J Clin Oncol 22:248s, 2004 (suppl; abstr 3514)[CrossRef] 15. Zeuli M, Gelibeter A, Nardoni C, et al: A feasibility study of gefitinib in association with capecitabine (CAP) and oxaliplatin (OXA) as first-line treatment in patients with advanced colorectal cancer. J Clin Oncol 22:306s, 2004 (suppl; abstr 3748) 16. Rothenburg M, Lafleur B, Washington M, et al: Changes in epidermal growth factor receptor signaling in serum and tumor biopsies obtained from patients with progressive metastatic colorectal cancer treated with gefitinib (ZD1839): An Eastern Cooperative Oncology Group Study. J Clin Oncol 22:195s, 2004 (suppl; abstr 3000) 17. Oza A, Townsley C, Siu L, et al: Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 22:196, 2003 (abstr 785) 18. Abbruzzese J, Rosenberg A, Xiong Q, et al: Phase II study of anti-epidermal growth factor receptor (EGFR) antibody cetuximab (IMC-C225) in combination with gemcitabine in patients with advanced pancreatic cancer. Proc Am Soc Clin Oncol 20:130a, 2001 (abstr 518) 19. Carneiro B, Brand R, Fine E, et al: Phase I trial of fixed dose rate infusion (FDRI) gemcitabine (GEM) with gefitinib in patients with advanced pancreatic carcinoma. J Clin Oncol 23:336s, 2005 (suppl; abstr 4118) 20. Blaszkowsky L, Kulke K, Ryan D, et al: A phase II study of erlotinib in combination with capecitabine in previously treated patients with metastatic pancreatic cancer. Proc Am Soc Clin Oncol 23:332, 2003 (abstr 4099) 21. Moore M, Goldstein D, Hamm J, et al: Erlotinib improves survival when added to gemcitabine in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. ASCO Gastrointestinal Symposium: 121, 2005 (abstr 77) 22. Bonner J, Harari P, Giralt J, et al: Cetuximab prolongs survival in patients with local regionally advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab. J Clin Oncol 22:489s, 2004 (suppl; abstr 5507) 23. Gastrointestinal Tumor Study Group: Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med 312:1465-1472, 1985[Abstract] 24. Gastrointestinal Tumor Study Group: Therapy of locally unresectable pancreatic carcinoma: A randomized comparison of high-dose (6000 Rads) radiation alone, moderate dose radiation (4000 Rads + 5-Fluorouracil) and high-dose radiation plus 5-Fluorouracil. Cancer 48:1705-1710, 1981[CrossRef][Medline] 25. Dunst J, Reese T, Sutter T, et al: Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer. J Clin Oncol 20:3983-3991, 2002 26. Ben-Josef E, Shields A, Vaishampayn U, et al: Intensity- modulated radiotherapy (IMRT) and concurrent capecitabine for pancreatic cancer. Int J Radiat Oncol Biol Phys 59:454-459, 2004[CrossRef][Medline] 27. Sawada N, Ishikawa T, Sekiguchi F, et al: X-ray irradiation induces thymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) in human cancer xenografts. Clin Cancer Res 5:2948-2953, 1999 28. Kalser M, Ellerberg S: Pancreatic cancer: Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 120:899-903, 1985[Abstract] 29. Kim J, Kim J, Cho M, et al: Preoperative chemoradiation using oral capecitabine in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 54:403-408, 2002[CrossRef][Medline] 30. Harari P, Haung S: Modulation of molecular targets to enhance radiation. Clin Cancer Res 6:323-325, 2000 31. Ngan S, Michael M, Mackay J, et al: A phase I trial of preoperative radiotherapy and capecitabine for locally advanced, potentially resectable rectal cancer. Br J Cancer 91:1019-1024, 2004[CrossRef][Medline] 32. Arnold D, Constine C, Seufferlein T, et al: Phase I study of gefitinib in combination with capecitabine and irinotecan for second- and/or third-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 23:292s, 2005 (suppl; abstr 3691) 33. Hartmann J, Kroening H, Bokemeyer C, et al: Phase I study of gefitinib in combination with oxaliplatin and weekly f-FU/FA (FUFOX) for second-/third-line treatment in patients (pts) with metastatic colorectal cancer (CRC). J Clin Oncol 23:230s, 2005 (suppl; abstr 3154)[CrossRef] 34. XELODA (capecitabine) tablets: Complete product information, 2005 35. Grothey A, Jordan K, Kellner O, et al: Randomized phase II trial of capecitabine plus irinotecan (CapIri) versus capecitabine plus oxaliplatin (CapOx) as first-line therapy of advanced colorectal cancer (ACRC). J Clin Oncol 22:255s, 2005 (suppl; abstr 1022) 36. Herbst R, Giaccone G, Schiller J, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small cell cancer: A phase III trial. J Clin Oncol 22:785-794, 2004 37. Giaccone G, Herbst R, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small cell lung cancer: A phase III trial. J Clin Oncol 22:777-784, 2004 38. Herbst R, Prager D, Hermann R, et al: TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 23:5892-5899, 2005 39. Shepherd F, Rodriguez Pereira J, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132, 2005 40. Yamaguchi N, Mayer I, Malzyner A, et al: A pilot feasibility study of gefitinib (ZD1839) and celecoxib in metastatic GI tumors. J Clin Oncol 22:216s, 2004 (suppl; abstr 3086) 41. Jimeno A, Sevilla C, Gravalos M, et al: Phase I/II trial of capecitabine and gefitinib in patients with advanced colorectal cancer after failure of first-line therapy. J Clin Oncol 23:235s, 2005 (suppl; abstr 3176) 42. Keilholz U, Arnold D, Niederle N, et al: Erlotinib as a 2nd or 3rd line monotherapy in patients with metastatic colorectal cancer: Results of a multicenter 2-cohort phase II trial. J Clin Oncol 23:264s, 2005 (suppl; abstr 3575) 43. Lenz H, Mayer R, Gold P, et al: Activity of erbitux (Cetuximab) in patients with colorectal cancer refractory to a fluoropyrimidine, irinotecan, and oxaliplatin. ASCO Gastrointestinal Symposium: 121, 2005 (abstr 225) Submitted September 8, 2005; accepted November 16, 2005. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
80%, and adequate bone marrow function (leukocytes > 2,000/mm3, platelets > 100,000/mm3, hemoglobin > 9.0). Adequate renal (creatinine clearance > 50 mL/min) and hepatic function (bilirubin < 1.5x upper normal limit; AST, ALT, and alkaline phosphatase < 3x upper normal limit or < 5x upper normal limit, if known hepatic metastases) was required. Patients were not allowed to use medications that could potentially interfere with the metabolism of capecitabine or gefitinib. 
100%; stable disease, decrease in cross sectional less than 50% to 
