Epidermal growth factor receptor-targeted therapies in colorectal cancer.Introduction During the last decade, we have witnessed the emergence of molecular-targeted therapies in clinical practice. The development of epidermal growth factor receptor This article is about a cell suface receptor. For estimated measure of kidney function (eGFR), see Glomerular filtration rate. The epidermal growth factor receptor (EGFR EGFR Epidermal Growth Factor Receptor (a kinase enzyme) EGFR Estimated Glomerular Filtration Rate )-targeted therapies in colorectal cancer colorectal cancer Malignant tumour of the large intestine (colon) or rectum. Risk factors include age (after age 50), family history of colorectal cancer, chronic inflammatory bowel diseases, benign polyps, physical inactivity, and a diet high in fat. has been among the early successes in this era of targeted therapies. Preclinical data indicated the ability of EGFR-targeted antibodies to potentiate po·ten·ti·ate v. 1. To make potent or powerful. 2. To enhance or increase the effect of a drug. 3. To promote or strengthen a biochemical or physiological action or effect. the activity of irinotecan in colorectal tumour xenografts, and potentially reverse chemoresistance [1]. These preclinical data shaped the initial clinical development of EGFR-targeted antibody therapy antibody therapy Clinical immunology Any therapeutic intervention in which a monoclonal or other concentrated antibody is used to manage a condition–eg, cancer or severe infection in colorectal cancer. The aim of this article is to review the history and current status of EGFR-targeted therapies in colorectal cancer. The early clinical development of EFGR-targeted antibody therapy After the completion of early-phase clinical trials, Phase II trials evaluating cetuximab in colorectal cancer were instituted. A study evaluating single-agent cetuximab in 57 patients with EGFR-expressing chemorefractory colorectal cancer showed a promising response rate of 11% [2]. A further single-arm Phase II trial assessed the efficacy and safety of the combination of irinotecan and cetuximab in 121 patients with irinotecan-refractory colorectal cancer. The combination therapy produced a response rate of 17% in this patient group, providing the first clinical evidence of the ability of cetuximab to reverse chemoresistance [3]. Following these promising results in single-arm studies, the randomised Adj. 1. randomised - set up or distributed in a deliberately random way randomized irregular - contrary to rule or accepted order or general practice; "irregular hiring practices" Phase II Bowel Oncology With Cetuximab Antibody (BOND) study [4] was undertaken. The BOND study enrolled 329 patients with progressive colorectal cancer refractory to irinotecan chemotherapy; 62% of patients had also received prior oxaliplatin therapy. Patients were randomly assigned to either single-agent cetuximab or combination therapy with cetuximab and irinotecan. In this irinotecan-refractory patient population a response rate of 23% was seen with combination therapy, and 11% with single-agent cetuximab therapy. The results of this study led to the approval by the US Food and Drug Administration (FDA FDA abbr. Food and Drug Administration FDA, n.pr See Food and Drug Administration. FDA, n.pr the abbreviation for the Food and Drug Administration. ) of cetuximab in the setting of irinotecan-refractory colorectal cancer. Since the presentation of the BOND results at the 2003 Annual Meeting of the American Society for Clinical Oncology (ASCO ASCO American Society of Clinical Oncology ASCO Association of Schools and Colleges of Optometry (since 1941; Rockville, Maryland) ASCO Australian Standard Classification of Occupations ASCO Automatic Switch Company ), EGFR-targeted therapies have been subjected to intense evaluation in clinical and translational studies. EGFR-targeted antibody therapy versus best supportive care supportive care, n medical and other interventions that attempt to support and make comfortable rather than to cure. in chemorefractory patients Phase III Noun 1. phase III - a large clinical trial of a treatment or drug that in phase I and phase II has been shown to be efficacious with tolerable side effects; after successful conclusion of these clinical trials it will receive formal approval from the FDA trials comparing EGFR-targeted antibody therapy to best supportive care (BSC (Binary Synchronous Communications) See bisync. ) in patients with chemorefractory disease have been undertaken, utilising both cetuximab and panitumumab. In a Phase III study evaluating single-agent panitumumab, 463 patients with chemoresistant disease were randomly assigned to receive either panitumumab monotherapy or BSC alone [5]. This trial allowed for patients in the BSC arm to crossover and receive panitumumab as part of an extension protocol. The primary endpoint of the main study was progression-free survival (PFS PFS, n post facilitation stretch; therapeutic approach utilized during proprioceptive neuromuscular facilitation in which the patient begins the stretch midway between the fully relaxed and fully stretched position and uses maximum level of effort to ). A radiological response rate of 8% was seen in the panitumumab arm together with a statistically significant improvement in PFS as compared to the BSC arm [hazard ratio The hazard ratio in survival analysis is the effect of an explanatory variable on the hazard or risk of an event. For a less technical definition than is provided here, consider hazard ratio to be an estimate of relative risk and see the explanation on that page. , 0.54; 95% confidence interval confidence interval, n a statistical device used to determine the range within which an acceptable datum would fall. Confidence intervals are usually expressed in percentages, typically 95% or 99%. (CI), 0.44-0.66; log-rank test, P<0.0001]. A total of 76% of patients in the BSC arm crossed over to receive panitumumab; a response rate of 9% was seen in these patients. There was no difference in overall survival between treatment arms, which is understandable given the crossover design. On the basis of these data, panitumumab received FDA approval as monotherapy in chemorefractory colorectal cancer. A further randomised study comparing single-agent cetuximab to BSC has also been undertaken. The National Cancer Institute of Canada (NCIC NCIC National Crime Information Center NCIC National Cancer Institute of Canada NCIC North Carolina Industrial Commission NCIC National Cartographic Information Center NCIC National Cancer Information Center (American Cancer Society) )-CO17 study randomly assigned 572 patients refractory to both irinotecan- and oxaliplatin-based treatments to receive either cetuximab monotherapy or BSC alone. In contrast to the panitumumab study, there was no provision for patients in the BSC arm to crossover to receive cetuximab, and the primary endpoint was overall survival. The results demonstrated a radiological response rate of 6.6% in the cetuximab arm and a statistically significant improvement in time to progression (hazard ratio, 0.68; 95%CI, 0.57-0.80; P<0.0001) and overall survival (P<0.0001) [6]. Combination treatment with EGFR-and vascular endothelial endothelial /en·do·the·li·al/ (-the´le-al) pertaining to or made up of endothelium. Endothelial A layer of cells that lines the inside of certain body cavities, for example, blood vessels. growth factor-targeted therapies The combination of targeted agents inhibiting both EGFR and vascular endothelial growth factor Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). (VEGF VEGF vascular endothelial growth factor. ) together with irinotecan was tested in the randomised Phase II study, BOND 2 [7]. Irinotecan-refractory patients were randomly assigned to receive either cetuximab, irinotecan and bevacizumab (CBI CBI abbr. cumulative book index CBI Confederation of British Industry CBI n abbr (= Confederation of British Industry) → C.E.O.E. ) or cetuximab and bevacizumab (CB) alone. The reported response rates were 20% in the CB arm and 37% in the CBI arm. When compared with the outcomes of patients in the BOND I study, it appeared that the addition of bevacizumab may improve treatment efficacy. However, the preliminary finding of the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE PACCE Professional Association for Construction Computing Excellence LLC ) study (see below) have raised concerns regarding the efficacy and toxicity of combining EGFR- and VEGF-targeted antibody therapy. First- and second-line use of EGFR-targeted therapies in combination with chemotherapy Panitumumab and cetuximab have both gained a licence for use in the setting of chemorefractory disease, and there are emerging data to support their use earlier during the course of therapy. Numerous Phase II studies have demonstrated that EGFR-targeted antibodies can be safely delivered in combination with commonly used cytotoxic cy·to·tox·ic adj. Of, relating to, or producing a toxic effect on cells. cy  to·tox·ic chemotherapy schedules, with encouraging efficacy data (Table
1). The potential value of combination treatment schedules is being
evaluated in a variety of Phase III studies (Table 2).
In the Cetuximab Combined with Irinotecan in First Line Therapy for Metastatic Metastatic The term used to describe a secondary cancer, or one that has spread from one area of the body to another. Mentioned in: Coagulation Disorders metastatic pertaining to or of the nature of a metastasis. Colorectal Cancer (CRYSTAL) study, 1200 chemotherapy-naive patients were randomly assigned to receive irinotecan/leucovorin/5-fluorouracil (FOLFIRI FOLFIRI Folinic Acid, Fluorouracil & Irinotecan (chemo treatment) ) chemotherapy with or without the addition of cetuximab. Preliminary findings reported in a press release [8] indicate that the primary endpoint of improvement in PFS in the cetuximab arm was met. A similar study, Panitumumab Randomized ran·dom·ize tr.v. ran·dom·ized, ran·dom·iz·ing, ran·dom·iz·es To make random in arrangement, especially in order to control the variables in an experiment. Trial In Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME), assessing the combination of panitumumab and leucovorin/5-fluorouracil/oxaliplatin (FOLFOX FOLFOX 5-Fluorouracil, Leucovorin and Oxaliplatin (chemo treatment) ) chemotherapy continues to recruit patients. Since the licensing of cetuximab, the VEGF-targeted antibody bevacizumab has been licensed and gained widespread use in first-line therapy in the USA and other parts of the world. In view of this, a number of trials have evaluated the addition of EGFR-targeted antibody therapy to bevacizumab and cytotoxic chemotherapy in the first-line treatment A first-line treatment or first-line therapy is a medical therapy recommended for the initial treatment of a disease, sign or symptom, usually on the basis of empirical evidence for its efficacy. setting. The PACCE study has evaluated the combination of FOLFOX or FOLFIRI chemotherapy with bevacizumab given either with or without the addition of panitumumab. The results of an interim analysis published in a press release revealed that patients in the panitumumab arm had a significantly lower PFS compared to the control arm and showed an increased incidence of grade 3 diarrhoea, dehydration and infections. An increased incidence of pulmonary embolism Pulmonary Embolism Definition Pulmonary embolism is an obstruction of a blood vessel in the lungs, usually due to a blood clot, which blocks a coronary artery. was also noted in the panitumumab arm (4% versus 2%) [9]. The increased toxicity associated with the combination of antibody therapies was unexpected, and the findings of trials such as Cetuximab Added to Capecitabine, Oxaliplatin and Bevacizumab in Patients with Previously Untreated Colorectal Cancer (CAIRO) 2 and the Cancer and Leukemia Group B Cancer and Leukemia Group B (CALGB) is a cancer research cooperative group in the United States. CALGB research is focused on seven major disease areas: leukemia, lymphoma, breast cancer, lung cancer, gastrointestinal malignancies, genito-urinary malignancies, and melanoma. (CALGB CALGB Cancer and Leukemia Group B ) 80405 study assessing similar combinations are keenly awaited. The potential benefit of the addition of cetuximab to irinotecan in second-line therapy has also been assessed. The European Prospective Investigation of Cancer (EPIC) study enrolled 1300 patients who progressed on first-line oxaliplatin-based therapy and randomly assigned them to receive either single-agent irinotecan or the combination of irinotecan and cetuximab. Results presented at the 2007 Annual Meeting of the American Association for Cancer Research Wikipedia is not the place for advertisement or self-advertising. The American Association for Cancer Research (AACR) is an organization based in Philadelphia, Pennsylvania, that focuses on all aspects of cancer research including basic, clinical and translational (AACR AACR American Association for Cancer Research AACR Anglo-American Cataloging Rules AACR Australasian Association of Cancer Registries AACR African Armed Conflicts Resolved ), demonstrated an improvement in PFS and response rates with the addition of cetuximab therapy; no difference in overall survival was detected [10]. Neoadjuvant treatment of potentially resectable re·sect·a·ble adj. Suitable for resection. liver disease Liver Disease Definition Liver disease is a general term for any damage that reduces the functioning of the liver. Description The liver is a large, solid organ located in the upper right-hand side of the abdomen. Given the potential for EGFR-targeted antibodies to augment the response of cytotoxic agents, there has been interest in their clinical value in patients with resectable or potentially resectable liver disease. The New peri-operative chemotherapy with anti-EGFR antibody (EPOC A 32-bit operating system for handheld devices from Symbian Ltd., London, (www.symbian.com). Used in Psion and other handheld computers, it supports Java applications, e-mail, fax, infrared exchange, data synchronization with PCs and includes a suite of PIM and productivity applications. ) study is a Phase III study evaluating pre- and post-operative oxaliplatin/modified de Gramond or capecitabine/oxaliplatin chemotherapy with or without the addition of cetuximab in colorectal cancer patients with resectable liver metastases Metastasis (plural, metastases) A tumor growth or deposit that has spread via lymph or blood to an area of the body remote from the primary tumor. Mentioned in: Malignant Melanoma . A European Organisation for Research and Treatment of Cancer (EORTC EORTC European Organization for Research and Treatment of Cancer ) study is evaluating the feasibility and tolerance of the combination of FOLFOX with cetuximab and the combination of FOLFOX with cetuximab and bevacizumab as peri-operative treatment in patients with resectable liver metastases from colorectal cancer. A further randomised Phase II study, Cetuximab in Neoadjuvant Treatment of Non-Resectable Colorectal Liver Metastases (CELIM CELIM Organizzazione di Volontariato Internazionale Cristiano ), is evaluating cetuximab in the neoadjuvant treatment of patients with non-resectable liver metastases. EGFR-targeted tyrosine kinase inhibitors Noun 1. tyrosine kinase inhibitor - a drug used in cases of chronic myeloid leukemia medicament, medication, medicinal drug, medicine - (medicine) something that treats or prevents or alleviates the symptoms of disease The EGFR-targeted tyrosine kinase inhibitors erlotinib, gefitinib and lapatinib have also undergone evaluation in colorectal cancer. Whereas the EGFR-targeted antibodies have shown consistent single-agent activity in chemorefractory disease, the tyrosine kinase inhibitors have not (Table 3). Furthermore, trials assessing the combination of tyrosine kinase inhibitors with cytotoxic agents have noted problems with toxicity (Table 4). Although the results achieved with the first generation of tyrosine kinase inhibitors have been disappointing, new agents with greater potency and specificity are undergoing clinical development and may yet have a role to play in the treatment of colorectal cancer. Response prediction An intriguing pattern noted across many trials evaluating EGFR-targeted agents in colorectal cancer, as well as other tumour types, has been the consistent correlation between the development of a skin rash and response to therapy. Currently the development of a skin rash remains the most reliable early marker of treatment response. The mechanisms involved in the development of skin rash and treatment response are poorly understood. The EVEREST study is a prospective trial that was designed to assess the relationship between cetuximab dose, skin rash and treatment response. All patients in this study started treatment with a standard combination of cetuximab and irinotecan. Following 22 days of standard therapy, patients who had not developed a skin rash of at least grade 2 were randomly assigned either to continue standard therapy or to dose-escalated cetuximab. In the dose-escalating arm, the cetuximab dose was increased by 50 mg/[m.sup.2] every 2 weeks until the development of at least grade 2 skin rash (up to a maximum of 500 mg/[m.sup.2]). The protocol included a study of biomarkers with patients undergoing skin biopsies for molecular pathological assessment. Overall a total of 99 patients were randomly assigned to treatment [11]. The results of this exploratory study, summarised in Table 5, indicate that dose escalation in patients failing to develop at least grade 2 skin rash may improve treatment response. Further confirmatory studies will be required before cetuximab dose escalation could be adopted into standard practice. It is hoped that the translational aspects of this study may reveal additional information as to the mechanisms underlying the relationship between skin rash and response. Although the clinical development of EGFR-targeted therapies in colorectal cancer was to an extent based on the high rates of EGFR expression seen in tumours, we have subsequently seen in clinical trials that there is no correlation between EGFR expression by immunohistochemistry and tumour response. Skin rash represents an early predictive indicator of response, but no other clinical, histopathological or molecular indicators have yet been identified for use in the clinical setting. Current avenues of translational research include EGFR copy number [12], immune response immune response n. An integrated bodily response to an antigen, especially one mediated by lymphocytes and involving recognition of antigens by specific antibodies or previously sensitized lymphocytes. [13], KRAS KRAS Knowledge Representation for Autonomous Systems mutational status [14], high-affinity EGFR distribution [15] and EGFR dimerisation patterns [16]. Given the heterogenicity of malignant disease and the complexity of the molecular pathways involved, it is quite possible that a number of inter-related variables are involved. EGFR-targeted therapy in the adjuvant adjuvant /ad·ju·vant/ (aj?dbobr-vant) (a-joo´vant) 1. assisting or aiding. 2. a substance that aids another, such as an auxiliary remedy. 3. setting Given the activity that EGFR-targeted antibodies have shown in the advanced disease setting, a number of studies are evaluating their role in the adjuvant setting. Pan European Trial of Adjuvant Colorectal Cancer (PETACC)-8 is a multinational European Phase III study designed to evaluate the efficacy of cetuximab in addition to FOLFOX-4 in patients with resected stage III colon cancer colon cancer, cancer of any part of the colon (often called the large intestine). Colon cancer is the second most common cancer diagnosed in the United States. . In North America North America, third largest continent (1990 est. pop. 365,000,000), c.9,400,000 sq mi (24,346,000 sq km), the northern of the two continents of the Western Hemisphere. the National Cancer Institute-sponsored N0147 trial is also evaluating the role of cetuximab in the adjuvant setting. Conclusion The EGFR-targeted antibodies have gained a firm place in the management of advanced chemorefractory colorectal cancer, and increasing data are emerging to support their use in earlier disease settings. The true potential of these agents will only be reached with an improved understanding of the underlying mechanism involved in defining treatment response, or resistance, and this remains a high research priority. References [1.] Prewett MC, Hooper AT, Bassi bas·si n. A plural of basso. R et al. Enhanced antitumor an·ti·tu·mor also an·ti·tu·mor·al adj. Counteracting or preventing the formation of malignant tumors; anticancer. Adj. 1. activity of anti-epidermal growth factor receptor A growth factor receptor is a receptor which binds to growth factor. External links
• • monoclonal antibody monoclonal antibody, an antibody that is mass produced in the laboratory from a single clone and that recognizes only one antigen. Monoclonal antibodies are typically made by fusing a normally short-lived, antibody-producing B cell (see immunity) to a fast-growing IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res, 2002, 8, 994-1003. [2.] 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. [3.] Saltz L, Hochster H, Tchekmeydian NS et al. Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC (Cyclical Redundancy Checking) An error checking technique used to ensure the accuracy of transmitting digital data. The transmitted messages are divided into predetermined lengths which, used as dividends, are divided by a fixed divisor. ) that expresses epidermal growth factor receptor (EGFR). Proc ASCO, 2001, 20, Abstr. 7. [4.] Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecanrefractory metastatic colorectal cancer. N Engl J Med, 2004, 351, 337-345. [5.] Peeters M, Van Cutsem E, Siena S et al. A phase 3, multicenter, randomized controlled tial (RCT RCT Randomized Controlled Trial RCT Regimental Combat Team (infantry regiment with their own artillery, engineers, medical and tanks) RCT Rollercoaster Tycoon RCT Randomized Clinical Trial RCT Rhondda Cynon Taff ) of panitumumab plus best supportive care (BSC) vs BSC alone in patients (pts) with metastatic colorectal cancer (mCRC). 97th American Association for Cancer Research Annual Meeting, Washington, DC, 2006, Abstr. CP-1. [6.] Derek J, Jonker CSK CSK see chronic superficial keratitis. , Moore M et al. Randomized Phase III trial of cetuximab monotherapy plus best supportive care (BSC) versus BSC alone in patients with pretreated metastatic epidermal growth factor receptor (EGFR)-positive colorectal carcinoma: A trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG CTG Cartridge CTG Center for Technology in Government (SUNY, Albany, New York) CTG Center for Technology in Government CTG Computer Task Group (IT consulting company; Buffalo, NY, USA) ) and the Australasian Gastro-Intestinal Trials Group (AGITG). American Association for Cancer Research Annual Meeting, Los Angeles Los Angeles (lôs ăn`jələs, lŏs, ăn`jəlēz'), city (1990 pop. 3,485,398), seat of Los Angeles co., S Calif.; inc. 1850. , CA, 2007, Abstr. LB-1. [7.] Saltz LB, Lenz H-J, Hochster H et al. Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer. Proc ASCO, 2005, 23, Abstr. 3508. [8.] Merck. Erbitux meets primary endpoint in first-line phase III metastatic colorectal cancer study. Press release, 2007. http://me.merck.de/EMD/UK/uknews2.nsf/d4c60a303233fb87c12 56fc500368312/5be1c55bdca32e01c125725e004dfbe1?OpenDo cument (accessed 1 May 2007). [9.] Amgen Press Release: Amgen discontinues Vectibix(TM) treatment in PACCE trial evaluating Vectibix(TM) as part of triple combination regimen. http://www.amgen.com/media/media_pr_detail.jsp?year=2007&re leaseID=977186 (accessed 1 May 2007). [10.] Alberto F, Sobrero LF, Rivera F et al. Randomized Phase III trial of cetuximab plus irinotecan versus irinotecan alone for metastatic colorectal cancer in 1298 patients who have failed prior oxaliplatin-based therapy: The EPIC trial. American Association for Cancer Research Annual Meeting, Los Angeles, CA, 2007, Abstr. LB-2. [11.] Van Cutsem E, Gelderblom H, Vermorken JB et al. Cetuximab dose-escalation study in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): pharmacokinetic and efficacy data of a randomized study. Proc ASCO Gastrointestinal Cancers Symposium, 2007, Orlando, FL, Abstr. 237. [12.] Moroni M, Veronese S, Benvenuti S et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study A cohort study is a form of longitudinal study used in medicine and social science. It is one type of study design. In medicine, it is usually undertaken to obtain evidence to try to refute the existence of a suspected association between cause and disease; failure to refute . Lancet Oncol, 2005, 6, 279-286. [13.] Bleeker WK, Lammerts van Bueren JJ, van Ojik HH et al. Dual mode of action of a human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy. J Immunol, 2004, 173, 4699-4707. [14.] Lievre A, Bachet J-B, Le Corre D et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res, 2006, 66, 3992-3995. [15.] Francoual M, Etienne-Grimaldi MC, Formento JL, et al. EGFR in colorectal cancer: more than a simple receptor. Ann Oncol, 2006, 17, 962-967. [16.] Yatabe Y, Cao L, Tan Y et al. Correlation of ErbB/HER receptor expression and dimerization patterns as measured by a proximity-based assay using formalin-fixed, paraffin-embedded specimens with clinical response in a cohort of non-small-cell lung cancer lung cancer, cancer that originates in the tissues of the lungs. Lung cancer is the leading cause of cancer death in the United States in both men and women. Like other cancers, lung cancer occurs after repeated insults to the genetic material of the cell. patients treated with gefitinib. Proc AACR-EORTC, Anaheim, CA, 2005, Abstr. A123. [17.] Folprecht G, Lutz MP, Schoffski P et al. Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma. Ann Oncol, 2006, 17, 450-456. [18.] Rougier P, Raoul JL, Van Laethem JL et al. Cetuximab+FOLFIRI as first-line treatment for metastatic colorectal CA. Proc ASCO, 2004, 22, Abstr. 3513. [19.] Van Cutsem E. An international phase II study of cetuximab in combination with oxaliplatin/SFU/folinic acid (FOLFOX-4) in the first line treatment of patients with metastatic colorectal cancer (CRC) expressing epidermal growth factor receptor (EFGR). Ann Oncol, 2004, 15 (suppl 3), iii69-101. [20.] Berlin J, Neubauer M, Swanson P et al. Panitumumab antitumor activity in patients (pts) with metastatic colorectal cancer (mCRC) expressing >10% epidermal growth factor receptor (EGFr). Proc ASCO, 2006, 24, Abstr. 3548. [21.] Fields ALA, Rinaldi DA, Henderson CA et al. An open-label multicenter phase II study of oral lapatinib (GW572016) as single agent, second-line therapy in patients with metastatic colorectal cancer. Proc ASCO, 2005, 23, Abstr. 3583. [22.] Keilholz U, Arnold D, Niederle N et al. Erlotinib as 2nd and 3rd line monotherapy in patients with metastatic colorectal cancer. Results of a multicenter two-cohort phase II trial. Proc ASCO, 2005, 23, Abstr. 3575. [23.] Townsley CA, Major P, Siu LL et al. Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Br J Cancer, 2006, 94, 1136-1143. [24.] 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 adenocarcinoma: see neoplasm. . J Clin Oncol, 2005, 23, 9265-9274. [25.] Mackenzie MJ, Hirte HW, Glenwood G et al. A phase II trial of ZD1839 (Iressa) 750 mg per day, an oral epidermal growth factor Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation and differentiation. Human EGF is a 6045 Da protein with 53 amino acid residues and three intramolecular disulfide bonds. receptor-tyrosine kinase inhibitor, in patients with metastatic colorectal cancer. Invest New Drugs, 2005, 23, 165-170. [26.] Fisher GA, Kuo T, Cho CD et al. A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer. Proc ASCO, 2004, 22, Abstr. 3514. [27.] Zampino MG, Lorizzo K, Massacesi C et al. First-line gefitinib combined with simplified FOLFOX-6 in patients with epidermal growth factor receptor-positive advanced colorectal cancer. Proc ASCO, 2005, 23, Abstr. 3659. [28.] Meyerhardt JA, Stuart K, Zhu A et al. Phase II study of FOLFOX, bevacizumab and erlotinib as initial therapy for patients with metastatic colorectal cancer (MCRC). Proc ASCO, 2006, 24, Abstr. 3545. [29.] Kuo T, Cho CD, Halsey J et al. Phase II study of gefitinib, fluorouracil fluorouracil: see metabolite. , leucovorin, and oxaliplatin therapy in previously treated patients with metastatic colorectal cancer. J Clin Oncol, 2005, 23, 5613-5619. [30.] Veronese ML, Sun W, Giantonio B et al. A phase II trial of gefitinib with 5-fluorouracil, leucovorin, and irinotecan in patients with colorectal cancer. Br J Cancer, 2005, 92, 1846-1849. [31.] Chau I, Cunningham D, Hickish T et al. Gefitinib and irinotecan in patients with fluoropyrimidine-refractory, irinotecan-naive advanced colorectal cancer: a phase I-II study. Ann Oncol, 2007, 18, 730-737. Parvez Hamdulay Department of Medicine, Royal Marsden Hospital, London and Sutton, UK Correspondence to: Parvez Hamdulay (email: parvez.hamdulay@rmh.nhs.uk)
Table 1: Phase II studies assessing first-line use of
epidermal growth factor receptor inhibitors.
Author Combination Patients Response
rate (%)
Folprecht et al. Irinotecan/5-FU/LV 21 67
[17] + cetuximab
Rougier et al. FOLFIRI 52 43
[18] + cetuximab
Van Cutsem FOLFOX-4 50 18
et al. [19] + cetuximab
Berlin et al. [20] FOLFIRI 19 47
+ Panitumumab
5-FU, 5-fluorouracil; LV, leucovorin; FOLFIRI, irinotecan/LV/FU;
FOLFOX, LV/5-FU/oxaliplatin.
Table 2: First-line Phase III studies evaluating
epidermal growth factor receptor-targeted antibodies.
Study Chemotherapy/agent Recruitment Recruitment
number status
CRYSTAL FOLFIRI+/-cetuximab 1212 Completed
PRIME FOLFOX+/-panitumumab 900 Ongoing
COIN 5-FU/oxaliplatin+/- 2500 Ongoing
cetuximab
CALGB FOLFIRI or FOLFOX+either 2300 Ongoing
80405 cetuximab
bevacizumab, or
cetuximab+bevacizumab
Cairo 2 XELOX+bevacizumab 750 Ongoing
study +/-panitumumab
PACCE FOLFOX or FOLFIRI 1000 Completed
+bevacizumab
+/-panitumumab
5-FU, 5-fluorouracil; FOLFIRI, irinotecan/LV/5-FU; FOLFOX,
LV/5-FU/oxaliplatin; XELOX, capecitabine/oxaliplatin; CRYSTAL,
Cetuximab Combined with Irinotecan in First Line Therapy for
Metastatic Colorectal Cancer; PRIME, Panitumumab Randomized
Trial In Combination With Chemotherapy for Metastatic Colorectal
Cancer to Determine Effacacy; COIN, Continuous or Intermittent
Chemotherapy with Cetuximab; CALGB, Cancer and Leukemia
Group B; Cairo, Cetuximab Added to Capecitabine, Oxaliplatin
and Bevacizumab in Patients with Previously Untreated Colorectal
Cancer; PACCE, Panitumumab Advanced Colorectal Cancer
Evaluation.
Table 3: Single-agent Phase II studies using tyrosine
kinase inhibitors (TKIs).
TKI/dose Disease Patients Response
state rate (%)
Lapatinib Second line 86 1
1250 mg [21]
Erlotinib Second line 41 8
150 mg [22] Third line 28 --
Erlotinib Second line 31 0
150 mg [23]
Gefitinib 3Second line 115 1
250 mg and
500 mg [24]
Gefitinib First line 5 0
750 mg [25] Second line 23 --
FOLFIRI, irinotecan/leucovorin/5-fluorouracil; FOLFOX, leucovorin/
5-fluorouracil/oxaliplatin.
Table 4: Tyrosine kinase inhibitors (TKIs) in combination
with cytotoxic chemotherapy.
Regimen TKI Patients Response
rate (%)
FOLFOX [26] Gefitinib 30 53
mFOLFOX6 [27] Gefitinib 47 74
FOLFOX+bevacizumab [28] Erlotinib 35 35
FOLFOX4 second line [29] Gefitinib 27 33
FOLFIRI [30] Gefinitib 13 8
Irinotecan second line [31] Gefitinib 50 mg 27 11
Regimen Comments
FOLFOX [26] 54% grade III/IV diarrhoea
mFOLFOX6 [27]
FOLFOX+bevacizumab [28] Problematic grade III/IV toxicity
FOLFOX4 second line [29] 48% grade III/IV diarrhoea
FOLFIRI [30] Excessive toxicity, seven patients
hospitalised
Irinotecan second line [31] Irinotecan dose 225 mg every 3 weeks
FOLFIRI, irinotecan/leucovorin/5-fluorouracil; FOLFOX,
leucovorin/5-fluorouracil/oxaliplatin.
Table 5: Everest study results.
Patients with < grade 1 skin rash at day 22
Standard dose (%) Escalating dose (%)
Skin rash Grade 2 22 25
Grade 3/4 0 5
Radiological response 13 30
Patients with [greater than or equal
to] grade 1 skin rash at day 22
Non-randomly assigned patients (%)
Skin rash Grade 2 43
Grade 3/4 9
Radiological response 22
|
|
||||||||||||||||||
Printer friendly
Cite/link
Email
Feedback
Reader Opinion