Originally published as JCO Early Release 10.1200/JCO.2004.10.182 on March 1 2004
Journal of Clinical Oncology, Vol 22, No 7 (April 1), 2004: pp. 1201-1208
© 2004 American Society of Clinical Oncology.
Phase II Trial of Cetuximab in Patients With Refractory Colorectal Cancer That Expresses the Epidermal Growth Factor Receptor
Leonard B. Saltz,
Neal J. Meropol,
Patrick J. Loehrer, Sr,
Michael N. Needle,
Justin Kopit,
Robert J. Mayer
From the Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA; Indiana University Cancer Center and the Walther Cancer Institute, Indianapolis, IN; Imclone Systems Inc, Somerville, NJ; Bristol Myers Squibb Inc, Wallingford, CT; and the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
Address reprint requests to Leonard B. Saltz, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: Saltzl{at}mskcc.org
 |
ABSTRACT
|
|---|
PURPOSE: To evaluate the antitumor activity and toxicity of single-agent cetuximab in patients with chemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor.
PATIENTS AND METHODS: Phase II, open-label clinical trial. Patients were required to have EGFr expression demonstrated on formalin-fixed paraffin-embedded tumor tissue by immunohistochemical staining before study participation. Patients were required to have received irinotecan, either alone or in a combination regimen, and to have demonstrated clinical failure on this regimen before study entry. Cetuximab was administered weekly by intravenous infusion. The first dose of 400 mg/m2 was given during the course of 2 hours. Subsequent weekly treatments were given at a dose of 250 mg/m2 during the course of 1 hour.
RESULTS: Fifty-seven eligible patients were treated. All were assessable for toxicity and response. The most commonly encountered grade 3 to 4 adverse events, regardless of relationship to study drug, were an acne-like skin rash, predominantly on the face and upper torso (86% with any grade; 18% with grade 3), and a composite of asthenia, fatigue, malaise, or lethargy (56% with any grade, 9% with grade 3). Two patients (3.5%) experienced grade 3 allergic reactions requiring discontinuation of study treatment. A third patient experienced a grade 3 allergic reaction that resolved, and the patient continued on the study. Neither diarrhea nor neutropenia were dose limiting in any of the 57 patients treated. Five patients (9%; 95% CI, 3% to 19%) achieved a partial response. Twenty-one additional patients had stable disease or minor responses. The median survival in these previously treated patients with chemotherapy-refractory colorectal cancer is 6.4 months.
CONCLUSION: Cetuximab on this once-weekly schedule has modest activity and is well-tolerated as a single agent in patients with chemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor. Further studies of cetuximab will evaluate the use of cetuximab in conjunction with first-line and adjuvant treatments for this disease.
|
INTRODUCTION
|
|---|
Colorectal cancer is a major cause of morbidity and mortality worldwide. In the United States, it is the fourth most common type of cancer and is the second leading cause of cancer death.1 While early stage colorectal cancer is frequently curable with surgery, unresectable metastatic disease is uniformly fatal. Palliative treatment for metastatic colorectal cancer centers on the use of chemotherapy with the antineoplastic agents fluorouracil (FU), irinotecan, and more recently in the United States, oxaliplatin.2-5 Once a patient's cancer becomes refractory to these agents, however, there are essentially no established treatment options with demonstrated efficacy. Clearly, there is a desperate need for new and improved therapies for this lethal disease.
Aberrations in the regulation and expression of growth factors and/or their receptors have been extensively implicated in the development and prognosis of malignancies.6 The epidermal growth factor receptor (EGFr) is a commonly expressed 170,000-kDa trans-membrane glycoprotein that is involved in signaling pathways affecting cellular growth, differentiation, and proliferation.7,8 It is a member of the HER tyrosine kinase growth factor receptor family and is expressed in many types of normal tissues. EGFr expression has been previously demonstrated in multiple tumor types, including colorectal cancer. EGFr is encoded by the proto-oncogene c-erb-B.9,10 Activation of the c-erb-B proto-oncogene results in expression of EGFr in many human tumors; hence the initial interest in investigating this growth factor receptor as a potential target for anticancer therapy.
The EGFr is composed of an extracellular ligand-binding region, a lipophilic trans-membrane anchor sequence, and an intracellular domain characterized by an ATP-dependent tyrosine kinase.7,8,11 The extracellular domain of the EGFr is the ligand-binding site for both the epidermal growth factor and for transforming growth factor–alpha (TGF- ). On ligand binding, receptor dimerization occurs, and the tyrosine kinase of the intracellular domain is activated, thereby triggering many signaling reactions that regulate cell growth and survival. Some cells overexpressing the EGFr also produce an endogenous ligand for these receptors, and are thus able to activate the EGFr through an autocrine pathway, which leads to an auto-stimulated proliferation of cell growth and survival in vitro.12,13 In the laboratory setting, monoclonal antibodies to EGFr are able to inhibit the proliferation of cells that simultaneously produce both EGFr and an activating ligand.14,15
Cetuximab (C225, ErbituxTM) is an Immunoglobulin G1 human-murine chimeric counterpart of the murine monoclonal antibody M225. Both M225 and cetuximab are antibodies directed against the ligand-binding site of the EGFr.16,17 M225 has been shown to be able to block the activation of the EGFr tyrosine kinase by EGF or TGF-, and to inhibit the growth of tumor cells expressing high levels of EGFr.16-20 Studies have demonstrated that both M225 and cetuximab exhibit similar capacities for competing with 123Iodine-labeled EGF for binding to the EGFr.17 Furthermore, cetuximab has shown similar growth-inhibitory capacity to M225 in cell culture assays.
Studies in cell lines have shown the capacity of MAb 225 (either M225 or cetuximab) to modulate tumor cell proliferation, cell cycle phase distribution, apoptosis, and radiosensitivity.21 Mechanisms of anti-EGFr antibody blockade leading to cell cycle arrest have been extensively investigated. Blockade of the EGFr with a monoclonal antibody in the DiFi colon cancer cell line, an autostimulating cell line that is dependent on autocrine EGFr stimulation for survival, induces a cell cycle arrest in G1. Further studies exploring the mechanism of EGFr blockade-induced G1 arrest in the DiFi colorectal carcinoma cell line demonstrate that addition of the M225 to cell cultures in saturating concentrations resulted in substantial CDK2 kinase inhibition and Rb hypophosphorylation.22,23 CDK2, cyclin E, and cyclin A protein levels were unaffected; however, protein levels of the CDK inhibitor p27KIP1 were found to be increased two- to three-fold, and removal of p27KIP1 from cell extracts restored activity of CDK2. Other cell lines were also subsequently shown to have G1 arrest associated with elevated levels of p27KIP1 following exposure to MAb 225.24,25
While the vast majority of preclinical data with cetuximab alone has demonstrated primarily cytostatic activity, data combining cetuximab with marginally effective or ineffective cytotoxic chemotherapy have demonstrated marked synergy with dramatic improvement in antitumor activity for the combination.26-28 Two consistent findings in these preclinical studies are that EGFr expression is needed for cetuximab activity, and that cetuximab, while having modest activity as a single-agent in some systems, has consistently better activity when given in conjunction with inactive or minimally active doses of cytotoxic chemotherapy. Recent studies of cetuximab plus irinotecan in irinotecan-resistant human colorectal tumor xenografts have shown marked synergy between these two agents, with antitumor activity seen with the combination of cetuximab plus irinotecan, while tumor growth occurred with either agent alone.29
Based on this scientific background, and encouraged by a favorable anecdotal case of a patient with irinotecan-refractory colorectal cancer responding to cetuximab plus irinotecan,30 we conducted a phase II study to formally evaluate the activity and safety of cetuximab plus irinotecan in patients with irinotecan-refractory colorectal cancer. That trial was found by an independent response assessment review committee to show a 22.5% major objective response rate in a population of 120 colorectal cancer patients who were determined by their treating physicians to have previously experienced clinical failure on irinotecan.31 This positive finding for the combination prompted the clinical and regulatory need to define the activity, or lack thereof, of single-agent cetuximab in a similar patient population. We therefore conducted a phase II trial to assess the safety and efficacy of single agent cetuximab in patients with chemotherapy-refractory metastatic colorectal cancers that express EGFr.
|
PATIENTS AND METHODS
|
|---|
Study Design and Entry Criteria
We conducted a phase II, nonrandomized, open-label, multicenter trial. To be eligible, patients had to have histologically or pathologically documented colorectal cancer and measurable metastatic disease. In addition, immunohistochemical evidence of EGFr expression measured semiquantitatively (> 0 on a scale of 0, 1+, 2+, or 3+) in a single reference laboratory was required. These measurements were performed and graded using a now commercially available kit (EGFRpharmDx; Dako Corporation, Carpentino, CA) according to the manufacturer's instructions. Patients were permitted to undergo the screening process for tumor EGFr expression before meeting other entry criteria and before study entry. For example, patients were allowed to undergo EGFr screening before study registration, while still receiving initial irinotecan therapy, before documentation of clinical progression. However, to be included in this study, patients were required before study entry to have demonstrated radiologic evidence of failure, as determined by the treating physician, on irinotecan or an irinotecan-containing regimen. Patients were not permitted to have received additional chemotherapy between the time of documented irinotecan failure and entry onto this clinical trial. Patients were required to have at study entry an Eastern Cooperative Oncology Group performance score of 0 to 2, and were required to have an absolute neutrophil count of  1,500 cells/mm3, a platelet count of 100,000 cells/mm3, a WBC count 3,500 cells/mm3, and a hemoglobin level of 9 g/dL. The total serum bilirubin level was required to be  1.5x the upper limit of normal, and the alkaline phosphatase and AST levels were required to be 5x the upper limit of normal. The serum creatinine level was required to be less than 1.5x the upper limit of normal. Patients were required to have recovered from toxicities of prior chemotherapy, and may not have had either radiation therapy or investigational drug therapy within 4 weeks of initiating cetuximab. Bidimensionally measurable disease outside of any previously irradiated field, with a baseline tumor measurement within 4 weeks of initiation of treatment, was required for protocol entry.
This protocol was reviewed and approved by the institutional review board of each participating center, and all patients gave written informed consent before participation.
Therapy
Patients were scheduled to receive cetuximab once weekly. On day 1 of treatment, an initial dose of 400 mg/m2 was given by a 2-hour intravenous infusion. This loading dose was preceded by a 20-mg test dose to observe for evidence of allergic reactions. All patients were to be premedicated with diphenhydramine 50 mg intravenously. No routine antiemetic medications were given. Cetuximab infusions were then continued weekly at a dose of 250 mg/m2 unless toxicity necessitated interruptions. The dose and schedule used in this phase II trial were selected to be consistent with those used in other phase II trials of this agent, particularly in colorectal cancer,31 and are based on extrapolations from previously derived phase I clinical and pharmacokinetic data.32
Evaluation of Patients
Response was assessed every 6 weeks during the course of this study. An objective response was identified as a reduction of at least 50% in the area of all measurable lesions on computed tomography or other scans. All objective responses were required to be confirmed by a follow-up scan at least 4 weeks following documentation of the response. Tumor progression on study was defined as an increase of at least 25% in the overall area of the tumor, or the appearance of new lesions. Response to cetuximab was also evaluated retrospectively by an independent response assessment committee that was blinded to the investigator-reported measurements and assessments. Patients underwent weekly blood counts, and physical examinations were performed at every third week while on study.
Statistical Analysis
The study utilized a modified Gehan two-stage design to allow for early stopping in the event of lack of efficacy. The planned sample size for the study was 40 patients, with 20 in each stage. Ultimately, 57 patients were registered and treated. The higher number was due to more rapid accrual than originally anticipated. Continuation to the second stage of the study was contingent on one or more patients from the first stage having a response (partial or complete). Twenty patients were chosen for the first stage in order to limit to 5% the probability of stopping the study early if the true response rate were 15%.
The primary end point in this study was response rate. An exact, two-sided, 95% CI for response rate was computed using the Clopper and Pearson method.33 Response as a function of EGFR status was evaluated by Fisher's exact test.
Secondary end points included duration of response, time to progression, survival duration, and toxicity. Toxicities, which were categorized using Coding Symbols for Thesaurus of Adverse Reaction Terms and graded using National Cancer Institute common toxicity criteria version 2.0, were summarized by frequencies and percents. Duration of response, time to progression, and survival duration were estimated using the Kaplan-Meier method34 and summarized by medians. Kaplan-Meier estimates of survival were generated for patients with no skin rash and those who suffered any grade skin rash during the therapy and the curves were compared using the log-rank  2 test.
|
RESULTS
|
|---|
Patient Characteristics
Tumor samples from 140 patients were centrally screened for EGFr expression for possible registration onto this trial. Of these, 105 patients, or 75%, demonstrated at least a 1+ expression of EGFr. Of these 105 EGFr+ patients, 61 who were determined by their treating physician to have had radiological evidence of failure on irinotecan or an irinotecan-containing regimen and who met all other eligibility criteria were registered on this trial between April 17, 2001, and July 12, 2001, and 57 went on to receive cetuximab. Four patients who were registered experienced clinical deterioration before initiation of cetuximab therapy and were therefore not treated. The demographic breakdown of the 57 treated patients is shown in Table 1. The median age of patients participating in this trial was 56 years, with a range of 28 to 80 years. The median Eastern Cooperative Oncology Group performance score was 0, with a range of 0 to 2, and the median time from last prestudy irinotecan dose to initiation of on-study cetuximab therapy was 2.0 months, with a range of 0.5 months to 10.6 months. Forty-seven patients (82%) were treated within 3 months of their last irinotecan dose, seven patients (12%) were treated within 3 to 6 months of their last irinotecan dose, and 3 patients (5%) were treated more than 6 months after their last irinotecan dose.
Sixteen patients had received one prior regimen for their disease before study entry. All 16 of these had received previous concurrent irinotecan + FU + leucovorin. Forty-one patients had received two or more chemotherapy regimens (including adjuvant regimens, if given) for their disease before study entry. The median duration of irinotecan treatment before participation in this trial for all patients was 16 weeks (range, 1 to 97 weeks).
Although oxaliplatin was not approved for use in the United States during the time that this trial was being conducted, eight patients had received prior oxaliplatin-based treatment before enrolling onto this trial.
Duration of Treatment and Dose Intensity of Cetuximab
The median duration of treatment on study was 6.4 weeks (range, 1 to 67 weeks). Nearly all cetuximab doses administered were given at the full planned dose of 400 mg/m2 for the loading dose and 250 mg/m2 for subsequent weekly doses. Sixty-three percent of patients (n = 36) received all planned doses of cetuximab during participation on study. Thirty-two percent of patients (n = 18) missed either one or two planned doses of cetuximab. Less than 1% of patients (n = 1) missed more than two of the planned doses of cetuximab. Two patients (3.5%) received only the test dose of cetuximab.
Efficacy
Response rate.
All patients who received any cetuximab on this trial were considered evaluable for efficacy. Of the 57 treated, 6 patients (10.5%; 95% exact CI, 4% to 22%) obtained a partial response based on investigator assessments. Twenty additional patients (35%) had either a minor response (tumor reduction between 25% and 49%) or stable disease (either growth or shrinkage of less than 25%) that lasted for at least 12 weeks from the date of initiation of cetuximab treatment. The independent response assessment committee concurred with five of the six investigator-adjudicated responses (major response rate of 8.8%; 95% CI, 3% to 19%) reclassifying one investigator-adjudicated major response as a minor response. As demonstrated in Table 2, response did not seem to correlate with the observed degree of EGFr expression.
In an exploratory analysis of the 16 patients who had received only one prior regimen, only one patient (as determined by both the investigators and the independent review committee) experienced a partial response, for a response rate of 6.3% (95% exact CI, 0.2% to 30.2%). Because of this, we did not see evidence that the response rate was either superior or different in those patients who had received one versus more than one prior regimen; however, the numbers are too small to permit firm conclusions.
Progression-free and overall survival.
The median time to tumor progression on this trial was 1.4 months, with a median duration of response of 4.2 months in the five patients judged by both the investigators and the independent response assessment committee to be major responders. The median survival from time of initiation of protocol therapy for the 57 treated patients was 6.4 months.
Adverse Events
Skin reactions were observed in 88% of patients. In 86% of patients, we saw a subset of skin reaction, acne-like rash, which is characteristic of cetuximab toxicity, as reported previously.31 Eighteen percent (n = 10) were grade 3. No grade 4 skin reactions were observed. This rash characteristically manifested within the first 1 to 3 weeks of therapy. Standard topical administration of drying agents, topical antibiotics, or topical steroids did not seem to substantially affect the course of the rash, though in patients who appeared clinically to have a bacterial superinfection of the rash, oral antibiotics seemed to provide some clinical improvement. In general, some degree of spontaneous partial improvement in the rash during the first 1 to 2 months of therapy was subjectively noted in many of patients without modification of the cetuximab dose.
Another manifestation of cetuximab cutaneous toxicity was paronychial cracking. These lesions occurred either on the fingers or toes and were reported in 12% of patients. They tended to be relatively persistent throughout the duration of the patient's treatment. Anecdotally, some individuals required several months to effect complete healing after cessation of therapy of these paronychial lesions.
Two patients (3.5%) experienced grade 3 or 4 allergic reactions leading to cessation of therapy. Both occurred during the test dose, and one of these patients required hospitalization. These reactions were characterized as anaphylactoid in nature, and were managed with epinephrine, antihistamines, corticosteroids, and supportive-care measures, and resolved without sequelae. One additional patient experienced a grade 3 allergic reaction on day 233. The patient continued in the study and subsequently discontinued on day 310 due to disease progression. A listing of all grade 3 or 4 cetuximab-related adverse events is presented in Table 3. No grade 3 or 4 neutropenia or thrombocytopenia was encountered.
Correlation of Survival With Rash
There was a correlation between the presence and severity of the acnelike rash and survival. As presented in Table 4, patients with skin rash of any grade had a superior survival to patients with no skin rash (P = .02). There was a trend towards improved survival with increasing grade of rash, with patients with grade 3 rash seeming to have the longest survival, and patients with grade 1 or 2 skin rash having intermediary survival relative to those with grade 3 or grade 0.
|
DISCUSSION
|
|---|
Treatment options for colorectal cancer patients after failure of FU and irinotecan are extremely limited. At the time that this trial was conducted, there were no approved standard treatments in the United States for patients in this setting. For patients previously treated with bolus FU, a course of infusional FU therapy is often attempted, though there is scant if any literature to support this practice. Recently, capecitabine, an oral FU prodrug with antitumor activity in the first-line treatment of colorectal cancer,35 has become a popular replacement for infusional FU in the irinotecan-refractory setting, though data indicate a lack of significant efficacy of this agent in this refractory setting. Since the conclusion of our trial, oxaliplatin, a diamino cyclohexane platinum analog has become commercially available in the United States, with approval based on a trial that showed a 9.9% major objective response rate for the combination of oxaliplatin plus infusional FU/leucovorin (FOLFOX-4), and virtually no activity of oxaliplatin as a single agent.36 From a mechanistic perspective, there is no reason to expect cross-resistance between oxaliplatin and cetuximab, and indeed, some of the responses in our trial were noted in patients who had received prior oxaliplatin-based therapy. Both cetuximab and FOLFOX-4 have modest levels of clinical activity in irinotecan-refractory colorectal cancer, and each would seem to bring some modest potential for clinical benefit to this population of patients who are in desperate need of additional therapeutic alternatives.
Preclinical data predict a substantially higher degree of clinical activity for cetuximab in combination with a cytotoxic agent than would be expected with cetuximab treatment alone. Using the concept of evidence-based, rational design of clinical trials based on preclinical data, the combination of irinotecan plus cetuximab was explored first.31 The identification of activity with cetuximab plus irinotecan in a population of patients in whom irinotecan had previously failed, seemed to confirm preclinical expectations. Nevertheless, the activity seen on that trial of cetuximab plus irinotecan raised the question of what single-agent cetuximab might accomplish in this setting. This clinical trial to investigate this question in irinotecan-refractory colorectal cancer patients was therefore performed. Subsequently, Cunningham et al37 performed a confirmatory randomized phase II trial that evaluated both cetuximab alone and cetuximab plus irinotecan in patients with irinotecan-refractory colorectal cancer. The response rates reported in that trial in abstract form were 10.8% for cetuximab alone and 22.9% for cetuximab plus irinotecan. These numbers very closely approximate the results of the trial we report here, as well as those of the previously reported combination trial,31 confirming the preclinical hypotheses that cetuximab has modest preclinical activity and the combination of cetuximab plus irinotecan has superior activity in irinotecan-refractory colorectal cancer.
The response rate of 9% in this chemotherapy-refractory group of patients is equivalent to the level of activity seen in a similar refractory colorectal population with the FOLFOX combination of oxaliplatin and biweekly infusional FU + leucovorin, although the progression-free survival of 1.4 months is shorter than that reported for FOLFOX.36 As such, it seems that single agent cetuximab provides a salvage option that may be comparable, at least in terms of antitumor response, to the degree of efficacy seen with oxaliplatin based-combinations following irinotecan/FU failures. Results reported previously with irinotecan plus cetuximab appear to be superior to both cetuximab alone and to what has been reported for FOLFOX in this setting, though randomized comparisons would of course be required to assess the relative efficacy and tolerability of FOLFOX versus cetuximab or versus cetuximab-based combinations in this setting.
The toxicity of cetuximab on this trial was manageable, and was similar to those previously reported for this agent.31 These included grade 3 or 4 allergic reactions (5%) characterized by typical symptoms of severe hypersensitivity and rapidly responsive to standard management with epinephrine, antihistamines, and corticosteroids. Also seen was the typical skin reaction associated with this agent, and with other agents that block EGFr signaling. This rash, while at times quite esthetically unpleasing, was rarely a source of physical discomfort. None of the 57 patients discontinued treatment on this trial because of the skin rash.
An exploratory analysis suggests a correlation between the presence and severity of the rash and survival. We can only hypothesize as to the meaning of this at this time. The rash may be an indicator of sensitivity to EGFr blockade, both in the patient and the tumor. One possibility is that the rash is a surrogate indicator of an adequate degree of receptor saturation by cetuximab. If this is the case, then targeting doses to achieve a desired level of cutaneous toxicity may further increase the efficacy of this agent. While this is an appealing prospect from a potential efficacy point of view, it would suggest, if true, that there might be a narrow therapeutic window to work with for this agent. Trials are being planned to test this hypothesis, with those patients who do not experience a skin rash after the first few weeks of therapy receiving dose escalations until cutaneous toxicity occurs. Alternatively, it is possible that a particular EGFr polymorphism might correlate with both antitumor activity and cutaneous toxicity. Further studies of this possibility are also planned.
Preclinical data have suggested synergy between cetuximab and a number of cytotoxic agents, including irinotecan, cisplatin, gemcitabine, and doxorubicin. The exact mechanism of this synergy has not been definitively determined. A working hypothesis is that abrogation of activity in the EGFr-mediated signaling pathways leads to a decrease in EGFr-mediated antiapoptotic messages transmitted within the cell. This may be sufficient for cytotoxicity in some cell lines that sustain an autocrine loop of EGF production and EGFr expression and that are particularly dependent on this pathway for survival. In the majority of cell lines studied, however, the blockage of EGFr signaling is insufficient for cytotoxicity, but may leave the cells more vulnerable to the cytotoxic effects of otherwise minimally efficacious chemotherapy.
The favorable clinical response rate seen in this single agent trial raises a number of important clinical questions, which are the subject of further ongoing and/or planned investigations. The lack of correlation between the degree of EGFr expression and response raises the question of whether non-EGFr–expressing tumors might also be potentially sensitive to cetuximab-based therapy. It would appear, on the basis of these data, that immunohistochemistry for EGFr expression is a poor indicator of which tumors are most treatable by this EGFr-targeted therapy. Other means of assessing EGFr expression, such as RT-PCR, will need to be explored. Correlative studies will also be needed to assess downstream effects of EGFr blockade to further elucidate patterns that may be predictive of cetuximab activity and so permit appropriate selection of patients for treatment.
Based on preclinical data, we would anticipate that the greatest degree of benefit from cetuximab in colorectal cancer is likely to be seen in combination with chemotherapy in first line or adjuvant use, although we cannot know the actual utility of such an approach until data are available from randomized trials. Pilot trials to incorporate cetuximab into first line regimens of irinotecan/FU/leucovorin have been completed,38 and randomized phase III trials in first line and adjuvant combination use are in the process of activation. Finally, heterogeneity in the qualitative, as well as quantitative expression of EGFr, may be clinically relevant to the successful application of cetuximab. Human EGFr polymorphisms have been described, and future large-scale trials will attempt to characterize these polymorphisms and correlate them with clinical activity and toxicity. Studies are also underway to characterize molecular phenotypes that predict response to this agent.
|
Authors' Disclosures of Potential Conflicts of Interest
|
|---|
The following authors or their immediate family members have 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. Owns stock (not including shares held through a public mutual fund): Michael Needle, Imclone; Justin Kopit, Bristol-Myers Squibb. Acted as a consultant within the last 2 years: Neal Meropol, Bristol-Myers Squibb. Performed contract work within the last 2 years: Leonard Saltz, Imclone; Neal Meropol, Imclone, Bristol-Myers Squibb. Served as an officer or member of the Board of a company: Michael Needle, Imclone; Justin Kopit, Bristol-Myers Squibb. Received more than $2,000 a year from a company for either of the last 2 years: Michael Needle, Imclone; Justin Kopit, Bristol-Myers Squibb.
|
NOTES
|
|---|
Supported by ImClone Systems Inc, Somerville, NJ.
Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
|
REFERENCES
|
|---|
1. Jemal A, Murray T, Samuels A, et al: Cancer statistics 2003. CA Cancer J Clin 53:5-26, 2003[Abstract/Free Full Text]
2. Leichman CG, Fleming TR, Muggia FM, et al: Phase II study of fluorouracil and its modulation in advanced colorectal cancer: A Southwest Oncology Group study. J Clin Oncol 13:1303-1311, 1995[Abstract]
3. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343:905-914, 2000[Abstract/Free Full Text]
4. Cunningham D, Pyrhonen S, James RD, et al: Randomized trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413-1418, 1998[CrossRef][Medline]
5. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000[Abstract/Free Full Text]
6. Aaronson S: Growth factors and cancer. Science 254:1146-1153, 1991[Abstract/Free Full Text]
7. Carpenter G: Receptors for epidermal growth factor and other polypeptide mitogens. Annu Rev Biochem 56:881-914, 1987[CrossRef][Medline]
8. Carpenter G, Cohen S: Epidermal growth factor. J Biol Chem 265:7709-7712, 1990[Free Full Text]
9. Downward J, Yarden Y, Mayes E, et al: Close similarity of epidermal growth factor receptor and V-erb-B oncogene protein sequences. Nature 307:521-527, 1984[CrossRef][Medline]
10. Real FX, Rettig WJ, Chesa PG, et al: Expression of epidermal growth factor receptor in human cultured cells and tissues. Cancer Res 46:4726-4731, 1986[Abstract/Free Full Text]
11. Yarden Y, Ullrich A: Growth factor receptor tyrosine kinases. Annu Rev Biochem 57:443-478, 1988[CrossRef][Medline]
12. Di Marco E, Pierce JG, Fleming TP, et al: Autocrine interaction between TGF alpha and the EGF receptor: Quantitative requirements for induction of the malignant phenotype. Oncogene 4:831-838, 1989[Medline]
13. Van de Vijver MJ, Kumar R, Mendelsohn J: Ligand-induced activation of A431 cell epidermal growth factor receptors occurs primarily by an autocrine pathway that acts upon receptors on the surface rather than intracellularly. J Biol Chem 266:7503-7508, 1991[Abstract/Free Full Text]
14. Baselga J, Norton L, Masui H, et al: Antitumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies. J Natl Cancer Inst 85:1327-1333, 1993[Abstract/Free Full Text]
15. Masui H, Boman B, Hyman J, et al: Treatment with anti-EGF receptor monoclonal antibody causes regression of DiFi human colorectal carcinoma xenografts. Proc Am Assoc Cancer Res 32:394, 1991
16. Sato JD, Kawamoto T, Le AD, et al: Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med 1:511-529, 1983[Medline]
17. Goldstein NI, Prewett M, Zuklys K, et al: Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1:1311-1318, 1995[Abstract]
18. Gill GN, Kawamoto T, Cochet C, et al: Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem 259:7755-7760, 1984[Abstract/Free Full Text]
19. Masui H, Kawamoto T, Sato JD, et al: Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 44:1002-1007, 1984[Abstract/Free Full Text]
20. Vande Woude GF, Schultz N, Zhou R, et al: Cell cycle regulation, oncogenes, and antineoplastic drugs, in: Fornter JG, Rhoads JE (eds). Accomplishments in Cancer Res Foundation. Philadelphia, PA, JB Lippincott Co, 1990, pp 128-143
21. Huang SM, Bock JM, Harari PM: Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 59:1935-1940, 1999[Abstract/Free Full Text]
22. Wu X, Fan Z, Masui H, et al: Apoptosis induced by antiepidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin. J Clin Invest 95:1897-1905, 1995
23. Xu X, Rubin M, Fan Z, et al: Involvement of p27KIP1 in G1 arrest mediated by an epidermal growth factor receptor monoclonal antibody. Oncogene 12:1397-1403, 1996[Medline]
24. Fax Z, Shang BY, Wu X, et al: Blockade of epidermal growth factor receptor by anti-EGFR monoclonal antibody 225 causes G1 arrest of A431 cells with induction of p27KIP1. Proc Am Assoc Cancer Res 17:10, 1996
25. Peng D, Fan Z, Lu Y, et al: Anti-epidermal growth factor monoclonal antibody 225 upregulates p27KIP1 and induced G1 arrest in prostatic cancer cell lineDU145. Cancer Res 56:3666-3669, 1996[Abstract/Free Full Text]
26. Fan Z, Baselga J, Masui H, Mendelsohn J: Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diaminedichloroplatinum on well established A431 cell xenografts. Cancer Res 53:4637-4642, 1993[Abstract/Free Full Text]
27. Baselga J, Pfisher D, Cooper MR, et al: Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol 18:904-914, 2000[Abstract/Free Full Text]
28. Ciardiello F, Bianco R, Damiano V, et al: Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225. Clin Cancer Res 5:909-916, 1999[Abstract/Free Full Text]
29. Prewett M, Hooper A, Bassi R, et al: Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res 8:994-1003, 2002[Abstract/Free Full Text]
30. Rubin M, Shin D, Pasmantier M, et al: Monoclonal antibody IMC-C225 and anti-epidermal growth factor receptor antibody for patients with EGFr-positive tumors refractory to or in relapse from previous therapeutic regimens. Proc Am Soc Clin Oncol 19:474a, 2000
31. Saltz L, Hochster H, Rubin M, 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 20:3a, 2001 (abstr 7)
32. Baselga J, Pfister D, Cooper MR, et al: Phase I studies of antiepidermal growth factor receptor chimeric antibody c225 alone and in combination with cisplatin. J Clin Oncol 18:904-914, 2000
33. Clopper CJ, Pearson ES: The use of confidence of fiducial limits illustrated in the case of the binomial. Biometrika 26:404-413, 1934[Free Full Text]
34. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1959[CrossRef]
35. Hoff PM, Ansari R, Batist G, et al: Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: Results of a randomized phase III study. J Clin Oncol 19:2282-2292, 2001[Abstract/Free Full Text]
36. Rothenberg M, Oza AM, Bigelow RH, et al: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: Interim results of a phase III trial. J Clin Oncol 21:2059-2069, 2003[Abstract/Free Full Text]
37. 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). Proc Am Soc Clin Oncol 22:252a, 2003 (abstr 1012)
38. Rosenberg A, 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 20:135a, 2001 (abstr 536)
Submitted October 24, 2003;
accepted December 9, 2003.
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Facebook  Reddit  Technorati  Twitter What's this?
Related Editorial
- Targeting the Epidermal Growth Factor Receptor: An Important Incremental Step in the Battle Against Colorectal Cancer
Lee M. Ellis and Paulo M. Hoff
JCO 2004 22: 1177-1179
[Full Text]
Related Correspondence
- Is Immunohistochemistry for Epidermal Growth Factor Receptor Expression a Poor Predictor of Response to Epidermal Growth Factor Receptor-Targeted Therapy?
Mamoun Younes
JCO 2005 23: 923
[Full Text]
This article has been cited by other articles:
|
|
|
|
 
G. Niu, Z. Li, J. Xie, Q.-T. Le, and X. Chen
PET of EGFR Antibody Distribution in Head and Neck Squamous Cell Carcinoma Models
J. Nucl. Med.,
July 1, 2009;
50(7):
1116 - 1123.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L.-C. Yen, Y.-S. Yeh, C.-W. Chen, H.-M. Wang, H.-L. Tsai, C.-Y. Lu, Y.-T. Chang, K.-S. Chu, S.-R. Lin, and J.-Y. Wang
Detection of KRAS Oncogene in Peripheral Blood as a Predictor of the Response to Cetuximab Plus Chemotherapy in Patients with Metastatic Colorectal Cancer
Clin. Cancer Res.,
July 1, 2009;
15(13):
4508 - 4513.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Fojo and C. Grady
How Much Is Life Worth: Cetuximab, Non-Small Cell Lung Cancer, and the $440 Billion Question
J Natl Cancer Inst,
June 29, 2009;
(2009)
djp177v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Debucquoy, K. Haustermans, A. Daemen, S. Aydin, L. Libbrecht, O. Gevaert, B. De Moor, S. Tejpar, W. H. McBride, F. Penninckx, et al.
Molecular Response to Cetuximab and Efficacy of Preoperative Cetuximab-Based Chemoradiation in Rectal Cancer
J. Clin. Oncol.,
June 10, 2009;
27(17):
2751 - 2757.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Neyns, J. Sadones, E. Joosens, F. Bouttens, L. Verbeke, J.-F. Baurain, L. D'Hondt, T. Strauven, C. Chaskis, P. In't Veld, et al.
Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma
Ann. Onc.,
June 2, 2009;
(2009)
mdp032v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Muro, T. Yoshino, T. Doi, K. Shirao, H. Takiuchi, Y. Hamamoto, H. Watanabe, B.-B. Yang, and D. Asahi
A Phase 2 Clinical Trial of Panitumumab Monotherapy in Japanese Patients with Metastatic Colorectal Cancer
Jpn. J. Clin. Oncol.,
May 1, 2009;
39(5):
321 - 326.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-H. Kohne and H.-J. Lenz
Chemotherapy with Targeted Agents for the Treatment of Metastatic Colorectal Cancer
Oncologist,
May 1, 2009;
14(5):
478 - 488.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Wang, A. Rajput, J. L. C. Kan, R. Rose, X.-Q. Liu, K. Kuropatwinski, J. Hauser, A. Beko, I. Dominquez, E. A. Sharratt, et al.
Knockdown of Ron Kinase Inhibits Mutant Phosphatidylinositol 3-Kinase and Reduces Metastasis in Human Colon Carcinoma
J. Biol. Chem.,
April 17, 2009;
284(16):
10912 - 10922.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Levy, G. Sycz, J. M. Arriaga, M. M. Barrio, E. M. von Euw, S. B. Morales, M. Gonzalez, J. Mordoh, and M. Bianchini
Cetuximab-mediated cellular cytotoxicity is inhibited by HLA-E membrane expression in colon cancer cells
Innate Immunity,
April 1, 2009;
15(2):
91 - 100.
[Abstract]
[PDF]
|
|
|
|
|
|
|
N. Yamamoto, Y. Yamada, Y. Fujiwara, K. Yamada, Y. Fujisaka, T. Shimizu, and T. Tamura
Phase I and Pharmacokinetic Study of HER2-targeted rhuMAb 2C4 (Pertuzumab, RO4368451) in Japanese Patients with Solid Tumors
Jpn. J. Clin. Oncol.,
April 1, 2009;
39(4):
260 - 266.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. L. Barros Costa
Review Article: Targeted Therapy: Comprehensive Review
American Journal of Hospice and Palliative Medicine,
April 1, 2009;
26(2):
137 - 146.
[Abstract]
[PDF]
|
|
|
|
|
|
|
V Martin, L Mazzucchelli, and M Frattini
An overview of the epidermal growth factor receptor fluorescence in situ hybridisation challenge in tumour pathology
J. Clin. Pathol.,
April 1, 2009;
62(4):
314 - 324.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Mutsaers, G. Francia, S. Man, C. R. Lee, J. M.L. Ebos, Y. Wu, L. Witte, S. Berry, M. Moore, and R. S. Kerbel
Dose-Dependent Increases in Circulating TGF-{alpha} and Other EGFR Ligands Act As Pharmacodynamic Markers for Optimal Biological Dosing of Cetuximab and Are Tumor Independent
Clin. Cancer Res.,
April 1, 2009;
15(7):
2397 - 2405.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Bibeau, E. Lopez-Crapez, F. Di Fiore, S. Thezenas, M. Ychou, F. Blanchard, A. Lamy, F. Penault-Llorca, T. Frebourg, P. Michel, et al.
Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa Polymorphisms and KRAS Mutations on the Clinical Outcome of Patients With Metastatic Colorectal Cancer Treated With Cetuximab Plus Irinotecan
J. Clin. Oncol.,
March 1, 2009;
27(7):
1122 - 1129.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Bengala, S. Bettelli, F. Bertolini, S. Salvi, S. Chiara, C. Sonaglio, L. Losi, N. Bigiani, G. Sartori, C. Dealis, et al.
Epidermal growth factor receptor gene copy number, K-ras mutation and pathological response to preoperative cetuximab, 5-FU and radiation therapy in locally advanced rectal cancer
Ann. Onc.,
March 1, 2009;
20(3):
469 - 474.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Bokemeyer, I. Bondarenko, A. Makhson, J. T. Hartmann, J. Aparicio, F. de Braud, S. Donea, H. Ludwig, G. Schuch, C. Stroh, et al.
Fluorouracil, Leucovorin, and Oxaliplatin With and Without Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer
J. Clin. Oncol.,
February 10, 2009;
27(5):
663 - 671.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Pantaleo, M. Nannini, A. Maleddu, S. Fanti, C. Nanni, S. Boschi, F. Lodi, G. Nicoletti, L. Landuzzi, P. L. Lollini, et al.
Experimental results and related clinical implications of PET detection of epidermal growth factor receptor (EGFr) in cancer
Ann. Onc.,
February 1, 2009;
20(2):
213 - 226.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. E. THEODOROPOULOS, E. KARAFOKA, J. G. PAPAILIOU, P. STAMOPOULOS, C. P. ZAMBIRINIS, K. BRAMIS, S.-G. PANOUSSOPOULOS, E. LEANDROS, and J. BRAMIS
p53 and EGFR Expression in Colorectal Cancer: A Reappraisal of 'Old' Tissue Markers in Patients with Long Follow-up
Anticancer Res,
February 1, 2009;
29(2):
785 - 791.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Guarino, C. J. Schneider, M. A. Hosford, J. R. Brahmer, C. M. Rudin, F. G. Finckenstein, R. E. Philip-Norton, H. Lu, M. R. Weber, and D. S. Ettinger
Dual Inhibition of the Epidermal Growth Factor Receptor Pathway with Cetuximab and Erlotinib: A Phase I Study in Patients with Advanced Solid Malignancies
Oncologist,
February 1, 2009;
14(2):
119 - 124.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Takano, S. Ota, A. Hori, N. Seki, and K. Eguchi
Can Epidermal Growth Factor Receptor-Fluorescent in Situ Hybridization Predict Clinical Benefit From Cetuximab Treatment in Patients With Non-Small-Cell Lung Cancer?
J. Clin. Oncol.,
January 20, 2009;
27(3):
464 - 465.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Manganoni, C. Farisoglio, V. Ferrari, A. Zaniboni, G. Beretta, F. Meriggi, and P. Calzavara-Pinton
Multidisciplinary Team-Working Indicators of Good Practice in the Clinical Management of EGFR-Inhibitor Dermatologic Toxicities
Ann. Surg. Oncol.,
January 1, 2009;
16(1):
224 - 225.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Papamichael, R. Audisio, J.-C. Horiot, B. Glimelius, J. Sastre, E. Mitry, E. Van Cutsem, M. Gosney, C.-H. Kohne, and M. Aapro
Treatment of the elderly colorectal cancer patient: SIOG expert recommendations
Ann. Onc.,
January 1, 2009;
20(1):
5 - 16.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Peeters, T. Price, and J.-L. Van Laethem
Anti-Epidermal Growth Factor Receptor Monotherapy in the Treatment of Metastatic Colorectal Cancer: Where Are We Today?
Oncologist,
January 1, 2009;
14(1):
29 - 39.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Di Nicolantonio, M. Martini, F. Molinari, A. Sartore-Bianchi, S. Arena, P. Saletti, S. De Dosso, L. Mazzucchelli, M. Frattini, S. Siena, et al.
Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer
J. Clin. Oncol.,
December 10, 2008;
26(35):
5705 - 5712.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Milano, M.-C. Etienne-Grimaldi, L. Dahan, M. Francoual, J.-P. Spano, D. Benchimol, M. Chazal, C. Letoublon, T. Andre, F.-N. Gilly, et al.
Epidermal growth factor receptor (EGFR) status and K-Ras mutations in colorectal cancer
Ann. Onc.,
December 1, 2008;
19(12):
2033 - 2038.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Lurje, F. Nagashima, W. Zhang, D. Yang, H. M. Chang, M. A. Gordon, A. El-Khoueiry, H. Husain, P. M. Wilson, R. D. Ladner, et al.
Polymorphisms in Cyclooxygenase-2 and Epidermal Growth Factor Receptor Are Associated with Progression-Free Survival Independent of K-ras in Metastatic Colorectal Cancer Patients Treated with Single-Agent Cetuximab
Clin. Cancer Res.,
December 1, 2008;
14(23):
7884 - 7895.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Wilke, R. Glynne-Jones, J. Thaler, A. Adenis, P. Preusser, E. A. Aguilar, M. S. Aapro, R. Esser, A. H. Loos, and S. Siena
Cetuximab Plus Irinotecan in Heavily Pretreated Metastatic Colorectal Cancer Progressing on Irinotecan: MABEL Study
J. Clin. Oncol.,
November 20, 2008;
26(33):
5335 - 5343.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. C. Manning, N. B. Merchant, A. C. Foutch, J. M. Virostko, S. K. Wyatt, C. Shah, E. T. McKinley, J. Xie, N. J. Mutic, M. K. Washington, et al.
Molecular Imaging of Therapeutic Response to Epidermal Growth Factor Receptor Blockade in Colorectal Cancer
Clin. Cancer Res.,
November 15, 2008;
14(22):
7413 - 7422.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Tahara, K. Shirao, N. Boku, K. Yamaguchi, Y. Komatsu, Y. Inaba, T. Arai, N. Mizunuma, T. Satoh, H. Takiuchi, et al.
Multicenter Phase II Study of Cetuximab Plus Irinotecan in Metastatic Colorectal Carcinoma Refractory to Irinotecan, Oxaliplatin and Fluoropyrimidines
Jpn. J. Clin. Oncol.,
November 1, 2008;
38(11):
762 - 769.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Yonesaka, K. Zejnullahu, N. Lindeman, A. J. Homes, D. M. Jackman, F. Zhao, A. M. Rogers, B. E. Johnson, and P. A. Janne
Autocrine Production of Amphiregulin Predicts Sensitivity to Both Gefitinib and Cetuximab in EGFR Wild-type Cancers
Clin. Cancer Res.,
November 1, 2008;
14(21):
6963 - 6973.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. S. Karapetis, S. Khambata-Ford, D. J. Jonker, C. J. O'Callaghan, D. Tu, N. C. Tebbutt, R. J. Simes, H. Chalchal, J. D. Shapiro, S. Robitaille, et al.
K-ras Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer
N. Engl. J. Med.,
October 23, 2008;
359(17):
1757 - 1765.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. J. Poston, J. Figueras, F. Giuliante, G. Nuzzo, A. F. Sobrero, J.-F. Gigot, B. Nordlinger, R. Adam, T. Gruenberger, M. A. Choti, et al.
Urgent Need for a New Staging System in Advanced Colorectal Cancer
J. Clin. Oncol.,
October 10, 2008;
26(29):
4828 - 4833.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. L. Schilsky, G. Gordon, T. M. Gilmer, S. A. Courtneidge, L. M. Matrisian, O. Grad, W. G. Nelson, and on behalf of the Translational Research Working Gr
The Translational Research Working Group Developmental Pathway for Anticancer Agents (Drugs or Biologics)
Clin. Cancer Res.,
September 15, 2008;
14(18):
5685 - 5691.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Arnold, T. Hohler, C. Dittrich, F. Lordick, T. Seufferlein, J. Riemann, E. Woll, T. Herrmann, A. Zubel, and H.-J. Schmoll
Cetuximab in combination with weekly 5-fluorouracil/folinic acid and oxaliplatin (FUFOX) in untreated patients with advanced colorectal cancer: a phase Ib/II study of the AIO GI Group
Ann. Onc.,
August 1, 2008;
19(8):
1442 - 1449.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.-C. Etienne-Grimaldi, J.-L. Formento, M. Francoual, E. Francois, P. Formento, N. Renee, P. Laurent-Puig, M. Chazal, D. Benchimol, J.-R. Delpero, et al.
K-Ras Mutations and Treatment Outcome in Colorectal Cancer Patients Receiving Exclusive Fluoropyrimidine Therapy
Clin. Cancer Res.,
August 1, 2008;
14(15):
4830 - 4835.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S. Pino, M. Balsamo, F. Di Modugno, M. Mottolese, M. Alessio, E. Melucci, M. Milella, D. J. McConkey, U. Philippar, F. B. Gertler, et al.
Human Mena+11a Isoform Serves as a Marker of Epithelial Phenotype and Sensitivity to Epidermal Growth Factor Receptor Inhibition in Human Pancreatic Cancer Cell Lines
Clin. Cancer Res.,
August 1, 2008;
14(15):
4943 - 4950.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Borner, D. Koeberle, R. Von Moos, P. Saletti, D. Rauch, V. Hess, A. Trojan, D. Helbling, B. Pestalozzi, C. Caspar, et al.
Adding cetuximab to capecitabine plus oxaliplatin (XELOX) in first-line treatment of metastatic colorectal cancer: a randomized phase II trial of the Swiss Group for Clinical Cancer Research SAKK
Ann. Onc.,
July 1, 2008;
19(7):
1288 - 1292.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Vincenzi, D. Santini, S. Galluzzo, A. Russo, F. Fulfaro, M. Silletta, F. Battistoni, L. Rocci, B. B. Zobel, V. Adamo, et al.
Early Magnesium Reduction in Advanced Colorectal Cancer Patients Treated with Cetuximab Plus Irinotecan as Predictive Factor of Efficacy and Outcome
Clin. Cancer Res.,
July 1, 2008;
14(13):
4219 - 4224.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Shimura, H. Kataoka, N. Ogasawara, E. Kubota, M. Sasaki, S. Tanida, and T. Joh
Suppression of proHB-EGF Carboxy-Terminal Fragment Nuclear Translocation: A New Molecular Target Therapy for Gastric Cancer
Clin. Cancer Res.,
June 15, 2008;
14(12):
3956 - 3965.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Pfeiffer, D. Nielsen, J. Bjerregaard, C. Qvortrup, M. Yilmaz, and B. Jensen
Biweekly cetuximab and irinotecan as third-line therapy in patients with advanced colorectal cancer after failure to irinotecan, oxaliplatin and 5-fluorouracil
Ann. Onc.,
June 1, 2008;
19(6):
1141 - 1145.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. R. Hecht
Current and emerging therapies for metastatic colorectal cancer: Applying research findings to clinical practice
Am. J. Health Syst. Pharm.,
June 1, 2008;
65(11_Supplement_4):
S15 - S21.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Krishnan, K. D'Silva, and A. Al-Janadi
Cetuximab-Related Tumor Lysis Syndrome in Metastatic Colon Carcinoma
J. Clin. Oncol.,
May 10, 2008;
26(14):
2406 - 2408.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. F. Sobrero, J. Maurel, L. Fehrenbacher, W. Scheithauer, Y. A. Abubakr, M. P. Lutz, M. E. Vega-Villegas, C. Eng, E. U. Steinhauer, J. Prausova, et al.
EPIC: Phase III Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer
J. Clin. Oncol.,
May 10, 2008;
26(14):
2311 - 2319.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Labianca, M. Garassino, and V. Torri
Predicting response of molecular targeted therapies: a still possible challenge?
Ann. Onc.,
May 1, 2008;
19(5):
829 - 830.
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. A. Press, W. Zhang, M. A. Gordon, D. Yang, G. Lurje, S. Iqbal, A. El-Khoueiry, and H.-J. Lenz
Gender-Related Survival Differences Associated with EGFR Polymorphisms in Metastatic Colon Cancer
Cancer Res.,
April 15, 2008;
68(8):
3037 - 3042.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Yamada, Y. Ichikawa, S. Yamagishi, N. Momiyama, M. Ota, S. Fujii, K. Tanaka, S. Togo, S. Ohki, and H. Shimada
Amphiregulin Is a Promising Prognostic Marker for Liver Metastases of Colorectal Cancer
Clin. Cancer Res.,
April 15, 2008;
14(8):
2351 - 2356.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Pessino, S. Artale, S. Sciallero, A. Guglielmi, G. Fornarini, I.C. Andreotti, S. Mammoliti, D. Comandini, F. Caprioni, E. Bennicelli, et al.
First-line single-agent cetuximab in patients with advanced colorectal cancer
Ann. Onc.,
April 1, 2008;
19(4):
711 - 716.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Jhawer, S. Goel, A. J. Wilson, C. Montagna, Y.-H. Ling, D.-S. Byun, S. Nasser, D. Arango, J. Shin, L. Klampfer, et al.
PIK3CA Mutation/PTEN Expression Status Predicts Response of Colon Cancer Cells to the Epidermal Growth Factor Receptor Inhibitor Cetuximab
Cancer Res.,
March 15, 2008;
68(6):
1953 - 1961.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. H. Chung, B. Mirakhur, E. Chan, Q.-T. Le, J. Berlin, M. Morse, B. A. Murphy, S. M. Satinover, J. Hosen, D. Mauro, et al.
Cetuximab-Induced Anaphylaxis and IgE Specific for Galactose-{alpha}-1,3-Galactose
N. Engl. J. Med.,
March 13, 2008;
358(11):
1109 - 1117.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Ciardiello and G. Tortora
EGFR Antagonists in Cancer Treatment
N. Engl. J. Med.,
March 13, 2008;
358(11):
1160 - 1174.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. H. El-Maraghi and E. A. Eisenhauer
Review of Phase II Trial Designs Used in Studies of Molecular Targeted Agents: Outcomes and Predictors of Success in Phase III
J. Clin. Oncol.,
March 10, 2008;
26(8):
1346 - 1354.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. De Roock, H. Piessevaux, J. De Schutter, M. Janssens, G. De Hertogh, N. Personeni, B. Biesmans, J.-L. Van Laethem, M. Peeters, Y. Humblet, et al.
KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab
Ann. Onc.,
March 1, 2008;
19(3):
508 - 515.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Giusti, K. Shastri, A. M. Pilaro, C. Fuchs, R. Cordoba-Rodriguez, K. Koti, M. Rothmann, A. Y. Men, H. Zhao, M. Hughes, et al.
U.S. Food and Drug Administration Approval: Panitumumab for Epidermal Growth Factor Receptor-Expressing Metastatic Colorectal Carcinoma with Progression Following Fluoropyrimidine-, Oxaliplatin-, and Irinotecan-Containing Chemotherapy Regimens
Clin. Cancer Res.,
March 1, 2008;
14(5):
1296 - 1302.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Italiano, P. Follana, F.-X. Caroli, J.-L. Badetti, D. Benchimol, G. Garnier, J. Gugenheim, J. Haudebourg, F. Keslair, G. Lesbats, et al.
Cetuximab Shows Activity in Colorectal Cancer Patients With Tumors for Which FISH Analysis Does Not Detect an Increase in EGFR Gene Copy Number
Ann. Surg. Oncol.,
February 1, 2008;
15(2):
649 - 654.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Vigneron, E. Gamelin, and O. Coqueret
The EGFR-STAT3 Oncogenic Pathway Up-regulates the Eme1 Endonuclease to Reduce DNA Damage after Topoisomerase I Inhibition
Cancer Res.,
February 1, 2008;
68(3):
815 - 825.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Conrad, M. Remberger, K. Cederlund, O. Ringden, and L. Barkholt
A comparison between low intensity and reduced intensity conditioning in allogeneic hematopoietic stem cell transplantation for solid tumors
Haematologica,
February 1, 2008;
93(2):
265 - 272.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Tabernero, P. Pfeiffer, and A. Cervantes
Administration of Cetuximab Every 2 Weeks in the Treatment of Metastatic Colorectal Cancer: An Effective, More Convenient Alternative to Weekly Administration?
Oncologist,
February 1, 2008;
13(2):
113 - 119.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Lievre, J.-B. Bachet, V. Boige, A. Cayre, D. Le Corre, E. Buc, M. Ychou, O. Bouche, B. Landi, C. Louvet, et al.
KRAS Mutations As an Independent Prognostic Factor in Patients With Advanced Colorectal Cancer Treated With Cetuximab
J. Clin. Oncol.,
January 20, 2008;
26(3):
374 - 379.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Weiner, A. S. Belldegrun, J. Crawford, A. W. Tolcher, P. Lockbaum, R. H. Arends, L. Navale, R. G. Amado, G. Schwab, and R. A. Figlin
Dose and Schedule Study of Panitumumab Monotherapy in Patients with Advanced Solid Malignancies
Clin. Cancer Res.,
January 15, 2008;
14(2):
502 - 508.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. M. Pawlik, R. D. Schulick, and M. A. Choti
Expanding Criteria for Resectability of Colorectal Liver Metastases
Oncologist,
January 1, 2008;
13(1):
51 - 64.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Butts, D. Bodkin, E. L. Middleman, C. W. Englund, D. Ellison, Y. Alam, H. Kreisman, P. Graze, J. Maher, H. J. Ross, et al.
Randomized Phase II Study of Gemcitabine Plus Cisplatin or Carboplatin, With or Without Cetuximab, As First-Line Therapy for Patients With Advanced or Metastatic Non-Small-Cell Lung Cancer
J. Clin. Oncol.,
December 20, 2007;
25(36):
5777 - 5784.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Scope, A. L. C. Agero, S. W. Dusza, P. L. Myskowski, J. A. Lieb, L. Saltz, N. E. Kemeny, and A. C. Halpern
Randomized Double-Blind Trial of Prophylactic Oral Minocycline and Topical Tazarotene for Cetuximab-Associated Acne-Like Eruption
J. Clin. Oncol.,
December 1, 2007;
25(34):
5390 - 5396.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Tabernero, E. Van Cutsem, E. Diaz-Rubio, A. Cervantes, Y. Humblet, T. Andre, J.-L. Van Laethem, P. Soulie, E. Casado, C. Verslype, et al.
Phase II Trial of Cetuximab in Combination With Fluorouracil, Leucovorin, and Oxaliplatin in the First-Line Treatment of Metastatic Colorectal Cancer
J. Clin. Oncol.,
November 20, 2007;
25(33):
5225 - 5232.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. Jonker, C. J. O'Callaghan, C. S. Karapetis, J. R. Zalcberg, D. Tu, H.-J. Au, S. R. Berry, M. Krahn, T. Price, R. J. Simes, et al.
Cetuximab for the Treatment of Colorectal Cancer
N. Engl. J. Med.,
November 15, 2007;
357(20):
2040 - 2048.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. D Francis, M. Dimech, L. Giles, and A. Hopkins
Frequency and reliability of oestrogen receptor, progesterone receptor and HER2 in breast carcinoma determined by immunohistochemistry in Australasia: results of the RCPA Quality Assurance Program
J. Clin. Pathol.,
November 1, 2007;
60(11):
1277 - 1283.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Roda, T. Joshi, J. P. Butchar, J. W. McAlees, A. Lehman, S. Tridandapani, and W. E. Carson III
The Activation of Natural Killer Cell Effector Functions by Cetuximab-Coated, Epidermal Growth Factor Receptor Positive Tumor Cells is Enhanced By Cytokines
Clin. Cancer Res.,
November 1, 2007;
13(21):
6419 - 6428.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Adam, T. Aloia, F. Levi, D. A. Wicherts, R. J. de Haas, B. Paule, M.-P. Bralet, M. Bouchahda, D. Machover, M. Ducreux, et al.
Hepatic Resection After Rescue Cetuximab Treatment for Colorectal Liver Metastases Previously Refractory to Conventional Systemic Therapy
J. Clin. Oncol.,
October 10, 2007;
25(29):
4593 - 4602.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Ferrari and P. Foa
Targeted Therapies: Cui Prodest?
J. Clin. Oncol.,
October 10, 2007;
25(29):
4691 - 4692.
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. B. Saltz, H.-J. Lenz, H. L. Kindler, H. S. Hochster, S. Wadler, P. M. Hoff, N. E. Kemeny, E. M. Hollywood, M. Gonen, M. Quinones, et al.
Randomized Phase II Trial of Cetuximab, Bevacizumab, and Irinotecan Compared With Cetuximab and Bevacizumab Alone in Irinotecan-Refractory Colorectal Cancer: The BOND-2 Study
J. Clin. Oncol.,
October 10, 2007;
25(29):
4557 - 4561.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. M. Harari, G. W. Allen, and J. A. Bonner
Biology of Interactions: Antiepidermal Growth Factor Receptor Agents
J. Clin. Oncol.,
September 10, 2007;
25(26):
4057 - 4065.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Scartozzi, I. Bearzi, C. Pierantoni, A. Mandolesi, F. Loupakis, A. Zaniboni, V. Catalano, A. Quadri, F. Zorzi, R. Berardi, et al.
Nuclear Factor-kB Tumor Expression Predicts Response and Survival in Irinotecan-Refractory Metastatic Colorectal Cancer Treated With Cetuximab-Irinotecan Therapy
J. Clin. Oncol.,
September 1, 2007;
25(25):
3930 - 3935.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Zhang, M. Gordon, A. M. Schultheis, D. Y. Yang, F. Nagashima, M. Azuma, H.-M. Chang, E. Borucka, G. Lurje, A. E. Sherrod, et al.
FCGR2A and FCGR3A Polymorphisms Associated With Clinical Outcome of Epidermal Growth Factor Receptor Expressing Metastatic Colorectal Cancer Patients Treated With Single-Agent Cetuximab
J. Clin. Oncol.,
August 20, 2007;
25(24):
3712 - 3718.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Khambata-Ford, C. R. Garrett, N. J. Meropol, M. Basik, C. T. Harbison, S. Wu, T. W. Wong, X. Huang, C. H. Takimoto, A. K. Godwin, et al.
Expression of Epiregulin and Amphiregulin and K-ras Mutation Status Predict Disease Control in Metastatic Colorectal Cancer Patients Treated With Cetuximab
J. Clin. Oncol.,
August 1, 2007;
25(22):
3230 - 3237.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Morgensztern and R. Govindan
Is There a Role for Cetuximab in Non Small Cell Lung Cancer?
Clin. Cancer Res.,
August 1, 2007;
13(15):
4602s - 4605s.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Damiano, R. Caputo, S. Garofalo, R. Bianco, R. Rosa, G. Merola, T. Gelardi, L. Racioppi, G. Fontanini, S. De Placido, et al.
TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts
PNAS,
July 24, 2007;
104(30):
12468 - 12473.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Meyerhardt, K Stuart, C. Fuchs, A. Zhu, C. Earle, P Bhargava, L Blaszkowsky, P Enzinger, R. Mayer, S Battu, et al.
Phase II study of FOLFOX, bevacizumab and erlotinib as first-line therapy for patients with metastastic colorectal cancer
Ann. Onc.,
July 1, 2007;
18(7):
1185 - 1189.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Al-Kuraya, H. Novotny, P. Bavi, A. K Siraj, S. Uddin, A. Ezzat, N. A. Sanea, F. Al-Dayel, H. Al-Mana, S. S Sheikh, et al.
HER2, TOP2A, CCND1, EGFR and C-MYC oncogene amplification in colorectal cancer
J. Clin. Pathol.,
July 1, 2007;
60(7):
768 - 772.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W.-S. Wang, P.-M. Chen, T.-J. Chiou, J.-H. Liu, J.-K. Lin, T.-C. Lin, H.-S. Wang, and Y. Su
Epidermal Growth Factor Receptor R497K Polymorphism Is a Favorable Prognostic Factor for Patients with Colorectal Carcinoma
Clin. Cancer Res.,
June 15, 2007;
13(12):
3597 - 3604.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. M. Hoff and L. M. Ellis
Targeted Therapy Trials: Approval Strategies, Target Validation, or Helping Patients?
J. Clin. Oncol.,
May 1, 2007;
25(13):
1639 - 1641.
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Van Cutsem, M. Peeters, S. Siena, Y. Humblet, A. Hendlisz, B. Neyns, J.-L. Canon, J.-L. Van Laethem, J. Maurel, G. Richardson, et al.
Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer
J. Clin. Oncol.,
May 1, 2007;
25(13):
1658 - 1664.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. M. Wolpin, J. A. Meyerhardt, H. J. Mamon, and R. J. Mayer
Adjuvant Treatment of Colorectal Cancer
CA Cancer J Clin,
May 1, 2007;
57(3):
168 - 185.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I Chau, D Cunningham, T Hickish, A Massey, L Higgins, R Osborne, N Botwood, and A Swaisland
Gefitinib and irinotecan in patients with fluoropyrimidine-refractory, irinotecan-naive advanced colorectal cancer: a phase I-II study
Ann. Onc.,
April 1, 2007;
18(4):
730 - 737.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Benvenuti, A. Sartore-Bianchi, F. Di Nicolantonio, C. Zanon, M. Moroni, S. Veronese, S. Siena, and A. Bardelli
Oncogenic Activation of the RAS/RAF Signaling Pathway Impairs the Response of Metastatic Colorectal Cancers to Anti-Epidermal Growth Factor Receptor Antibody Therapies
Cancer Res.,
March 15, 2007;
67(6):
2643 - 2648.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Tabernero
The Role of VEGF and EGFR Inhibition: Implications for Combining Anti-VEGF and Anti-EGFR Agents
Mol. Cancer Res.,
March 1, 2007;
5(3):
203 - 220.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C Pinto, F Di Fabio, S Siena, S Cascinu, F. Rojas Llimpe, C Ceccarelli, V Mutri, L Giannetta, S Giaquinta, C Funaioli, et al.
Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study)
Ann. Onc.,
March 1, 2007;
18(3):
510 - 517.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Kurai, H. Chikumi, K. Hashimoto, K. Yamaguchi, A. Yamasaki, T. Sako, H. Touge, H. Makino, M. Takata, M. Miyata, et al.
Antibody-Dependent Cellular Cytotoxicity Mediated by Cetuximab against Lung Cancer Cell Lines
Clin. Cancer Res.,
March 1, 2007;
13(5):
1552 - 1561.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
