| HOME | HELP | CONTACT US | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA; Weill Medical College of Cornell University, New York, New York, USA
Key Words. Angiogenesis • Epidermal growth factor receptor • Monoclonal antibodies • Bevacizumab • Cetuximab
Correspondence: Ki Young Chung, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA. Telephone: 212-639-6121; Fax: 646-422-2246; e-mail: chungk{at}mskcc.org
Received April 11, 2005; accepted for publication July 25, 2005.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
LEARNING OBJECTIVES
Top
Learning objectives
Abstract
Introduction
Current practice recommendations
Disclosure of potential...
References
After completing this course, the reader will be able to:
|
ABSTRACT |
|---|
|
TopLearning objectivesAbstractIntroductionCurrent practice recommendationsDisclosure of potential...References |
|---|
|
INTRODUCTION |
|---|
|
TopLearning objectivesAbstractIntroductionCurrent practice recommendationsDisclosure of potential...References |
|---|
Monoclonal Antibodies
Monoclonal antibodies have traditionally been produced from hybridoma cells, which are immortalized mouse B cells derived from the fusion of B cells with myeloma cells. The major drawback to this method of antibody production is that the resultant antibody is a murine protein, and once injected into humans, murine antibodies are often highly antigenic, giving rise to a human anti-mouse antibody (HAMA) response [1]. The HAMA not only has the potential to result in an allergic response but also has the potential to neutralize the therapeutic antibody and so impair tumor targeting.
To circumvent these problems, researchers have developed a number of methods to make antibodies appear more human-like to the immune system. One approach has been to graft regions of human antibodies onto mouse antibodies, producing chimeric and humanized antibodies that can reduce the HAMA response, although this time-consuming process does not completely eliminate the immune reaction.
Another more recent technology is the use of the Xeno Mouse® (Amgen, Inc., Thousand Oaks, CA, http://www.amgen.com) to produce fully humanized antibodies [2]. This transgenic mouse has been genetically engineered by deleting murine immunoglobulin genes and replacing them with a repertoire of human antibody genes.
One antibody derived from the XenoMouse® is ABX-EGF, or panitumumab (Abgenix, Fremont, CA, http://www.abgenix.com). This fully humanized antibody targets the epidermal growth factor receptor (EGFR), which mediates growth signals that stimulate cell growth.
In addition to blocking or stimulating their targets, some monoclonal antibodies may work by inducing complement-dependent cytotoxicity and antibody-dependent cell cytotoxicity (ADCC). These multiple potential mechanisms of action may be at least in part responsible for the differences in clinical trial results of monoclonal antibodies in comparison with small molecule inhibitors (e.g., erlotinib [Tarceva®; OSI Pharmaceuticals, Inc., Melville, NY, http://www.osip.com], gefitinib [Iressa®; Astra-Zeneca Pharmaceuticals, Wilmington, DE, http://www.astrazeneca-us.com]) that target the same pathway.
Bevacizumab
Bevacizumab is a humanized monoclonal antibody that targets and binds to vascular endothelial growth factor-A (VEGF-A), reducing the availability of VEGF ligand for its intended receptor (R1-2) and thereby preventing receptor activation [3]
Kabbinavar et al. reported the first clinical trial of bevacizumab in combination with 5-fluorouracil and leucovorin (5-FU/LV) in previously untreated colorectal cancer patients [4]. This small phase II trial involved 104 patients randomized to two different dose levels of bevacizumab (5 mg/kg or 10 mg/kg) plus weekly 5-FU and high-dose LV (Roswell Park 5-FU/LV schedule) or to 5-FU/LV alone [4]. Despite the small study size, the response rate (RR), time to tumor progression (TTP), and overall survival (OS) were superior in the 5-FU/LV + 5 mg/kg bevacizumab arm, with the 10-mg/kg arm appearing modestly superior to chemotherapy alone but inferior to the low-dose 5-mg/ kg arm (Table 1
). Thrombosis was the most significant adverse event, with five patients in the 5-mg/kg arm and two patients in the 10-mg/kg arm developing a grade 3–4 thrombosis, with one fatality in the 10-mg/kg arm resulting from a pulmonary embolism. Hypertension, proteinuria, and epistaxis were also seen but were relatively infrequent. This randomized phase II trial provided enough preliminary evidence of activity of bevacizumab in combination with 5-FU/LV to justify a definitive phase III trial and suggested that 5 mg/kg every other week would be the appropriate dose to take forward for further development.
|
No crossover to second-line bevacizumab in the IFL/ placebo control arm was permitted. In the final efficacy analysis reported by Hurwitz et al. [6], the IFL/bevacizumab cohort experienced superior outcome to IFL/placebo in every major trial end point: RR (45% versus 35%; p < .003), progression-free survival (PFS) (10.6 months versus 6.2 months; p < .00001), and OS (20.3 months versus 15.6 months, p = .00003) (Table 2).
|
Two rare but extremely serious toxicities were encountered, however. The first was gastrointestinal (GI) perforation. This was a heterogenous group of events that included a perforated gastric ulcer, small bowel perforations, and free air under the diaphragm without an identified source. Six events characterized as GI perforation occurred in patients on the bevacizumab-containing arm (one fatal) compared with none on the chemotherapy-alone arm. No clear risk factors for perforation could be identified from this trial. The other issue of serious concern was that of arterial thrombotic events. Initially, no clear safety signal was detected in this area. However, when a subsequent analysis involving patients from multiple trials was conducted, a concerning pattern was detected. The total combined incidence of such events, which were defined as including cerebral vascular accidents, myocardial infarctions, transient ischemic attacks, and angina, was 2.5% in the nonbevacizumab-containing control arms and 5.0% in the bevacizumab-containing experimental arms. It was initially noted that patients with histories of cardiovascular and/or atherosclerotic disease appeared to be at greater risk for more bevacizumab-related arterial thrombotic complications.
In addition to the pivotal phase III trial, another phase II trial also demonstrated activity of bevacizumab in the first-line treatment of metastatic colorectal cancer [7]. This smaller trial, designed for those patients in whom irinotecan-based therapy was deemed inappropriate by the treating investigator, randomized patients to 5-FU/ LV (Roswell Park Schedule) with placebo or 5 mg/kg of bevacizumab every other week (Table 1
). While the study lacked adequate power to assess a survival advantage, superior response rates and TTP were seen with the bevacizumab-containing arm.
Not convinced of the appropriateness of the 5-mg/kg bevacizumab dose, the Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial (E2200) of IFL plus bevacizumab at 10 mg/kg [8, 9]. Ninety-two previously untreated metastatic colorectal cancer patients were treated. With a median follow-up of 16.7 months, five complete responses (CRs) (5%) and 35 partial responses (PRs) (38%) were reported, with OS yet to be reached (Table 2). Preliminary safety data from 87 patients revealed 47 bleeding events, but only four events of grade 
2. Eleven thrombotic episodes were reported, none fatal. It is difficult to know what we should glean from this trial. The 42% response rate does not appear to be different from (or superior to) the 45% response rate seen with the 5-mg/kg dose in the pivotal trial. Overall, the use of a dose <5 mg/kg dose does not appear to be justified in first-line treatment at this time.
Recently, the use of bevacizumab in second-line therapy in those patients who have not received bevacizumab in the first-line setting has been established by the phase III ECOG trial E3200 [10]. That trial randomized patients who had failed irinotecan and fluorouracil but were naïve to bevacizumab, to one of three arms: bevacizumab/FOLFOX4 (5-FU/LV/oxaliplatin [Eloxatin®; Sanofi-Synthelabo Inc., New York, http://www.sanofi-synthelabo.us]), FOLFOX4 alone, or bevacizumab. Again, ECOG chose to investigate a 10-mg/kg bevacizumab dose. A total of 829 patients was accrued from November 2001 to April 2003, with the bevacizumab monotherapy arm closed in March 2003 by the data safety monitoring committee, reportedly because of inferior activity. The overall RR and median PFS in the bevacizumab/FOLFOX4 arm were clearly superior to those of the FOLFOX4 and bevacizumab-alone arms (RR, 21.8% versus 9.2% versus 3%, respectively; p < .0001; PFS, 7.2 months versus 4.8 months versus 2.7 months, respectively; p < .0001) [11]. A small but statistically significant longer median overall survival was demonstrated in the combination arm compared with FOLFOX4 alone (12.5 months versus 10.7 months; p = .0024), and the incidences of grade 3–4 toxicities were not greater. Interestingly, the median OS times in the FOLFOX4 arm and the bevacizumab-alone arm were indistinguishable (10.7 months versus 10.2 months, respectively; p = .95) [11].
The safety of bevacizumab in combination with oxaliplatin was further addressed by the recently reported Three Regimens of Eloxatin® Evaluation-2 (TREE-2) study, a randomized phase II study of three oxaliplatin–fluoropyrimidine regimens in the first-line therapy of colorectal cancer [12]. The authors of that trial reported that the addition of bevacizumab to an oxaliplatin-containing regimen of infusional 5-FU (FOLFOX) or bolus 5-FU/LV (bFOL) or to capecitabine (Xeloda®; Hoffmann-La Roche Inc., Nutley, NJ, http://www.rocheusa.com) (cape/ox) appeared to produce a superior overall response rate (RR, 57% for FOLFOX; 95% confidence interval [CI], 37%–75%) relative to historic controls from an earlier trial (TREE-1) of FOLFOX alone, with no significant additive toxicity. In an attempt to address the benefit of bevacizumab to more current first-line combinations, a Southwest Oncology Group (SWOG) trial was initiated to compare FOLFOX with CapOx (capecitabine and oxaliplatin) with or without bevacizumab in a 2 x 2 factorial design; however, the trial was forced to close secondary to poor accrual once bevacizumab became commercially available in the U.S. A large industry-sponsored trial has randomized 1,600 patients to front-line FOLFOX4 versus CapOx, with a 2 x 2 randomization to bevacizumab versus placebo. That trial has completed accrual and data are maturing.
|
CURRENT PRACTICE RECOMMENDATIONS |
|---|
|
TopLearning objectivesAbstractIntroductionCurrent practice recommendationsDisclosure of potential...References |
|---|
An important question that remains unresolved at this time is whether to continue bevacizumab with second-line therapy following failure of a bevacizumab-containing first-line regimen. The ECOG 3200 study supports the position that patients who have not received bevacizumab with front-line therapy should receive it as part of their second-line therapy. However, that trial provided no data regarding the question of using bevacizumab in second-line therapy if the patient has failed front-line therapy that includes bevacizumab. A theoretical justification for the continuation of bevacizumab after failure can be made on preclinical grounds, invoking the hypothesis that bevacizumab may normalize tumor interstitial fluid pressure and thereby enhance chemotherapy delivery, as well as possibly inhibit the neovascularization and consequent vascular density of tumors. If the major role of bevacizumab is to normalize tumor interstitial fluid pressure and thereby improve chemotherapy delivery, then failure of clinical response with a bevacizumab-containing regimen could be a reflection of nonresponsiveness to the cytotoxic chemotherapeutic agent and not to bevacizumab. Hence, one could anticipate that bevacizumab might be effective when given with another effective cytotoxic agent. This is a hypothesis worthy of exploration. However, it is just that: a hypothesis. Standard practice should be dictated on evidence-based decisions, not on unsubstantiated hypotheses. A clinical trial addressing the potential benefit of continued bevacizumab with a new chemotherapy regimen after bevacizumab failure is warranted. Until such data are available, however, the risk and expense of continued bevacizumab do not seem justifiable, and continuation of bevacizumab after failure on a bevacizumab regimen should be regarded as investigational. Prospective randomized clinical trials to address this issue have been proposed, but thus far these trials have not been initiated.
The use of bevacizumab as a salvage agent after all other active chemotherapy has failed, even in bevacizumab-naïve patients, does not appear to be supported by current data, and the bevacizumab-naïve patient in the salvage setting should become a much less common phenomenon, as most patients will have received bevacizumab in the first- or second-line setting based on available data from clinical phase III trials [6, 10]. In a trial conducted by the U.S. National Cancer Institute, 350 patients with prior failure on 5-FU, irinotecan, and oxaliplatin (in any combination of regimens) were treated with 5-FU, LV, and bevacizumab [15]. A preliminary report at the American Society of Clinical Oncology meeting in June 2004 on the first 100 patients treated indicated that one of the 100 patients had achieved a major objective response. This would suggest that activity as a salvage agent in the absence of active chemotherapy is negligible, and the routine use of bevacizumab in this salvage setting is not recommended. The 1% RR must be weighed against the 1.5% GI perforation rate and the 2.5% higher incidence of arterial thrombotic events.
Currently, there is no evidence to support the use of bevacizumab in the adjuvant setting, although trials to assess this question are in progress. A U.S. follow-up of the Multicenter International Study of Oxaliplatin/5-Fluorouracil/ Leucovorin in the Adjuvant Treatment of Colorectal Cancer (MOSAIC) trial, a large phase III randomized adjuvant clinical trial by the National Surgical Adjuvant Breast and Bowel Project for stage II/III colorectal patients is comparing FOLFOX6 with FOLFOX6 plus bevacizumab, with the bevacizumab continued for an additional 6 months alone. A large European trial will randomize patients to one of three arms: FOLFOX4/placebo, FOLFOX4/bevacizumab, and CapOx/bevacizumab Pending data from these trials, the use of bevacizumab in stage II and III colon cancer should be regarded as investigational and cannot be recommended for routine standard use at this time.
Cetuximab
Cetuximab is a chimeric immunoglobulin G1 monoclonal antibody that targets the extracellular domain of the EGFR, competitively inhibiting ligand binding and, hence, EGFR activation [16]. Several recent trials have demonstrated the clinical activity of cetuximab in metastatic colorectal cancer. The EGFR, also called HER-1, is a transmembrane glycoprotein that binds specific ligands, EGF and transforming growth factor alpha, to the extracellular domain, leading to dimerization of the receptor with another EGFR (homodimerization) or another member of the EGFR family (heterodimerization). This in turn stimulates phosphorylation of the intracellular tyrosine kinases of the receptor, initiating a cascade of intracellular signaling that ultimately regulates cell proliferation, migration, adhesion, differentiation, and survival [17–19]. Preclinical models demonstrated modest in vitro and in vivo single-agent activity of cetuximab but significant enhancing activity in combination with cytotoxic chemotherapy. Based on these observations, and on a single anecdotal report of a major response to cetuximab plus irinotecan in a young irinotecan-refractory patient, a multicenter phase II trial was initiated and has been reported in abstract form [20]. Patients were treated with the same dose and schedule of irinotecan that they had previously failed, with the addition of cetuximab at the current standard of a 400-mg/m2 loading dose week 1 over 2 hours, followed by weekly doses of 250 mg/m2 over 1 hour. Irinotecan dose reductions made prior to study entry were maintained upon initiation of the trial. One hundred twenty patients with irinotecan-refractory colorectal cancer were identified and enrolled. An additional 28 patients with clinically and radiographically stable disease after receiving a minimum of 3 months of irinotecan therapy were also enrolled and treated by the addition of cetuximab to their irinotecan therapy. The response outcome of this "stable disease cohort" has not been reported. A 22.5% major objective RR for irinotecan-refractory patients was reported by an independent response assessment committee (Table 3). The reported irinotecan toxicity was, not unexpectedly, modest in this population in whom irinotecan dose modifications had already been made during prestudy treatment. Only 3% of patients developed an allergic, anaphylactoid reaction requiring discontinuation of cetuximab therapy. Seventy-five percent of patients treated experienced a skin rash (12% grade 3), characteristic of all EGFR inhibitors. This rash superficially resembles acne, leading to its description as an acneiform rash; however, it is pathophysiologically distinct and, hence, topical acne medications are not effective in its management. The presence of the rash appeared to be associated with response in this study, but this needs to be validated in larger trials.
|
).
A subsequent, larger trial reported by Cunningham et al. [22] provided strong confirmatory evidence of the activity of cetuximab in colorectal cancer. This was a large, randomized phase II trial in irinotecan-refractory patients comparing cetuximab plus irinotecan with cetuximab monotherapy. Three hundred twenty-nine patients were randomized in a 2:1 schema. The RRs of 22.9% for cetuximab plus irinotecan and 10.8% for cetuximab alone were virtually identical to the RRs reported in the U.S. phase II trials. TTP in the Cunningham et al. study was 4.1 months for the combination versus 1.5 months for single-agent cetuximab. Survival in the two arms was not significantly different (Table 3).
Addressing the role of second-line cetuximab in irinotecan-naïve disease, a randomized phase III trial (CA225-006) is comparing cetuximab plus irinotecan with irinotecan alone as second-line chemotherapy for patients with EGFR-positive metastatic colorectal cancer progressing on an oxaliplatin/5-FU–based regimen. A palliative National Cancer Institute of Canada Clinical Trial Group phase III clinical trial is comparing cetuximab plus best supportive care with best supportive care alone in patients for whom best supportive care is the only remaining treatment option. Again, EGFR positivity is mandatory for eligibility in this clinical trial. A total of 500 patients is expected for accrual, with treatment to continue in the absence of disease progression or unacceptable toxicity.
Cetuximab has established activity in the salvage setting; however, its role in first-line therapy remains investigational at this time. Preliminary data from phase II trials have reported encouraging results, however. A small phase II pilot trial of cetuximab plus weekly bolus IFL demonstrated a 44% RR [23]. A phase II experience of cetuximab plus irinotecan and weekly infusional 5-FU/LV has also been reported [24]. A phase II trial of FOLFOX4 plus cetuximab for previously untreated metastatic colorectal cancer patients reported preliminary encouraging activity [25]. Of 43 patients enrolled, 42 evaluable, 4 CRs and 30 PRs were reported for a RR of 81%, without a higher incidence of grade 3–4 diarrhea or neutropenia compared with historical controls. A phase I/II trial of cetuximab plus 5-FU/LV (two dose cohorts) and weekly oxaliplatin (50 mg/ m2) (FUFOX) in first-line treatment has reported preliminary data from 38 of 49 enrolled patients [26]. One CR and 20 PRs were reported with an overall RR of 55%. The 41 patients evaluable at dose level 2 reported significant grade 3–4 diarrhea (24%) and skin reactions (17%), and preliminarily 7% grade 3–4 neurotoxicity. Additionally, a phase I/II trial of FOLFIRI plus cetuximab in first-line therapy with two dose levels of 5-FU resulted in encouraging preliminary data [27]. Of 40 evaluable patients, a 43% PR rate (95% CI, 27%–59%) was reported, with five initially unresectable patients undergoing an R0 resection and with minimal grade 3–4 toxicities (17% leukopenia, 14% diarrhea, 11% nausea and vomiting, 7% asthenia, 7% skin reaction).
Thus far, no randomized trials of first-line cetuximab plus chemotherapy have been reported. As such, no data are available on what impact, if any, this drug will have on survival and other efficacy end points in first-line combinations. Several such trials are in progress or in the planning stages, but given the cutaneous toxicity as well as the significant economic cost of extended cetuximab treatment, front-line use of cetuximab must be regarded as investigational at this time. The role of cetuximab in adjuvant therapy of stage III colon cancer is also being investigated, but again this remains a study question and not part of standard care at this time.
A multicenter phase III clinical trial is currently comparing FOLFOX4 plus cetuximab with FOLFOX4 alone in irinotecan-refractory colorectal cancer patients. Similar to all the phase II trials to date, EGFR positivity by immunohistochemistry (IHC) is a mandatory eligibility requirement.
The development of cetuximab in colorectal cancer was grounded on the premise that EGFR expression by IHC would be prognostic for cetuximab activity, with all trials to date requiring EGFR positivity by IHC. Yet all the reported cetuximab trials demonstrate no correlation between intensity of EGFR expression and clinical response, challenging this premise [21, 22]. Lenz et al. reported, in abstract form, the results of a small cohort of nine EGFR-negative patients who were entered into a clinical trial of single-agent cetuximab [28]. Two major objective responses were reported by the investigators. On this basis, a decision was made at Memorial Sloan-Kettering Cancer Center that EGFR-negative colorectal cancer patients would not be excluded from standard off-protocol treatment with cetuximab simply on the basis of EGFR status. The retrospective institutional review of these patients treated in the first 3 months of cetuximab commercial availability identified 16 chemotherapy-refractory, EGFR-negative colorectal cancer patients who received cetuximab in a nonstudy setting [29]. Fourteen of those patients received cetuximab plus irinotecan and two received cetuximab monotherapy. Of the 16, four major objective responses were seen (RR, 25%; 95% CI, 4%–46%). This institutional series demonstrates that colorectal cancer patients with EGFR-negative tumors have the potential to respond to cetuximab-based therapies. EGFR analysis by current IHC techniques does not appear to have predictive value, and selection or exclusion of patients for cetuximab therapy on the basis of currently available EGFR IHC does not appear warranted.
Bevacizumab Plus Cetuximab
The Bowel Oncology with Cetuximab Antibody (BOND)-2 trial addressed the feasibility and, in a preliminary manner, efficacy of bevacizumab added to cetuximab alone or to cetuximab plus irinotecan in patients with irinotecan-refractory disease [30]. Preliminary data were encouraging, with 23% and 38% RRs, and 6.9-month and 8.5-month TTPs, respectively, which appear significantly better than those of historical controls from the BOND-1 trial (RR, 11% and 23%; TTP, 1.5 months and 4 months) [22, 30]. It should be noted, however that this is a small trial, with 39 and 35 patients, respectively, reported in the two arms in this preliminary report. Ninety percent of the patients in this study also previously received oxaliplatin, making the combination an effective salvage regimen. No unexpected grade 3–4 toxicities were discovered.
An intergroup trial (Cancer and Leukemia Group B [CALGB]/SWOG 80405) will attempt to address the role of cetuximab and bevacizumab in first-line therapy for colorectal cancer. Investigators will choose which initial chemotherapy regimen (modified FOLFOX6 or FOL-FIRI) will be used, and patients will then be randomized to receive either cetuximab, bevacizumab, or both agents together in conjunction with their chemotherapy. A follow-up study to the BOND-2 study, known as the BOND-2.5 trial, will assess the activity of the cetuximab–bevacizumab–irinotecan combination in patients who have previously progressed through a bevacizumab-containing regimen.
Other EGFR-Targeting Agents
Panitumumab, formally known as ABX-EGF, is a fully humanized monoclonal antibody that also targets the EGFR. Similar to cetuximab trials, preliminary data from a phase II trial of panitumumab in colorectal cancer patients reported a 10% RR, with over 90% of patients experiencing some degree of acneiform rash, although only 3% with grade 3 [31]. Only one of the 148 patients treated experienced a dose-limiting allergic reaction, supporting the contention that a humanized monoclonal antibody would elicit a lower incidence of allergic reactions than the chimeric monoclonal antibody cetuximab. Further clinical studies, including chemotherapy plus panitumumab trials, are yet to be reported.
EMD 72000, another fully humanized monoclonal antibody against the EGFR, has also demonstrated some anti-tumor activity in colorectal cancer patients in early clinical trials. The reported phase I trial enrolled 22 patients, 11 patients with heavily pretreated colorectal adenocarcinoma [32]. Two of the 11 enrolled colorectal cancer patients experienced a confirmed PR, with no grade 3 toxicities reported. Although encouraging, responses should be further validated in phase II trials. Thus far, the limited experience with the oral EGFR tyrosine kinase inhibitors gefitinib and erlotinib has not been encouraging in colorectal cancer, with no significant single-agent activity shown for either of these agents [33, 34]. A single-center, open-label phase II trial of FOLFOX4 plus gefitinib reported a 77% objective response rate in 30 evaluable patients [35]. However, the wide 95% CIs of such a small study and the significant toxicity reported, including 54% grade 3–4 diarrhea and 52% grade 3–4 neutropenia, makes the combination prohibitive at the dose levels used in the trial.
Conclusion
The integration of biologically targeted agents with conventional cytotoxic chemotherapy has already significantly impacted the survival of patients with advanced colorectal cancer. Through improvements in selecting responsive patients based on the molecular biology and behavior of colorectal cancers, we may eventually individualize the optimal therapeutic approach for each patient.
|
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST |
|---|
|
TopLearning objectivesAbstractIntroductionCurrent practice recommendationsDisclosure of potential...References |
|---|
|
REFERENCES |
|---|
|
TopLearning objectivesAbstractIntroductionCurrent practice recommendationsDisclosure of potential...References |
|---|
This article has been cited by other articles:
 |
|
 |
|
  S. DEEN, O. L. GRIFFITH, H. MASOUDI, A. GOWN, S. J.M. JONES, and S. M. WISEMAN Anaplastic Thyroid Carcinoma Exhibits Intratumoral Molecular Homogeneity for a Therapeutic Target Panel Anticancer Res, July 1, 2009; 29(7): 2437 - 2444. [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]
|
|
|
|
 |
|
 C. Maccalli, V. Di Cristanziano, V. Fodale, D. Corsi, G. D'Agostino, V. Petrangeli, L. Laurenti, S. Guida, A. Mazzocchi, F. Arienti, et al. Induction of Both CD8+ and CD4+ T-Cell-Mediated Responses in Colorectal Cancer Patients by Colon Antigen-1 Clin. Cancer Res., November 15, 2008; 14(22): 7292 - 7303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Prewett, D. S. Deevi, R. Bassi, F. Fan, L. M. Ellis, D. J. Hicklin, and J. R. Tonra Tumors Established with Cell Lines Selected for Oxaliplatin Resistance Respond to Oxaliplatin if Combined with Cetuximab Clin. Cancer Res., December 15, 2007; 13(24): 7432 - 7440. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J-P Machiels, C Sempoux, P Scalliet, J-C Coche, Y Humblet, E Van Cutsem, J Kerger, J-L Canon, M Peeters, S Aydin, et al. Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer Ann. Onc., April 1, 2007; 18(4): 738 - 744. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K. Hahn, J. J. Wolff, and J. M. Kolesar Pharmacogenetics and irinotecan therapy Am. J. Health Syst. Pharm., November 15, 2006; 63(22): 2211 - 2217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-J. Lenz, E. Van Cutsem, S. Khambata-Ford, R. J. Mayer, P. Gold, P. Stella, B. Mirtsching, A. L. Cohn, A. W. Pippas, N. Azarnia, et al. Multicenter Phase II and Translational Study of Cetuximab in Metastatic Colorectal Carcinoma Refractory to Irinotecan, Oxaliplatin, and Fluoropyrimidines J. Clin. Oncol., October 20, 2006; 24(30): 4914 - 4921. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Nagorsen and E. Thiel Clinical and immunologic responses to active specific cancer vaccines in human colorectal cancer. Clin. Cancer Res., May 15, 2006; 12(10): 3064 - 3069. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. R. Adams Evolving role of antineoplastic agents in colorectal cancer Am. J. Health Syst. Pharm., May 1, 2006; 63(9_Supplement_2): S4 - S11. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | CONTACT US | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| THE ONCOLOGIST | STEM CELLS | CME | ALPHAMED PRESS JOURNALS |
