Advances in the Management of Colorectal Cancer: Proceedings from ASCO 2004

Colorectal cancer continues to be a leading cause of cancer-related mortality, accounting for approximately 20% of the estimated U.S. cancer deaths in 2004. [1] Current research aimed at improving the management of colorectal cancer was presented at the 40th Annual Meeting of the American Society of Clinical Oncology (ASCO) held in New Orleans, LA, June 3-8, 2004.

The following is a summary and discussion of some of the notable abstracts that explore issues and options in the management of colorectal cancer that were presented at ASCO this year. The topics are divided into four general areas:

Researchers from the QUASAR cooperative group in the United Kingdom presented evidence that adjuvant chemotherapy produces a small, but statistically significant, overall survival benefit over observation in stage II colorectal patients.[2] While FOLFOX is the only combination regimen that has proven efficacy in the adjuvant treatment of colon cancer, results from several other regimens were reported this year at ASCO. Researchers from the Cancer and Leukemia Group B (CALGB) presented results indicating that IFL (Camptosar® (irinotecan), 5-FU, and lecovorin) did not improve overall survival or failure-free survival compared to 5-FU/LV.[3] A study completed by researchers from Europe, Australia, and Canada suggested that Xeloda® (capecitabine) may be an acceptable alternative to 5-FU/LV.[4] Furthermore, researchers from the National Surgical Adjuvant Bowel Project (NSABP) reported that tegafur and uracil (UFT) plus leucovorin produced outcomes equivalent to 5-FU/LV.[5]

Adjuvant chemotherapy vs. observation: Dr. Richard Grey reported in the oral session that chemotherapy with 5-FU plus leucovorin produces a small, but statistically significant, survival benefit for patients with stage II colorectal cancer. This study compared adjuvant chemotherapy versus observation in 3,238 patients with colorectal cancer who were deemed by their treating physician to have a questionable indication for adjuvant therapy. Of these 3,238 patients, 92% were stage II and 8% were stage III. The population included both colon and rectal patients, with 71% of the patients having colon cancer. Chemotherapy consisted of 5-FU/LV, given either as a daily x 5 or a weekly bolus schedule, with high or low-dose leucovorin and with or without levamisole. Previously reported data from the stage III patients in this trial (a population not reported on at this meeting) demonstrated that the different 5-FU schedules, the low versus high-dose leucovorin, and the presence or absence of levamisole all resulted in therapeutically equivalent regimens. As such, the treated patients can be appropriately viewed as having received a uniform therapy (5-FU/LV) and can be compared to the randomized, observation-only control arm.

Risk of recurrence was decreased and overall survival was improved, albeit modestly, with 5-FU/LV chemotherapy (see table 1). Treatment efficacy did not differ significantly by stage or site; however, an interesting observation was that the relative survival benefit for chemotherapy was almost absent in patients over the age of 70.

Table 1 Rate/risk of 5-year recurrence and 5-year survival with chemotherapy or observation

The researchers concluded that the small (2.9%) survival benefit of adjuvant chemotherapy sufficiently outweighed the inconvenience and cost for high-risk and younger patients (under 70 years of age).²

The 2%-3% survival benefit for treatment of stage II patients is consistent with what has been reported previously by the IMPACT group; however, this is the first large-scale trial to report this difference to be statistically significant. Many questions still remain. As the investigators point out, a metananalysis of randomized trials in stage II colon cancer would be useful; however, results would be likely to confirm what this trial has shown: that the survival advantage is small but real. This would leave physicians with the same conundrum they face now: is it worth it? Is the risk, discomfort, and expense of chemotherapy worth the improved 2%-3% cure rate? Is it appropriate for all patients or only higher-risk patients? Is it appropriate for younger patients? Where do the relative risks and expenses of more toxic and more expensive chemotherapies fit into the management of stage II disease? These are questions that remain to be addressed and physicians will likely be dealing with them, both on an individual and a societal level, for quite some time.

Adjuvant IFL : A phase III trial performed by the NCI intergroup (CALGB, NCCTG, ECOG, SWOG, and NCIC) showed that bolus IFL did not produce an improvement in overall survival or failure-free survival compared to bolus 5-FU/LV (Roswell Park Schedule) in the treatment of patients with stage III colon cancer. Furthermore, IFL was associated with a greater degree of neutropenia, neutropenic fever, and death on treatment compared to 5-FU/LV. The incidence of dose-limiting diarrhea and nausea/vomiting, however, was similar in both arms.

This trial involved 1,264 patients who had stage III (Tany/N1-2/M0) disease. After a median follow-up of 3 years, which included 75% of expected deaths and 95% of total expected failures, IFL showed no improvement , and absolutely no trend towards improvement, over 5-FU/LV in either overall survival (p=0.81) or failure-free survival (p=0.89). The firm conclusion from this study is that weekly IFL should not be used in the management of stage III colon cancer. ^{3< /SUP>}

At this time, there is no satisfactory explanation for why this trial was negative. Given the proven survival advantage of irinotecan as a second-line agent following first-line fluorouracil failure and the survival advantage shown in two large randomized first-line metastatic studies of irinotecan/fluorouracil/leucovorin over fluorouracil/leucovorin, a survival advantage for this combination in the adjuvant setting seemed a reasonable expectation. The study was adequately powered and the arms were well balanced. One possible hypothesis is that the higher hematologic toxicity of IFL led to a greater decrease in total drug delivery, and a greater number of patients withdrawing from study, on the IFL arm.

It is noteworthy that this trial investigated irinotecan plus bolus 5-FU/LV. Two trials ongoing in Europe, the PETACC III trial and the ACCORD II trial are assessing the use of Camptosar® plus biweekly infusional 5FU/LV (FOLFIRI) in the adjuvant treatment colon cancer. These trials have completed accrual and results from these trials are anticipated to be available in late 2004.

Perhaps one of the most important points that can be gleaned from the results of this trial is the importance of doing the definitive randomized trials to test out hypotheses and the importance of not making the leap that a therapy that has efficacy in metastatic disease will necessarily have efficacy in the adjuvant setting. There were some clinicians that felt that this trial was unnecessary, or even unethical, because physicians already “knew” that IFL was better, based on its superior efficacy in stage IV disease. This should serve as a cautionary note regarding newer active agents such as cetuximab (Erbitux®) or Avastin® (bevacizumab). The use of these agents in metastatic disease, as outlined in more detail below, is now part of standard practice. The use of these and other new agents in the adjuvant setting is an appropriate question for clinical trials, but not an appropriate addition to standard practice in the absence of both efficacy and safety data.

Adjuvant Xeloda®: Results from a phase III, international study (known as the X-ACT study) suggest that oral Xeloda® may be an acceptable alternative to parenteral 5-FU/LV in the adjuvant treatment of stage III colon cancer. Compared to the Mayo Clinic Schedule of 5-FU/LV, Xeloda® demonstrated an improved safety profile and equivalence in disease-free and overall survival, supported by statistically superior recurrence-free survival.

This study, involved a total of 1,987 patients from 164 centers. Patients with resected Dukes’ C colon carcinoma were randomized to receive either Xeloda® or 5-FU/LV. The pre-specified primary endpoint was event-driven, non-inferiority in disease-free survival.

Results showed a non-significant trend for improved disease-free survival and overall survival, with a significant improvement in relapse-free survival (see table 2). Furthermore, subgroup analysis showed Xeloda® treatment was superior across all groups, including age, nodal status, and gender.

When age, gender, lymph nodes, and baseline CEA were considered in multivariate analysis, treatment with Xeloda® predicted for improved DFS, RFS and OS (see table 3).

Table 3 Treatment with Xeloda® predicted for improved DFS, RFS and OS in Multivariate Analysis.

There was improved safety with Xeloda® compared to 5-FU/LV across all types and grades of adverse events, with the exception of hand-foot syndrome (p<0.0001). Xeloda® caused significantly less (p<0.0001) diarrhea, nausea/vomiting, alopecia, and neutropenia and less grade 3-4 neutropenia, stomatitis, and neutropenic fever/sepsis. This safety profile was maintained in older patients. Dose modifications, interruptions, or delays in Xeloda® were required in 57% of patients, however, indicating that active management of toxicities is required.⁴

It should be noted that this study was performed in Europe. For reasons not completely clear, Xeloda® appears to be better tolerated by European patients than by American patients. One hypothesis is that Americans, having higher folate levels secondary to folate supplementation in grain products, may be predisposed to higher toxicity on this basis. Both anecdotally and in clinical trials, dose reductions below the starting dose of 2500 mg/m2/day (divided b.i.d.) are commonly required and many American oncologists have begun routinely using a lower starting dose in the metastatic setting. Use of a lower starting dose would not be recommended in the adjuvant setting in the absence of supportive data, and the full 2500 mg/m2/day should be used, with dose adjustments applied as needed for toxicity.

Adjuvant UFT: A phase III trial (NSABP C-06) comparing oral tegafur and uracil (UFT) plus LV with 5-FU/LV showed equivalence of the two regimens in the treatment of stage II/III colon cancer. There were 1,608 patients involved in this study. There was no significant difference in relapse-free, disease-free, or overall survival after a 5-year follow-up (see table 4). Since this trial was adequately powered for non-inferiority, the researchers asserted that the primary endpoint was met.⁵

As reported by Dr. Norman Wolmark, UFT has shown equivalence to Mayo clinic 5-FU/LV in metastatic disease in two large, previously reported trials. (A supporting finding of the equivalence of UFT/LV and parenteral 5-FU/LV was a phase IV trial in the treatment of metastatic disease presented at the general poster session, which showed no significant difference in overall survival between treatment with tegafur plus leucovorin (375 days) and 5-FU/LV (377 days, p>0.05).)[6] This current adjuvant trial indicates that UFT/LV is an acceptable alternative to 5-FU/LV. UFT/LV is not, however, commercially available in the United States.

The monoclonal antibodies Avastin® and cetuximab continued to be the main points of interest for metastatic disease this year. Final phase III results reported in the New England Journal of Medicine just prior to the ASCO conference confirm that IFL plus Avastin® improves outcomes over IFL alone. [7] While a placebo-controlled trial produced only a trend toward improved survival with Avastin®, progression-free survival was significantly increased. Other treatments that were reported to be safe and/or effective in metastatic colorectal cancer include cetuximab combined with FOLFOX-4 or FOLFIRI and Iressa® combined with FOLFOX-4.

Avastin®: Avastin® is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF). VEGF appears to play an important role in tumor angiogenesis and blocking this activity should have an anti-tumor effect. Clinical trials of Avastin® have been carried out for the past 2-3 years without evidence of significant clinical activity as a single agent. However, more recent studies have suggested that combining Avastin® with chemotherapy can be effective in patients with advanced prostate, pancreatic, colon cancer, and advance or metastatic adenocarcinoma of the lung. The primary side effects of Avastin® identified in phase II studies include venous thrombosis and hypertension.

IFL plus Avastin®: The final results of a multi-center, randomized trial of IFL plus Avastin® were reported in the June 3, 2004 issue of the New England Journal of Medicine. This study was presented in preliminary form at the 39th Meeting of the American Society of Clinical Oncology in 2003. Final results show an improvement in outcomes with the addition of Avastin® to IFL among newly diagnosed patients with metastatic colorectal cancer.⁷

A previously reported phase II trial randomly allocated 104 patients with previously untreated metastatic colorectal cancer to receive 5-FU and leucovorin on the Roswell Park schedule, either alone, with Avastin® 5 mg/kg every other week, or with Avastin® 10 mg/kg every other week.[8] In this small, randomized, phase II study, the best response rate and time to tumor progression was seen in the arm that received 5FU/LV plus 5 mg/kg Avastin®. This dose of Avastin® was then taken forward for phase III study.

The definitive phase III study evaluated 813 patients with previously untreated metastatic colorectal cancer who were randomly allocated to receive weekly bolus IFL with either a placebo or Avastin® at 5 mg/kg. Results demonstrate that the addition of Avastin® to IFL chemotherapy produced an increase in response rate, time to tumor progression, 1-year survival, and overall survival (see table 5).

Overall levels of grade 3 or 4 adverse events were modestly higher in the Avastin®-containing arm (84.9% versus 74%, P<0.01). Much of this difference appears attributable to a higher incidence of grade 3 hypertension (11% versus 2.3%, p<0.01). There were no statistically significant differences in grade 3-4 leucopenia, diarrhea, or in thrombotic events. A 1.5% incidence (6 patients) of gastrointestinal perforation was seen on the Avastin®-containing arm, while no such events occurred on the chemotherapy-only arm. There were no differences in treatment-related deaths or adverse events leading to hospitalization. Interestingly, although concerns had been previously raised about possible proteinuria as a consequence of Avastin® treatment, there were no statistically significant differences between the two arms for proteinuria of any grade, proteinuria grade 2, or proteinuria grade 3.

Placebo-controlled results with Avastin®: At ASCO 2004, a placebo-controlled study was presented at a poster discussion session that demonstrated a statistically significant prolongation of progression-free survival with 5-FU/LV plus Avastin® compared to 5-FU/LV plus placebo. This study was conducted in patients with metastatic colorectal cancer who were felt by their treating investigators to be not suitable candidates for first-line Camptosar®-based therapy due to advanced age or compromised performance status. The patients who received 5-FU/LV plus Avastin® had a progression-free survival of 9.2 months, compared to 5.5 months for those who received 5-FU/LV plus placebo (p=0.0002). However, there was only a trend toward improved survival, the primary endpoint, with a median survival for the patients who received 5-FU/LV plus Avastin® of 16.6 months versus 12.9 months for patients who received the 5-FU/LV plus placebo (p=0.16).[9]

EGFR-inhibitors for metastatic colorectal cancer: Previous studies have shown that cetuximab produces response rates between 11%-23% in patients with Camptosar®-refractory colorectal cancer.[10],[11],[12] (The results of these studies are summarized in Table 6 below.) Building on this confirmed activity in colorectal cancer, several groups reported further data using cetuximab in colorectal cancer.

Lenz, et al reported a large multi-center trial of 346 patients who were refractory to both Camptosar® and Eloxatin® (oxaliplatin), who were treated with single agent cetuximab. The investigator-reported response rate was 12.1% and the independent radiology review confirmed an 11.6% response rate. [13]

Perhaps most importantly, this study enrolled a small cohort of 9 patients who were EGFR-negative by immunohistochemistry. Two of these patients were felt to have achieved major objective responses by the investigators, with one being confirmed by the radiology review committee and one being felt by radiology to be stable disease. In this context, it is appropriate to note that in all of the trials reported to date with cetuximab, there has been no correlation between EGFR intensity and cetuximab clinical activity. The small EGFR-negative cohort reported by Lenz is the first cohort of documented EGFR-negative patients to be treated with cetuximab, and that these patients show some activity further adds to the evidence that EGFR immunohistochemical staining is of no prognostic value. Selection of patients for cetuximab treatment on the basis of EGFR immunohistochemical staining appears to be a hypothesis that has turned out to be wrong. There does not appear to be evidence to support selection of a patient for cetuximab therapy because of high EGFR expression, nor does it appear appropriate to exclude a patient from cetuximab therapy on the basis of low or absent EGFR expression.

Several abstracts were presented which investigated the use of cetuximab in combination with chemotherapy in first-line treatment of metastatic disease. Tabernero, et al reported a small phase II trial of cetuximab plus FOLFOX. [14] Toxicity was tolerable and was what would be expected from the drugs involved. Activity was encouraging, with an 81% major objective response rate in 43 patients. Clearly this combination warrants further investigation, although the small numbers and wide confidence intervals would argue against routine off-study use of this regimen at this time.

Rougier, et al reported a small experience with FOLFIRI plus cetuximab. [15] Again, toxicity was manageable and predictable. Forty-six percent of patients had a major objective response and 41% had stable disease. The activity of this combination appears interesting; however, the numbers are quite small (only 22 patients evaluable for response) and again, randomized trials will be needed to establish whether front-line use of cetuximab is warranted.

Fisher, et al presented a phase II study of FOLFOX plus the small molecule EGFR inhibitor Iressa® in combination with FOLFOX. [16] In single-agent trials thus far, Iressa® has shown essentially no activity in colorectal cancer. Yet in this trial, the combination of FOLFOX plus gefitinib showed a high response rate, with 77% of 30 previously untreated patients and 29% of 24 previously treated patients achieving a partial response. Toxicity was extremely severe, however, with a 53% rate of grade 3-4 diarrhea. It is unclear whether there is a true synergy between Iressa® and FOLFOX. The response rate appears high; however, for the small numbers involved, this is within the expected 95% confidence intervals for FOLFOX alone. The greater than 50% grade 3-4 diarrhea rate appears to be unacceptable, especially given the available alternative of cetuximab, which does not appear to add to the GI toxicity of FOLFOX.

Hecht, et al reported an update of a large phase II trial of the humanized monoclonal anti-EGFR antibody panitumumab (ABX-EGF). [17] This agent appears thus far to be similar to cetuximab, with perhaps a somewhat lower incidence of allergic reactions. A 10% response rate and only one allergic reaction was seen in a population of 148 chemotherapy-refractory colorectal cancer patients. As is the case with cetuximab, no correlation between EGFR expression by immunohistochemstry and clinical activity was seen.

Dr. Jenny Poynter delivered a plenary session presentation of the results of a large population-based, case-controlled investigation of the effect of HMG-CoA reductase inhibitors (“statins”) on the risk of developing colorectal cancer. [18] HMG-CoA reductase has been shown to be overexpressed in colorectal cancer cell lines. In preclinical systems, statins have been shown to induce apoptosis in colorectal cancer cell lines and also reduce colorectal cancer development in animal models. Evaluation of patients in a randomized study of statin use for cholesterol management in patients with myocardial infarction suggested a decreased incidence of colorectal cancer in patients treated with statins.

In the study presented, called The Molecular Epidemiology of Colorectal Cancer Study (MECC), subjects participated in an interview that assessed personal and family history of cancer, screening practices, other medical conditions, medication use, physical activity, and nutritional data, including a food frequency questionnaire.

Use of statins was measured by self report. Those with a duration of use of five years or more were defined as “users” and accounted for 328 (17.1%) of the 3,773 cases evaluated in this study. The most commonly used statins were prevastatin (44 case and 100 control) and simvastatin (54 case and 118 control).

Results showed a significant protective effect among statin users, with an unadjusted odds ratio (OR) of 0.49 (p=0.0001). This association remained when adjusted for potential confounders including aspirin/NSAID use, ethnicity, physical activity, diet, hypercholesterolemia, family history of CRC (OR 0.54, p=0.0001). Thus, statin use was associated with a 46% reduction in the risk of colorectal cancer after adjustment for other known risk factors.

There was no evidence of synergy between statin and NSAID use (p=0.54). The reduction of cancer risk was significant for both colon and rectal cancer patients (OR 0.53, p<0.0007 and 0.38, <0.0038, respectively).^{18< /SUP>}

There are some limitations of this study. It is an observational study, not a randomized trial. Limited information is available on dose and duration of statin use and exposure data were collected retrospectively. Nevertheless, this is a compelling study that adds significantly to the growing body of evidence that alteration of lipid metabolism is a potentially useful approach to the prevention of colorectal cancer.

Two studies presented at the oral colorectal cancer session reported on evaluation of lymph nodes in colorectal cancer. Findings indicate that both the size, as well as the number, of lymph nodes examined may be related to survival and that examination of sentinel lymph nodes failed in a multi-center cooperative group trial to predict nodal status in more than half of cases.

Size and number of lymph nodes examined: Researchers from the MD Anderson Cancer Center reported that not only the number of lymph nodes examined, but also the size of the nodes as well, correlates with overall survival in patients with stage II colorectal cancer. [19]

Previous research has indicated that the number of lymph nodes reported in colorectal cancer surgical specimens is often suboptimal. Reporting of a greater number of lymph nodes may reflect greater thoroughness of the surgical dissection, greater thoroughness of the pathological examination, or both.

The investigators in this trial retrospectively evaluated all of the slides from 129 patients with stage II colorectal cancer treated with surgery alone. Number of lymph nodes sectioned, as well as overall size of the lymph nodes were assessed by pathologists blinded to the patients’ clinical outcomes. Results were then compared with overall survival results.

The mean number of lymph nodes examined was 10. A larger number of examined lymph nodes was associated with better overall survival. Mean survival for patients with more than the median number of lymph nodes examined was 127.7 months, compared to 103.1 months for the median (p=0.007). In addition, the mean overall survival of patients with larger lymph nodes was longer: 119.8 months versus 110.6 months (p=0.007) (determined on the basis of the largest lymph node present in the specimen). Overall survival was best in patients with large numbers of large nodes and worst in patients with small numbers of small nodes. The authors hypothesize that large and numerous nodes may be an indicator of a robust host immune response against the tumor.19

Evaluation of sentinel lymph nodes: Bertagnolli, et al from the CALGB reported that examination of sentinel lymph nodes failed to predict nodal status in 54% of cases. They concluded that analysis of sentinel nodes is unlikely to predict the nodal status of the patient, and studies to examine micrometastatic disease should involve all draining nodes removed. [20]

In conclusion, ASCO 2004 was not the watershed year for colorectal cancer data that 2003 was, but many useful and important abstracts were presented. Oral chemotherapy for adjuvant treatment of colorectal cancer has been validated as a viable option versus 5FU/LV. How these data will be used in the face of the FOLFOX data presented last year remains to be determined. The role of chemotherapy for stage II colon cancer remains an area of controversy, but now at least one study does show that the survival benefit, albeit small, to chemotherapy in this setting is statistically significant. The role of Avastin® and cetuximab continues to evolve, and the potential role of statins as chemopreventive agents in colorectal cancer has now been highlighted.

Colorectal cancer remains a major public health issue, and remains the number two cause of cancer death in the U.S.; however, it is clear that progress is being made, and clinicians will have to work to stay abreast of the continuing flood of new options and new information in order to be able to offer patients the best possible options.

[1]American Cancer Society. Cancer Statistics 2004: A Presentation from the American Cancer Society. http://www.cancer.org/downloads/PRO/Cancer%20Statistics%202004.ppt Accessed on June 15, 2004.

[2]Gray RG, Barnwell J, Hills R, McConkey C, et al. QUASAR: A randomized study of adjuvant chemotherapy (CT) vs observation including 3258 colorectal cancer patients. Proceedings from the 40^th annual meeting of the American Society of Clinical Oncology held in New Orleans LA, June 5-8, 2004; Abstract #3501.

[3]Saltz LB, Niedzwiecki D, Hollis D, Goldverg RM, et al. Irinotecan plus fluorouracil/leucovorin (IFL) versus fluorouracil/leucovorin along (FL) in stage III colon cancer (Intergroup trial CALGB C89803). Proceedings from the 40^th annual meeting of the American Society of Clinical Oncology, held in New Orleans LA, June 5-8, 2004; Abstract #3500.

[4]Cassidy J, Scheithauer W, McKendrick J, Kroning H, et al. Capecitabine (X) vs bolus 5-FU/leucovorin (LV) as adjuvant therapy for colon cancer (the X-ACT study): Efficacy results of a phase III trial. Proceedings from the 40^th annual meeting of the American Society of Clinical Oncology, held in New Orleans LA, June 5-8, 2004; Abstract #3509.

[5]Wolmark N, Wieand S, Lembersky B, Colangelo L, et al. A phase III trial comparing oral UFT to FULV in stage II and III carcinoma of the colon: Result of NSABP Protocol C-06. Proceedings from the 40^th annual meeting of the American Society of Clinical Oncology held in New Orleans LA, June 58, 2004; Abstract #3508.

[6]Salud A, Saigi E, Batiste-Alentorn E, Losa F, et al. Randomized phase IV trial of oral tegafur and low dose leucovorin versus intravenous 5-fluorouracil and leucovorin in the treatment of advanced colorectal cancer: Final results. Proceedings from the 40^th annual meeting of the American Society of Clinical Oncology, held in New Orleans LA, June 5-8, 2004; Abstract #3547.

[7]Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. New England Journal of Medicine. 2004;350:2335-2342.

[8]Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. Journal of Clinical Oncology. 2003;21:60-65.

[9]Kabbinavar F, Schulz J, McCleod M, Patel T, et al. Bevacizumab (Avastin™), a monocloncal antibody to vascular endothelial growth factor, prolongs progression-free survival in first-line colorectal cancer patients who are not suitable candidates for first-line CPT-11. Proceedings from the 40th annual meeting of the American Society of Clinical Oncology, New Orleans LA, June 5-8, 2004; Abstract #3516.

[10]Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. New England Journal of Medicine. 2004;351:337-345.

[11]Saltz L, Rubin M, Hochster H, et al. Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Proceedings from the 37^th Annual meeting of the American Society of Clinical Oncology 2001; Abstract #7.

[12]Saltz L, Meropol N, Loehrer P, et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. Journal of Clinical Oncology. 2004:1201-1208.

[13]Lenz HJ, Mayer RJ, Gold P, Mirtsching B, et al. Activity of cetuximab in patients with colorectal cancer refractory to both irinotecan and oxaliplatin. Proceedings from the 40th annual meeting of the American Society of Clinical Oncology, New Orleans LA, June 5-8, 2004; Abstract #3510.

[14]Tabernero J,Van Cutsen E, Sastre J, Cervantes A, et al.An international phase II study of cetuximab (Erbitux®) in combination with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with metastatic colorectal cancer (CRC) expressing Epidermal Growth Factor Receptor (EGFR). Preliminary results. Proceedings from the 40th annual meeting of the American Society of Clinical Oncology, New Orleans LA, June 5-8, 2004; Abstract #3512.

[15]Rougier P, Raoul JL, Van Laethem JL, Peeters M, et al. Cetuximab + FOLFIRI as first-line treatmetn for metastatic colorectal cancer. Proceedings from the 40th annual meeting of the American Society of Clinical Oncology, New Orleans LA, June 5-8, 2004; Abstract #3513.

[16]Fisher GA, Kuo T, Cho CD, Halsey J, et al. A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer.Proceedings from the 40th annual meeting of the American Society of Clinical Oncology, New Orleans LA, June 5-8, 2004; Abstract #3514.

[17]Hecht JR, Patnaik A, Malik I, Venook A, et al.ABX-EGF monotherapy in patients with metastatic colorectal cancer (mCRC): An updated analysis. Proceedings from the 40th annual meeting of the American Society of Clinical Oncology, New Orleans LA, June 5-8, 2004; Abstract #3511.

[18]Poynter JN, Rennert G, Bonner JD, Rennert HS, et al. HMG CoA reductase inhibitors and the risk of colorectal cancer. Proceedings from the 40th annual meeting of the American Society of Clinical Oncology, New Orleans LA, June 5-8, 2004; Abstract #1.

[19]Chirieac L, Suehiro Y, Niemistro A, Shmulevich I, et al. Size and number of examined lymph nodes impacts outcome in patients with stage II colorectal cancer. Proceedings from the 40^th annual meeting of the American Society of Clinical Oncology held in New Orleans LA, June 58, 2004; Abstract #3507.

[20] Bertagnolli MM, Redston M, Miedema B, Dowell J, et al. Sentinel node staging of resectable colon cancer: Results of CALGB 80001. Proceedings from the 40^th annual meeting of the American Society of Clinical Oncology held in New Orleans LA, June 58, 2004; Abstract #3506.