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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

Eric Van Cutsem, Marc Peeters, Salvatore Siena, Yves Humblet, Alain Hendlisz, Bart Neyns, Jean-Luc Canon, Jean-Luc Van Laethem, Joan Maurel, Gary Richardson, Michael Wolf, Rafael G. Amado

From the University Hospital Gasthuisberg, Leuven; Ghent University Hospital, Ghent; St Luc University Hospital, Université Catholique de Louvain; Jules Bordet Institute; AZ Vrije Universiteit Brussel; Erasme University Hospital, Brussels; Centre Hospitalier Notre Dame et Reine Fabiola, Charleroi, Belgium; Ospedale Niguarda Cá Granda, Milan, Italy; Hospital Clínic de Barcelona, Barcelona, Spain; Cabrini Hospital, Victoria, Australia; and Amgen Inc, Thousand Oaks, CA

Address reprint requests to Eric Van Cutsem, MD, PhD, Digestive Oncology Unit, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Leuven, Belgium; e-mail: eric.vancutsem{at}uz.kuleuven.ac.be

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix A Appendix B REFERENCES

 
Purpose: Panitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR). We compared the activity of panitumumab plus best supportive care (BSC) to that of BSC alone in patients with metastatic colorectal cancer who had progressed after standard chemotherapy.

Patients and Methods: We randomly assigned 463 patients with 1% or more EGFR tumor cell membrane staining, measurable disease, and radiologic documentation of disease progression during or within 6 months of most recent chemotherapy to panitumumab 6 mg/kg every 2 weeks plus BSC (n = 231) or BSC alone (n = 232). Tumor assessments by blinded central review were scheduled from week 8 until disease progression. The primary end point was progression-free survival (PFS). Secondary end points included objective response, overall survival (OS), and safety. BSC patients who progressed could receive panitumumab in a cross-over study.

Results: Panitumumab significantly prolonged PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66, [P < .0001]). Median PFS time was 8 weeks (95% CI, 7.9 to 8.4) for panitumumab and 7.3 weeks (95% CI, 7.1 to 7.7) for BSC. Mean (standard error) PFS time was 13.8 (0.8) weeks for panitumumab and 8.5 (0.5) weeks for BSC. Objective response rates also favored panitumumab over BSC; after a 12-month minimum follow-up, response rates were 10% for panitumumab and 0% for BSC (P < .0001). No difference was observed in OS (HR, 1.00; 95% CI, 0.82 to 1.22), which was confounded by similar activity of panitumumab after 76% of BSC patients entered the cross-over study. Panitumumab was well tolerated. Skin toxicities, hypomagnesaemia, and diarrhea were the most common toxicities observed. No patients had grade 3/4 infusion reactions.

Conclusion: Panitumumab significantly improved PFS with manageable toxicity in patients with chemorefractory colorectal cancer.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix A Appendix B REFERENCES

 
Colorectal cancer is the third most common cancer worldwide, with approximately 1 million new cases diagnosed yearly.¹ Although current use of irinotecan, oxaliplatin, and bevacizumab with long-time standards fluourouracil and leucovorin as first- or second-line treatment for metastatic colorectal cancer have resulted in median survival rates greater than 18 months,^2-14 most patients develop resistance to these therapies and die of their disease. Therefore, there is a need for new active treatment options in this setting.

Monoclonal antibodies against the epidermal growth factor receptor (EGFR) have shown activity in chemorefractory colorectal cancer. Phase II studies have demonstrated the activity of cetuximab (a chimeric monoclonal immunoglobulin G [IgG] 1 antibody) and panitumumab (a fully human monocolonal IgG2 antibody) in refractory colorectal cancer.^13-19 In a randomized phase II study, increased activity with cetuximab plus irinotecan compared with cetuximab alone was seen in patients with colorectal cancer who were refractory to irinotecan and had EGFR-positive tumors.²⁰ In this study, however, a best supportive care (BSC) control arm was not included. Other studies with new agents (eg, tipifarnib, a farnesyl transferase inhibitor) compared with BSC did not show activity in refractory colorectal cancer.²¹

Panitumumab binds to EGFR and prevents receptor dimerization, EGFR-tyrosine autophosphorylation, and activation of downstream signaling molecules, resulting in the inhibition of cellular proliferation and tumor growth and in the induction of apoptosis.^15,19 In phase II studies, panitumumab monotherapy for the treatment of chemorefractory colorectal cancer was active and well tolerated.^13,14,16 To fully evaluate the effect of panitumumab monotherapy in patients with chemorefractory metastatic colorectal carcinoma, we designed this randomized phase III study of panitumumab administered at 6 mg/kg every 2 weeks plus BSC compared with BSC alone.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix A Appendix B REFERENCES

 
Patients
Eligible patients had pathologic diagnosis of metastatic colorectal adenocarcinoma and radiologic documentation of disease progression during or within 6 months following the last administration of fluoropyrimidine, irinotecan, and oxaliplatin. To ensure adequate exposure to prior chemotherapy, average dose-intensity of irinotecan ( 65 mg/m² per week) and of oxaliplatin ( 30 mg/m² per week) were required. Both criteria of disease progression and dose-intensity were confirmed retrospectively and centrally.

Other key eligibility criteria included: 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2, two or three prior chemotherapy regimens for metastatic colorectal cancer, and 1% or more EGFR-positive membrane staining in evaluated tumor cells (primary or metastatic) by immunohistochemistry (DAKO, Carpinteria, CA) prospectively read centrally (after a protocol amendment; 10% or more in the original protocol). Exclusion criteria included symptomatic brain metastases, interstitial pneumonitis or pulmonary fibrosis, systemic chemotherapy or radiotherapy within 30 days before random assignment, and prior anti-EGFR agents.

The study protocol was approved by the independent ethics committee at participating study centers, and all patients provided written, informed consent before any study-related procedures were performed.

Study Design and Treatment Schedule
This is a phase III, multicenter, randomized controlled trial. The study was not blinded because of the expected skin toxicity related to panitumumab administration. Patients were randomly assigned 1:1 to receive panitumumab plus BSC (panitumumab) or BSC alone (BSC). Random assignment was stratified by ECOG performance status (0 or 1 v 2) and region (Western Europe v Central and Eastern Europe v the rest of the world [Canada, Australia, and New Zealand]). Panitumumab was administered by a 60-minute intravenous infusion at 6 mg/kg once every 2 weeks until patients progressed or unacceptable toxicity developed. Premedication was not required. BSC was defined as the best palliative care per investigator excluding antineoplastic agents.

Objective tumor response was evaluated by central radiology review using modified Response Evaluation Criteria in Solid Tumors²² at weeks 8, 12, 16, 24, 32, 40, and 48, and every 3 months thereafter until disease progression, and confirmed no less than 4 weeks after the criteria for response were first met. At the discretion of the investigator, patients could be evaluated for radiographic tumor assessment after developing symptoms consistent with disease progression.

All patients were followed for survival approximately every 3 months up to 2 years after random assignment. BSC patients determined by the investigator to have disease progression were eligible to receive panitumumab under a separate study. The cross-over study was included based on prior evidence of activity with panitumumab^15,16,23 and cetuximab.^18,20 Radiographic assessments in the cross-over study were performed by local review.

Statistical Analysis
The primary study end point was progression-free survival (PFS) by blinded central radiology assessment. PFS time was calculated from the day of random assignment until radiologic progression or death. The primary analysis of PFS included tumor assessments after cross over to panitumumab for BSC patients if disease progression was not centrally confirmed while the patient received BSC alone. Cosecondary study end points were best objective response by blinded central review and overall survival (OS) time. OS was calculated from the day of random assignment until death, censoring patients at the last day known to be alive. Additional descriptive secondary end points included time to and duration of response. Safety end points included the incidence of adverse events, infusion reactions, and antipanitumumab antibody formation.

The primary analysis set included all patients randomly assigned (all randomly assigned set). PFS was analyzed at the 5% significance level using a log-rank test stratified by baseline ECOG performance status and region. The study had 90% power for a two-sided 1% significance level test given a hazard ratio (HR; panitumumab relative to BSC) of 0.67. The sample size goal was 430 patients, with an event goal of 362 patients with progressive disease by central review or death. A 1% test of objective response at the primary analysis and a 4% test of OS were prespecified conditional on a significant PFS difference. The primary analysis of OS and an update of objective response rates and duration of response were conducted after a minimum of 12 months of follow-up.

Prospective sensitivity analyses for PFS assessed (1) inclusion of events only in the initial treatment phase (excluding data after cross over in the BSC group), (2) local radiology review, and (3) secondary analysis sets. A post-hoc analysis was performed that imputed unscheduled assessments of radiologic disease progression to the closest scheduled assessment to reduce time ascertainment bias (interval censored).

Kaplan-Meier methodology was used to estimate PFS, OS, and time to and duration of response, including 95% CI for event-free rates and differences in rates. The 95% CI for time-to-event quartiles were calculated per Brookmeyer and Crowley.²⁴ HRs for PFS and OS were estimated with a Cox proportional hazards regression model adjusted for the randomization factors.

Exploratory subset analyses were conducted for PFS by demography, disease characteristics, EGFR membrane positive staining level (1, 2, 3) or quantity (1% to < 10%, 10% to 100%), and severity of skin-related toxicity. Objective response rates also were assessed by EGFR categories and skin toxicity severity. For all skin toxicity severity analyses, a landmark approach including only patients who were progression free for 28 days or more was used to allow for time to onset. The methods and results of patient-reported outcome assessments are reported online in Appendix B.

Serum antipanitumumab antibody levels were measured using an enzyme-linked immunosorbent assay (ELISA; Amgen, Thousand Oaks, CA) with a sensitivity of 10 ng/mL. The ELISA included an acid dissociation step to disrupt antibody-panitumumab complexes before detection. All programming was performed with SAS version 8 or 9 (SAS Institute, Cary, NC) and StatXact version 6 (Cytel Inc, Cambridge, MA).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix A Appendix B REFERENCES

 
Patients
From January 2004 to June 2005, 1,040 patients were screened. Of these, 463 patients were enrolled and randomly assigned (231 to panitumumab and 232 to BSC; Fig 1). Of all patients screened, 38% of patients were ineligible because they did not meet a laboratory-inclusion criterion, and 27% specifically did not meet EGFR-staining criteria. The most common reason for discontinuation was disease progression (75% of patients enrolled onto panitumumab, and 85% of patients enrolled onto BSC). Median follow-up was approximately 35 weeks (range, 15 to 76). In the BSC group, 176 (76%) patients received panitumumab in a cross-over protocol. The median time to cross over was 7 weeks (range, 6.6 to 7.3). The median follow-up after cross over was 61 weeks (range, 18 to 103).

View larger version (28K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Consolidated Standards of Reporting Trials diagram. BSC, best supportive care.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Progression-free survival (all randomly assigned analysis set). BSC, best supportive care.

Consistent with the primary analysis, PFS favored panitumumab in all sensitivity analyses (HR range, 0.41 to 0.63; Table A1, online only). These included an interval-censored analysis to compensate for time ascertainment bias. In this analysis, which imputed radiologic disease progression to the nearest scheduled assessment time point, the HR for PFS continued to favor panitumumab (HR, 0.61).

Across all variables examined, the treatment effect on PFS was consistent with that of the primary analysis (Fig 3). By EGFR membrane–staining categories, PFS favored panitumumab (HR range, 0.47 to 0.62), and objective response rates were similar to those in the primary analyses (5% to 10%).

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Subset analyses of progression-free survival (PFS). Hazard ratios (HR) for PFS and the 95% CIs for HRs are shown and represented by the diamond and horizontal line, respectively. The HR for the all randomly assigned analysis was adjusted for randomization factors, as described. All other HRs were unadjusted.

It is known from previous studies that disease stabilization in chemorefractory metastatic colorectal cancer is clinically meaningful.^10,20 To explore the role of stable disease on the treatment effect of panitumumab on PFS, an analysis was conducted removing responding patients from the panitumumab group. Using this approach, the HR for PFS was 0.63 (95% CI, 0.52 to 0.77; P < .0001), indicating that approximately 80% (1 – 0.63/1 – 0.54) of the treatment effect on PFS was due to nonresponders.

Overall Survival
In the primary analysis of OS, a total of 380 (82%) had died (186 [81%] patients in the panitumumab group and 194 [84%] patients in the BSC group). The minimum follow-up time was 52 weeks, with a median follow-up time of 72 weeks for all patients (range, 52 to 113 weeks). No significant difference was observed between groups (HR, 1.00; 95% CI, 0.82 to 1.22; P = .81, stratified log-rank test; Fig 4A).

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. (A) Overall survival (OS)—primary analysis (all randomly assigned analysis set). (B) OS by worst severity of skin-related toxicity. Hazard ratio (grade 2-4 relative to grade 1) was adjusted for randomization factors as described.

Safety
The incidence of frequent adverse events is provided in Table 2. Two patients did not receive panitumumab and were included in the BSC group for safety analyses. Skin-related toxicities occurred in 90% of patients in the panitumumab group and in 9% of patients in the BSC group. One patient in the panitumumab group discontinued treatment because of grade 2 dermatitis acneiform.

In the panitumumab group, 36% of patients had declines in blood magnesium levels versus 1% in the BSC group. Grade 3 or 4 hypomagnesemia occurred in 3% of patients and required magnesium supplementation.

One patient discontinued treatment because of a grade 2 hypersensitivity reaction. Of 185 (83%) of 224 patients with both a baseline and post baseline sample available for testing, no patients tested positive for antipanitumumab antibodies.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix A Appendix B REFERENCES

 
This study was designed to assess the efficacy of an anti-EGFR antibody administered as monotherapy in a randomized setting. The rate of disease progression based on the HR was approximately half in the panitumumab group versus the BSC group. The upper bound of the 95% CI for the PFS HR excluded a PFS rate reduction of less than 33%, which was the hypothesized treatment effect. Sensitivity analyses confirmed the results of the primary analysis. Importantly, a meaningful treatment effect was observed despite the fact that 20 patients on BSC had central progression after cross over.

As expected for patients with advanced refractory disease, more than half progressed in both groups by week 8, the first scheduled visit. Therefore, the difference between median PFS times between groups was small. Although the absolute effect of panitumumab is relatively small, the magnitude of the improvement in PFS as measured by the HR of PFS for panitumumab relative to the BSC control compares favorably with those of recent trials leading to important advances in the treatment of metastatic colorectal cancer, including those testing novel agents in earlier lines of therapy.^6,7,20,25

The study design was subject to a potential bias favoring panitumumab because of its open-label nature, the availability of panitumumab in the cross-over study, and unscheduled radiographic assessments for patients with symptoms consistent with progressive disease. However, detection bias was mitigated by a blinded central radiology review, and BSC patients were followed in the cross-over study for central progression when investigator assessment of radiologic progression was not centrally confirmed. The post-hoc sensitivity analysis, including imputations of unscheduled assessments for disease progression, also indicated that the treatment effect of panitumumab was likely not confounded by ascertainment bias.

The response rate observed in this study is similar to previously reported response rates of 8.5% to 11.6% in irinotecan and oxaliplatin refractory patients treated with cetuximab monotherapy.^20,25a Interpretation of the time-to-progression results were limited by the lack of an adequate control for the monotherapy arm in those studies.

Evaluation of response rates alone may underestimate the overall treatment effect of targeted therapies. Despite modest effects on response rates, panitumumab resulted in a clinically significant improvement in PFS. In a post-hoc analysis, PFS in the panitumumab group was similar for patients with either a partial response or stable disease (data on file, Amgen). Moreover, an exploratory analysis excluding patients that experienced a response in the panitumumab group showed that 80% of the overall treatment effect as measured by the HR of PFS was retained. These data suggest that stable disease was associated with significant clinical benefit in these patients.

No differences in OS were observed in this study. The high rate and rapidity of cross over of the BSC patients and the similar activity of panitumumab seen in the cross-over population likely confounded the survival data. To evaluate the cross-over effect, we conducted an exploratory analysis on survival that censored BSC patients who subsequently responded (confirmed or otherwise) after cross over (30 of 176 patients) at the time they received their first dose of panitumumab (data on file, Amgen). In this exploratory analysis, the HR shifted from 1.00 in the primary analysis to 0.86, suggesting that had a cross over not been allowed, a treatment effect on OS may have been observed.

Even though the data have yet to be published, it was recently reported that the primary end point of OS was met in the NCIC CTG CO.17 phase III trial comparing cetuximab with BSC in metastatic colorectal cancer.^25b Although information on poststudy treatment after progression is not available, that study did not allow for cross over onto active treatment and was conducted in regions where access to cetuximab was limited. Appropriately designed studies with panitumumab are under way to further investigate whether panitumumab treatment improves OS in metastatic colorectal cancer.

Skin rash is a characteristic toxicity of most EGFR inhibitors. Consistent with previous reports, we found an association between clinical efficacy and rash severity.^18,20,26 The incidence of skin toxicity in panitumumab-treated patients is dose-related; however, we have not observed a correlation between dose and severity. The time to worst grade of rash did not differ from the time to any grade of rash (15 v 12 days, respectively; data on file, Amgen). Furthermore, whereas skin rash appears to be a pharmacodynamic marker of on-target activity associated with clinical benefit, it also often develops in patients who do not benefit from treatment. Other factors such as the dimerization of erbB family members in tumor cells,²⁶ EGFR gene copy number or mutations,^26,27 K-ras mutations,^27,28 and activation levels of downstream targets^29,30 may influence tumor response to anti-EGFR monoclonal antibodies. The role of these and other potential markers are currently under investigation.

Consistent with the fully human nature of panitumumab, we saw a low incidence of infusion reactions and no antibody formation. This important observation supports the current belief that fully human antibodies have the lowest risk for immunogenicity.³¹ Further experience with fully human antibodies is needed to understand their long-term immunogenic potential.

This study did not evaluate the efficacy of panitumumab in patients who progressed after bevacizumab treatment or in patients with undetectable EGFR tumor expression levels. At the time of enrollment, bevacizumab had not yet been approved.³² Given the different mechanisms of action, cross-resistance of panitumumab with this agent is not expected. Studies evaluating panitumumab activity in patients who progressed after receiving bevacizumab and in patients with EGFR-negative tumors are currently ongoing.

In conclusion, this study demonstrates that panitumumab given every 2 weeks is effective and well tolerated in patients with advanced colorectal cancer that had progressed after standard chemotherapy. Panitumumab represents a new treatment option that can improve PFS with manageable toxicity in patients with chemorefractory metastatic colorectal cancer. These results warrant investigation of panitumumab in combination with earlier lines of therapy in colorectal cancer.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix A Appendix B REFERENCES

 
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Michael Wolf, Amgen Inc; Rafael G. Amado, Amgen Inc Leadership: N/A Consultant: Eric Van Cutsem, Amgen Inc, Merck KgA; Marc Peeters, Amgen Inc, Roche, Merck KgA Stock: Michael Wolf, Amgen Inc; Rafael G. Amado, Amgen Inc Honoraria: Marc Peeters, Amgen Inc, Eli Lilly, Pfizer, Sanofi-aventis Research Funds: Marc Peeters, Amgen Inc; Jean-Luc Canon, Amgen, Wyeth, GlaxoSmithKline Testimony: Jean-Luc Canon, Roche Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix A Appendix B REFERENCES

 
Conception and design: Eric Van Cutsem, Rafael G. Amado

Provision of study materials or patients: Eric Van Cutsem, Marc Peeters, Salvatore Siena, Yves Humblet, Alain Hendlisz, Bart Neyns, Jean-Luc Canon, Jean-Luc Van Laethem, Joan Maurel, Gary Richardson

Data analysis and interpretation: Eric Van Cutsem, Marc Peeters, Salvatore Siena, Michael Wolf, Rafael G. Amado

Manuscript writing: Eric Van Cutsem, Marc Peeters, Salvatore Siena, Michael Wolf, Rafael G. Amado

Final approval of manuscript: Eric Van Cutsem, Marc Peeters, Salvatore Siena, Yves Humblet, Alain Hendlisz, Bart Neyns, Jean-Luc Canon, Jean-Luc Van Laethem, Joan Maurel, Gary Richardson, Michael Wolf, Rafael G. Amado

	Appendix A

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix A Appendix B REFERENCES

 
The following investigators participated in this study: Australia—E. Abdi, P. Clingan, M. Findlay, V. Ganju, P. Gibbs, D. Grimes, I. Kennedy, D. Kotasek, P. Mainwaring, G. Richardson, C. Underhill, G. van Hazel; Austria—C. Dittrich, W. Eisterer, W. Scheithauer, J. Thaler; Belgium—J-L Canon, A. Hendlisz, Y. Humblet, B. Neyns, M. Peeters, J-L Van Laethem, E. Van Cutsem; Canada—F. Couture, J. Gapski, M. Noble, D. Roitman, S. Spadafora, J. Wilson, L. Zibdawi; Czech Republic—J. Bartos, J. Jakesova, I. Kocakova, M. Kuta, M. Lysy, L. Petruzelka, P. Vodvarka, J. Vydra; France—T. André, P. Artru, O. Bouché, J-L Legoux, L. Mineur, H. Perrier, J-F Rey, P. Rougier, F. Viret; Germany—W. Brugger, D. Hempel, E-D Kreuser, H. Lambertz, W. Lange, H. Link, F. Lordick, D. Oruzio, J. Preiß, T. Seufferlein, T. Wolff; Greece—V. Georgoulias, C. Kalofonos, P. Kosmidis, E. Razis, D. Skarlos, K. Syrigos; Hungary—M. Baki, G. Bodoky, A. Csejtei, M. Dank, I. Lang, T. Pinter, M. Szucs, L. Thurzo; Italy—E. Bajetta, C. Barone, S. Cascinu, F. Cognetti, G. Colucci, P-F Conte, E. Cortesi, A. Santoro, S. Siena, A. Sobrero, C. Sternberg; Netherlands—G-J Creemers, P. Depres-Brummer, A. van Bochove, J. Van den Bosch, E. Voest; Portugal—J. Costa-Marques, R. Da Luz, J. Lopes, A. Moreira, J. Ribeiro; Slovakia—I. Andracina, T. Salek, S. Spanik; Spain—A. Abad, M. Benavides, A. Carrato, A. Cervantes, H. Cortés-Funes, E. Díaz-Rubio, B. Massuti, J. Maurel, J. Rodríguez, J. Tabernero; Switzerland—M. Borner, D. Köberle, C. Sessa.

	Appendix B

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix A Appendix B REFERENCES

 
Methods
Patient-reported outcomes were analyzed using the EUROQOL EQ-5D visual analog scale and selected questions from NCCN FACT and EORTC Quality of Life subscales, and a dermatology question.

Results
From the primary analysis of patient-reported outcomes, as expected, patients in the panitumumab group were more bothered by their skin conditions than patients in the best supportive care group. However, no clinically meaningful differences in overall quality of life were observed between the groups.

	ACKNOWLEDGMENTS

 
We are gratefully indebted to the patients who participated in this trial and to their families. We acknowledge the study site staffs, the Amgen country teams, and the following individuals from Amgen Inc: Cate Tucknott, MSc, for study management; Nicola Wright, MSc, for biostatisical support; Michiel Hagendoorn, MA, and Donald Paterson, MSc, for programming support; Sarah Edgington, PhD, and Tab Hoda, BS, for data management; Michael Mullenix, PhD, for antibody analyses; Alessandra Cesano, MD, and Sophie Visonneau, PhD, for extensive and critical data review; and Mee Rhan Kim, PhD, for assistance with the writing of the manuscript.

	NOTES

 
Supported by Amgen Inc, Thousand Oaks, CA.

Presented at the 97th Annual Meeting of the American Association for Cancer Research, April 1-5, 2006, Washington, DC; 2nd Annual Conference of the Hematology/Oncology Pharmacy Association, June 15-18, 2006, Orlando, FL; 8th Annual Conference of the World Congress on Gastrointestinal Cancer, June 28-July 1, 2006, Barcelona, Spain; and at the 31st European Society of Medical Oncology Congress, September 29-October 3, 2006, Istanbul, Turkey.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix A Appendix B REFERENCES

 
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Submitted July 14, 2006; accepted November 27, 2006.

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