This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schmoll, H.-J. Articles by Haller, D. G. Search for Related Content PubMed PubMed Citation Articles by Schmoll, H.-J. Articles by Haller, D. G.

Phase III Trial of Capecitabine Plus Oxaliplatin As Adjuvant Therapy for Stage III Colon Cancer: A Planned Safety Analysis in 1,864 Patients

Hans-Joachim Schmoll, Thomas Cartwright, Josep Tabernero, Marek P. Nowacki, Arie Figer, Jean Maroun, Timothy Price, Robert Lim, Eric Van Cutsem, Young-Suk Park, Joseph McKendrick, Claire Topham, Gemma Soler-Gonzalez, Filipo de Braud, Mark Hill, Florin Sirzén, Daniel G. Haller

From the Martin Luther University, Halle, Germany; US Oncology, Ocala, FL; University of Pennsylvania, Philadelphia, PA; Vall d'Hebron University Hospital; Institut Català d'Oncologia, Barcelona, Spain; Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Ottawa Regional Cancer Center, Ottawa, Canada; The Queen Elizabeth Hospital, Adelaide; Box Hill Hospital, Box Hill, Australia; National University Hospital, Singapore; University Hospital Gasthuisberg, Leuven, Belgium; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; St Lukes' Cancer Centre, Royal Surrey County Hospital, Guildford, Surrey; Kent Oncology Centre, Maidstone, United Kingdom; Istituto Europeo di Oncologia, Milan, Italy; and F. Hoffmann-La Roche AG, Basel, Switzerland

Address reprint requests to Hans-Joachim Schmoll, MD, PhD, Martin Luther University, Ernst-Grube-Strasse 40, 06120 Halle, Germany; e-mail: hans-joachim.schmoll{at}medizin.uni-halle.de

	ABSTRACT

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

 
Purpose: To report the results of a planned safety analysis from a phase III trial comparing capecitabine plus oxaliplatin (XELOX) with bolus fluorouracil/leucovorin (FU/LV) as adjuvant therapy for stage III colon cancer.

Patients and Methods: Patients with stage III colon carcinoma were randomly assigned to receive either XELOX (intravenous oxaliplatin plus oral capecitabine; 3-week cycle for eight cycles) or standard intravenous bolus FU/LV administered as the Mayo Clinic (Mayo; Rochester, MN) or Roswell Park (RP; Buffalo, NY) regimen for a similar length of time. A total of 1,886 patients were randomly assigned.

Results: The safety population comprised 1,864 patients, of whom 938 received XELOX and 926 received FU/LV. Most treatment-related adverse events (AEs) occurred at similar rates in both treatment arms. However, patients receiving XELOX experienced less all-grade diarrhea, alopecia, and more neurosensory toxicity, vomiting, and hand-foot syndrome than those patients receiving FU/LV. Compared with Mayo, XELOX showed fewer grade 3/4 hematologic AE and more grade 3/4 gastrointestinal AE. Compared with RP, XELOX showed less grade 3/4 gastrointestinal AE and more grade 3/4 hematologic AE. As expected grade 3/4 neurosensory toxicity and grade 3 hand-foot syndrome were higher with XELOX. Treatment-related mortality within 28 days from the last study dose was 0.6% in the XELOX group and 0.6% in the FU/LV group.

Conclusion: XELOX has a manageable tolerability profile in the adjuvant setting. Efficacy data will be available within the next 24 months.

	INTRODUCTION

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

 
The success of multiagent combination therapy in the treatment of metastatic colorectal cancer has provided a compelling basis for testing such regimens in the adjuvant setting. The addition of oxaliplatin to fluorouracil/leucovorin (FU/LV) has been shown to prolong disease-free survival significantly in patients with stage II/III colon cancer, with reductions in the risk of recurrence of 21% and 23% compared with FU/LV reported in two large trials.^1,2

Capecitabine (Xeloda; F. Hoffmann-La Roche, Basel, Switzerland) is an oral fluoropyrimidine that has established efficacy in the treatment of metastatic colorectal cancer³ and as single-agent adjuvant therapy as an alternative to bolus FU/LV.⁴ In both settings, capecitabine showed an improved tolerability profile compared with bolus FU/LV^5,6 with the convenience of oral administration. Medical resource use and associated costs were also lower with capecitabine in both settings.^7,8

Capecitabine and oxaliplatin in combination have been tested in a range of different administration schedules and doses with no evidence of major overlapping key toxicities, and have demonstrated supra-additive activity in preclinical xenograft models of colon cancer.⁹

The present international, randomized, phase III trial (No. 16968, XELOXA) was conducted to compare the safety and efficacy of adjuvant capecitabine plus oxaliplatin (XELOX) to bolus FU/LV, the standard regimen in stage III colon cancer at study initiation. Recruitment of 1,886 patients is now complete; we report here the final safety analysis performed in March 2006, 11 months after all enrolled patients had completed study treatment. Preliminary safety results have been presented previously.¹⁰

	PATIENTS AND METHODS

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

 
This study was conducted in accordance with the Declaration of Helsinki and all of its amendments, or with the laws and regulations of the country in which the research was conducted, whichever afforded greater protection to the patient. All patients gave full written informed consent before study entry.

Eligibility Criteria
Eligible patients were 18 years old with histologically confirmed stage III colon carcinoma (Dukes' stage C), and were fully recovered after curative resection within 8 weeks before random assignment. Patients were required to be ambulatory with an Eastern Cooperative Oncology Group performance status score of 0 or 1.

Study Design and Treatment
The study was designed to demonstrate that capecitabine plus oxaliplatin (3-week cycle for eight cycles; XELOX regimen) is superior to FU/LV in terms of disease-free survival (DFS) in patients who have undergone surgery for stage III colon carcinoma. Secondary end points were overall survival, safety, patients' satisfaction with and perception of treatment convenience, and medical resource utilization. The sample size was calculated considering that treatment with bolus FU/LV achieves a 3-year DFS rate of 62% and assuming a hazard ratio of 0.81 in favor of the XELOX arm corresponding to an absolute increase of 3-year DFS of 6%. Assuming a median follow-up of 30 months and linear recruitment during 18 months, the number of events necessary to detect this difference was 682 and the sample size 1,850.

Patients were assigned to adjuvant treatment with either XELOX or intravenous bolus FU/LV given by one of two regimens. The XELOX regimen consisted of a 2-hour intravenous infusion of oxaliplatin 130 mg/m² on day 1 and oral capecitabine 1,000 mg/m² twice daily given for 14 days of a 3-week cycle, for a total of eight cycles (24 weeks). The first dose of capecitabine was given on the evening of day 1 and the last dose on the morning of day 15 of each cycle. The Mayo Clinic (Mayo; Rochester, MN) regimen consisted of a rapid intravenous infusion of leucovorin 20 mg/m² followed by an intravenous bolus of FU 425 mg/m² on days 1 to 5 of a 4-week cycle, for a total of six cycles (24 weeks). The Roswell Park (RP; Buffalo, NY) regimen consisted of a 2-hour intravenous infusion of leucovorin 500 mg/m² plus an intravenous bolus injection of FU 500 mg/m² (initiated during the leucovorin infusion) on day 1 of weeks 1 to 6 of an 8-week cycle, for a total of four cycles (32 weeks). Each participating center used a single preferred FU/LV regimen, as the regimens have been shown to have equivalent efficacy in the adjuvant setting.¹¹

Dose Modification
Dose modifications were based on the most severe adverse events observed during the previous treatment cycle. The dose-modification schema for capecitabine and XELOX have been described previously.^5,9 The dose of oxaliplatin was reduced to 100 mg/m² for grade 3/4 nausea or vomiting, grade 4 stomatitis, and for paresthesias with pain or functional impairment lasting for more than 7 days, or paresthesias with pain persisting between cycles. Oxaliplatin was discontinued for paresthesias with functional impairment persisting between cycles. Capecitabine monotherapy was permitted in patients discontinuing oxaliplatin due to toxicity. The dose-modification schema for the bolus FU/LV regimens have been described previously.^11,12

Baseline Assessment
A physical examination, chest x-ray, ECG, carcinoembryonic antigen determination, and pregnancy test (for all women who were amenorrheic for < 12 months) were performed within 14 days before random assignment. Patient demographics, medical history, prior cancer and treatment history, and concomitant diseases/treatment were also assessed at this time. Patient height, weight, vital signs (body temperature, blood pressure, and heart rate), Eastern Cooperative Oncology Group performance status, as well as hematology and blood chemistry (including creatinine clearance calculation) were assessed within 7 days before random assignment.

Evaluation of Safety
Adverse events were monitored continuously during treatment and for 28 days after last administration of study drug. The intensity of adverse events and laboratory parameters were graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0. Non–National Cancer Institute Common Toxicity Criteria for Adverse Events-listed adverse events were evaluated using a 4-point scale (mild, moderate, severe, and life threatening). A pooled term for neurosensory toxicity included the following preferred terms: paresthesia, oral paresthesia, neuropathy, neuropathic pain, peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, polyneuropathy, neurotoxicity, dysesthesia, pharyngeal dysesthesia, oral dysesthesia, hypoesthesia, hyperesthesia, burning sensation, oral hypoesthesia, temperature intolerance, skin burning sensation, sensory loss, sensory disturbance, chronic polyneuropathy, and pharyngeal hypoesthesia.

A complete laboratory assessment was performed at screening and before each treatment cycle (ie, day 1 of each cycle). The following parameters were monitored: AST, ALT, alkaline phosphatase, albumin, bilirubin (total and direct), serum creatinine, sodium, potassium, phosphate, calcium, and complete blood count.

The safety profile of the XELOX regimen was compared with the safety profile of pooled FU/LV (Mayo and RP). As the Mayo and RP regimens have different safety profiles, with Mayo showing more hematologic toxicity and RP more gastrointestinal toxicity, the comparison was also done between XELOX, Mayo, and RP regimens.

Statistical Methods
The cutoff date for the present safety analysis was March 31, 2006. All safety analyses were performed using the safety population, defined as randomly assigned patients who received at least one dose of capecitabine, FU, or oxaliplatin. For random assignment, patients were stratified by geographic region, FU/LV regimen, baseline carcinoembryonic antigen levels (normal v abnormal), number of lymph nodes involved ( 3 v > 3), and geographic region by lymph nodes interaction (using crossclassification of the two factors mentioned). The interaction term was introduced in order to guarantee a balance between treatment arms in the subgroups of number of lymph nodes involved within a certain geographic region.

Safety parameters included adverse events (including serious adverse events), early treatment withdrawals, deaths, laboratory parameters, and exposure to trial treatment. Exposure to trial medication was assessed in three different ways: duration of treatment; number of treatment cycles; and comparison of drug received versus planned drug in total and per cycle.

In addition to the frequency of adverse events, the time to first onset of selected adverse events (ie, grade 3/4 diarrhea, grade 3/4 neutropenia, and grade 2/3/4 neurosensory toxicity) was also investigated. Hazard ratios, medians, and 95% CIs were reported for each study arm. The time to first onset of adverse events was measured as the time from treatment start to the date of first occurrence. Patients without any of these adverse events were censored at a date corresponding to 28 days after the last intake of study medication. Treatment arms were compared using the Wald test. Kaplan-Meier estimates were used for time to onset of adverse events.

For each treatment component (capecitabine, oxaliplatin, FU [Mayo], and FU [RP]), the total planned dose according to the protocol for the entire treatment was calculated. For all patients who received study drug, the total actual dose given from treatment start until treatment end was calculated for each treatment component. Dose intensity was calculated as follows: dose intensity = actual dose given/planned dose.

	RESULTS

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

 
Patient Population
The intention-to-treat population comprised 1,886 patients who were enrolled from 226 centers between April 2003 and October 2004. The median follow-up for the present analysis is 23.5 months. Twenty-two patients did not receive any study medication and were excluded from the safety population. Therefore, the safety population comprised 1,864 patients, of whom 938 received XELOX and 926 received FU/LV (Mayo, n = 657; RP, n = 269). Treatment groups were well balanced in terms of baseline demographics and clinical characteristics (Table 1).

View this table: [in this window] [in a new window]   Table 3. Most Common ( 20%) Treatment-Related AEs (all grades)

View this table: [in this window] [in a new window]   Table 4. Most Common ( 5%) Treatment-Related Grade 3/4 AEs

Mortality
There were six treatment-related deaths within 28 days from the last dose of study medication in each arm (0.6%). Reasons for death in the XELOX arm were pneumonia (n = 2), intestinal ischemia (n = 1), hypotension (n = 1), sepsis (n = 1), and septic shock (n = 1), and in the FU/LV arm, pneumonia (n = 1), clostridial infection (n = 1), myocardial ischemia (n = 1), neutropenic colitis (n = 1), neutropenic sepsis (n = 1), and sepsis syndrome (n = 1). The rate of 60-day all cause mortality was 1% (nine patients) in each arm. Three patients died suddenly of brain edema (XELOX), myocardial ischemia (FU/LV), and pulmonary edema (FU/LV).

Time to Onset of Adverse Events
Grade 3/4 treatment-related diarrhea was reported in 19%, 16%, and 29% of patients treated with the XELOX, Mayo, and RP regimens, respectively, with a median time to onset of 36 days (range, 1 to 221), 36 days (range, 1 to 183), and 34 days (range, 5 to 191), respectively. Hazard ratios for the Mayo and RP regimens versus XELOX were 0.84 (95% CI, 0.66 to 1.07; P = .1683) and 1.60 (95% CI, 1.23 to 2.09; P = .0005), respectively. Episodes of grade 3/4 treatment-related diarrhea lasted for a median duration of 7 days (range, 1 to 42), 8.5 days (range, 1 to 61), and 8 days (range, 1 to 35), respectively.

Grade 3/4 treatment-related neutropenia/granulocytopenia was reported in 9%, 20%, and 4% of patients, respectively. Median time to onset was 92 days (range, 14 to 225), 29 days (range, 14 to 173) and 33 days (range, 18 to 143), respectively. Hazard ratios for the Mayo and RP regimens versus XELOX were 2.55 (95% CI, 1.93 to 3.37; P < .0001) and 0.41 (95% CI, 0.22 to 0.77; P = .0059), respectively. Episodes of grade 3/4 treatment-related neutropenia lasted for a median duration of 8 days (range, 1 to 77), 8 days (range, 1 to 102) and 6 days (range, 2 to 14), respectively.

Grade 2 to 4 treatment-related neurosensory toxicity was, as expected, most frequent in XELOX-treated patients. Median time to onset was 60 days (range, 1 to 213) with the XELOX regimen versus 145 days (range, 7 to 283) and 130.5 days (range, 113 to 148) with the Mayo and RP regimens, respectively. Episodes of grade 2 to 4 treatment-related neurosensory toxicity lasted for a median duration of 35 days (range, 1 to 621), 38 days (range, 15 to 61) and 20.5 days (range, 18 to 23), respectively.

Effect of Age on Safety Profile
The safety profiles of XELOX and FU/LV were analyzed in patients age younger than 65 and 65 years (Table 5). While many adverse events such as nausea, infections/infestations, and cardiac disorders showed similar rates in both younger and older patients in both treatment arms, other adverse events such as diarrhea and dehydration showed elevated rates in elderly patients treated with XELOX. This was also reflected in the higher overall rate of grade 3/4 events with XELOX in older versus younger patients (65% v 57%). The same trend was also evident with serious adverse events and toxicity-related withdrawals (Table 5).

	DISCUSSION

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

Neurosensory toxicity was common with XELOX, but was mild to moderate in severity in most patients. Hand-foot syndrome was more common with XELOX compared with FU/LV but the rate was lower than in previous monotherapy trials. Despite the addition of oxaliplatin, the median time to onset of grade 3/4 diarrhea and grade 3/4 neutropenia was the same or longer than that reported with the FU/LV regimens.

More treatment discontinuations occurred with XELOX versus FU/LV. However, a comparable number of patients treated with XELOX (88%) and FU/LV (82%) completed the first 12 weeks of treatment, possibly because there was no single dominant toxicity as a reason for discontinuation. Furthermore, neurotoxicity, which could be expected to be a dominant cause of treatment discontinuation, is a late event. The median dose intensity of capecitabine was similar to that of the two FU/LV regimens, and also similar to the dose intensity of FU/LV for the oxaliplatin, FU, and folinic acid (FOLFOX4) regimen in the Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial.¹ The median dose intensity of oxaliplatin, 87%, was also similar to that in MOSAIC.¹

Some of the previously reported tolerability advantages of capecitabine monotherapy over the Mayo Clinic regimen, such as less severe myelosuppression and stomatitis,^5,6 were retained despite adding oxaliplatin. Importantly, the rate of hand-foot syndrome in the present trial (all grade, 29%; grade 3, 5%) is considerably lower than that reported with capecitabine monotherapy (62%; 18%).⁶ This reduced rate is likely due to the 20% lower dose of capecitabine in the XELOX regimen versus standard-dose monotherapy.

While direct comparisons of multiagent regimens are required to establish conclusively the relative merits of each, safety data from large-scale comparisons of oxaliplatin plus FU/LV and FU/LV^1,18 provide some insight into the safety profiles of these regimens. In the MOSAIC trial,¹ FOLFOX4 was associated with an increased rate of diarrhea, vomiting, neurosensory toxicity, and neutropenia versus a bolus plus infusional regimen of FU/LV (LV5FU2), although the rate of other adverse events was similar in the two treatment arms. Safety data from the National Surgical Adjuvant Breast and Bowel Project C-07 trial have not been published in detail, although the rates of diarrhea and nausea were higher with bolus FU/LV plus oxaliplatin (FLOX) compared with bolus FU/LV, while vomiting and neutropenia were similar with both regimens.¹⁸ Cross trial comparisons showing the differences in safety profiles of XELOX, FOLFOX4, and FLOX are shown in Figure 1.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Grade 3/4 adverse events (related and unrelated) with capecitabine plus oxaliplatin (XELOX), oxaliplatin, fluorouracil (FU), and folinic acid (FOLFOX4), and bolus FU/leucovorin plus oxaliplatin (FLOX)—cross trial comparison. (*) Not reported. HFS, hand-foot syndrome.

In conclusion, this safety analysis expands the amount of data concerning the safety profile of XELOX considerably and shows that it has a manageable tolerability profile in the adjuvant setting. Efficacy data will be available within the next 24 months.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix 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: Arie Figer, Roche, Teva; Florin Sirzén, Roche Leadership: N/A Consultant: Hans-Joachim Schmoll, Sanofi-Aventis, Roche; Arie Figer, Roche, Teva; Jean Maroun, Roche; Timothy Price, Roche, Sanofi-Aventis; Eric Van Cutsem, Roche, Sanofi-Aventis; Joseph McKendrick, Roche; Clare Topham, Roche, Sanofi-Aventis; Mark Hill, Roche, Sanofi-Aventis; Daniel G. Haller, Sanofi-Aventis, Roche Stock: Clare Topham, Sanofi-Aventis Honoraria: Arie Figer, Roche; Jean Maroun, Roche; Timothy Price, Roche, Sanofi-Aventis; Young Suk Park, Brisol-Myers Squibb, Sanofi-Aventis; Joseph McKendrick, Roche; Clare Topham, Roche, Sanofi-Aventis; Filipo de Braud, Sanofi-Aventis; Daniel G. Haller, Sanofi-Aventis, Roche Research Funds: Thomas Cartwright, Roche; Josep Tabernero, Roche; Arie Figer, Roche; Timothy Price, Sanofi-Aventis; Young Suk Park, Roche, Novartis, Sanofi-Aventis; Daniel G. Haller, Roche Testimony: Arie Figer, Roche Other: Timothy Price, Roche

	AUTHOR CONTRIBUTIONS

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

 
Conception and design: Hans-Joachim Schmoll, Jean Maroun, Florin Sirzén, Daniel G. Haller

Provision of study materials or patients: Thomas Cartwright, Josep Tabernero, Marek P. Nowacki, Arie Figer, Jean Maroun, Timothy Price, Robert Lim, Young Suk Park, Joseph McKendrick, Clare Topham, Filipo de Braud, Mark Hill, Daniel G. Haller

Collection and assembly of data: Josep Tabernero, Marek P. Nowacki, Eric Van Cutsem, Clare Topham, Daniel G. Haller

Data analysis and interpretation: Hans-Joachim Schmoll, Thomas Cartwright, Josep Tabernero, Eric Van Cutsem, Florin Sirzén, Daniel G. Haller

Manuscript writing: Hans-Joachim Schmoll, Thomas Cartwright, Josep Tabernero, Eric Van Cutsem, Florin Sirzén, Daniel G. Haller

Final approval of manuscript: Hans-Joachim Schmoll, Thomas Cartwright, Josep Tabernero, Marek Nowacki, Arie Figer, Jean Maroun, Timothy Price, Robert Lim, Eric Van Cutsem, Young Suk Park, Joseph McKendrick, Clare Topham, Gemma Soler-Gonzalez, Filipo de Braud, Mark Hill, Florin Sirzén, Daniel G. Haller

	Appendix

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

 
The authors would like to thank the following study investigators: Australia (Begbie S., Clarke S., Clingan P., Gibbs P., Van Hazel G.); Belgium (Canon J.-L., Humblet Y., Peeters M., Van Cutsem E., Vergauwe P.); Brazil (Beato C., Malzyner A., Rodrigues V.H.); Canada (Aucoin N., Bjarnison G., Butts C., Charpentier D., Colwell B., Couture F., Czaykowski P., Dalfen R., Dube P., Fitzgerald C., Gurjal A., Kaizer L., Lesperance B., Major P., Siu L., Taylor M., Vincent M., Wierzbicki R., Wilson J., Wong A.); China (Cai S., Deng Y., Feng-Yi F., Law W.-L., Li K., Luo R., Pan L., Song S., Xiong J., Yu B., Yu S.-Y., Zheng L.); Finland (Hietanen T., Pyrhoenen S.); France (Dufour P., Hebbar M., Husseini F., Viret F.); Germany (Clemens M., Kettner E., Marschner N.); Greece (Georgoulias V., Kalofonos H., Katsos I., Mouratidou D., Papakostas P., Vaslamatzis M.); Hungary (Bodoky G., Lang I., Szanto J., Thurzo L.); Ireland (Keane M., Kennedy J., O'Reilly S.); Israel (Aderka D., Ben Shahar M., Beny A., Gabizon A., Hubert A., Klein B., Mahrshak G., Man S., Sela A., Shani A., Stemmer S.); Italy (Aprile G., Cascinu S., Cotu A., Crispino S., De Braud F., Falcone A., Labianca R., Pasquini E., Ravaioli A., Rosso R., Salvagni S.); Korea (Im S.A., Kim T.W., Lee Y.Y., Rha S.Y.); Mexico (Barriguete L., Green-Renner D., Lugo Quintana R.S., Soto Collins C.); New Zealand (Allan S., Gibbs D., Perez D., Simpson A., Thompson P.); Panama (Lopez Sanchez R.I.); Poland (Blasinska-Morawiec M., Foszczynska-Kloda M., Koralewski P., Rozmiarek A., Zaluski J.); Portugal (Barroso S., Cotes P., Sanches E.); Russian Federation (Lichinitser M., Manikhas G.M., Moiseenko V., Ushakov I.); Singapore (Ong S.); South Africa (Cohen G., Du Toit J.S., Vorobiof D.A.); Spain (Aparicio J., Aranda E., Benavides M., Carrato A., Cervantes A., Diaz-Rubio E., Duenas R., Feliu J., Fernandez-Martos C., Garcia Carbonero R., Garcia-Alfonso P., Gravalos C., Lopez-Vivancos G., Manzano H., Maurel J., Navarro Garcia M., Provencio M., Rivera F., Velasco Ortiz de Taranco); Switzerland (Herrmann R.); Taiwan (Changchien C.-R., Hsu H.-H., Liu M.-C.); Thailand (Chakrapee-Sirisuk S., Seetalarom K., Sirisinha T., Sookprasert A.); United Kingdom (Bessell E., Cassidy J., Chakraborti P., Corrie P., Coxon F., Cunningham D., Ford H., Francis D., Glynne-Jones R., Gollins S., Harper P., Iveson T., Leslie M., Phillips R., Samuel L., Seymour M., Steward W., Valle J., Wadd N., Wasan H., Webb A., Wilson R.); United States (Ardalan B., Beeker T., Bosserman L., Caggiano V., Castillo R., Chakrabarti A., Cobb P., Damjanov N., Davidson S., Del Prete S., Feldmann J., Giudice R.O., Harker W.G., Harrer G., Hu E., Hwang J., Jakub J., Kane M., Kass F., Lee M.W., Li Z., Lloyd R., Mackintosh F.R., McIntyre R., Mena R., Miller W., Morrison A., Mulkerin D., Orlowski R., Papish S., Patel R., Polikoff J., Rangineni R., Reiling R., Saidman B., Saleh M., Schwartzberg L., Sims D., Stoller R., Thomas S., Tweedy C., Von Stubbe W., Wax M., Woodson M.).

	ACKNOWLEDGMENTS

 
We thank the other investigators from the following participating countries: Australia, Belgium, Brazil, Canada, China, Finland, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Korea, Mexico, New Zealand, Panama, Poland, Portugal, Russian Federation, Singapore, South Africa, Spain, Switzerland, Taiwan, Thailand, United Kingdom, and the United States.

	NOTES

 
Supported by F. Hoffmann-La Roche Ltd.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005; the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006; and the World Congress of Gastrointestinal Cancer, Barcelona, Spain, June 28-July 1, 2006.

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

	REFERENCES

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

 
1. André T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343-2351, 2004[Abstract/Free Full Text]

2. Wolmark N, Wieand HS, Kuebler JP, et al: A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: Results of NSABP Protocol C-07. J Clin Oncol 23:246s, 2005 (abstr 3500)[CrossRef]

3. Van Cutsem E, Hoff PM, Harper P, et al: Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: Integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer 90:1190-1197, 2004[CrossRef][Medline]

4. Twelves C, Wong A, Nowacki MP, et al: Capecitabine as adjuvant treatment for stage III colon cancer (X-ACT Trial). N Engl J Med 352:2696-2704, 2005[Abstract/Free Full Text]

5. Cassidy J, Twelves C, Van Cutsem E, et al: First-line oral capecitabine therapy in metastatic colorectal cancer: A favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol 13:566-575, 2002[Abstract/Free Full Text]

6. Scheithauer W, McKendrick J, Begbie, et al: Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: Safety results of a randomized, phase III trial. Ann Oncol 14:1735-1743, 2003[Abstract/Free Full Text]

7. Twelves C, Boyer M, Findlay M, et al: Capecitabine (Xeloda) improves medical resource use compared with 5-fluorouracil plus leucovorin in a phase III trial conducted in patients with advanced colorectal carcinoma. Eur J Cancer 37:597-604, 2001[CrossRef][Medline]

8. Cassidy J, Douillard J-Y, Twelves C, et al: Pharmacoeconomic analysis of adjuvant oral capecitabine versus intravenous 5-FU/LV in Dukes' C colon cancer: The X-ACT trial. Br J Cancer 24:1122-1129, 2006

9. Cassidy J, Tabernero J, Twelves C, et al: XELOX (capecitabine plus oxaliplatin): Active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 22:2084-2091, 2004[Abstract/Free Full Text]

10. Schmoll HJ, Tabernero J, Nowacki M, et al: Early safety findings from a phase III trial of capecitabine plus oxaliplatin (XELOX) vs. bolus 5-FU/LV as adjuvant therapy for patients (pts) with stage III colon cancer. J Clin Oncol 23:251s, 2005 (abstr 3523)

11. Haller DG, Catalano PJ, Macdonald JS, et al: Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: Final report of Intergroup 0089. J Clin Oncol 23:8671-8678, 2005[Abstract/Free Full Text]

12. O'Connell MJ, Mailliard JA, Kahn MJ, et al: Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 15:246-250, 1997[Abstract/Free Full Text]

13. Scheithauer W, Kornek GV, Raderer M, et al: Randomized multicenter phase II trial of two different schedules of capecitabine plus oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 21:1307-1312, 2003[Abstract/Free Full Text]

14. Bennouna J, Lledo G, Ychou M, et al: Initial safety findings from a phase III study of capecitabine (X) plus oxaliplatin (XELOX) vs. infusional 5-FU/LV plus oxaliplatin (FOLFOX-6) in first-line treatment of patients (pts) with metastatic colorectal cancer (MCRC). Proc ECCO 2005 (abstr 636)

15. Massuti B, Gomez A, Sastre J, et al: Randomized phase III trial of the TTD Group comparing capecitabine and oxaliplatin (XELOX) vs. oxaliplatin and 5-fluorouracil in continuous infusion (FUFOX) as first line treatment in advanced or metastatic colorectal cancer (CRC). J Clin Oncol 24:165s, 2006 (suppl; abstr 3580)

16. Arkenau H, Schmoll H, Kubicka S, et al: Infusional 5-fluorouracil/folinic acid plus oxaliplatin (FUFOX) versus capecitabine plus oxaliplatin (CAPOX) as first line treatment of metastatic colorectal cancer (MCRC): Results of the safety and efficacy analysis. J Clin Oncol 23:247s, 2005 (suppl; abstr 3507)[CrossRef]

17. Cassidy J, Clarke S, Diaz-Rubio E, et al: First efficacy and safety results from XELOX-1/NO16966, a randomised 2x2 factorial phase III trial of XELOX vs. FOLFOX4 + bevacizumab or placebo in first-line metastatic colorectal cancer (MCRC). Ann Oncol 17, 2006 (suppl 9; abstr LBA3)

18. Smith RE, Colangelo L, Wieand S, et al: The occurrence of severe enteropathy among patients with stage II/III resected colon cancer (CC) treated with 5-FU/leucovorin (FL) plus oxaliplatin (FLOX). Proc Am Soc Clin Oncol 22:294, 2003 (abstr 1181)

Submitted July 10, 2006; accepted October 12, 2006.

This article has been cited by other articles:

				R. N. Schwartz Management of early and advanced colorectal cancer: Therapeutic issues Am. J. Health Syst. Pharm., June 1, 2008; 65(11_Supplement_4): S8 - S14. [Abstract] [Full Text] [PDF]

				D. G. Haller, J. Cassidy, S. J. Clarke, D. Cunningham, E. Van Cutsem, P. M. Hoff, M. L. Rothenberg, L. B. Saltz, H.-J. Schmoll, C. Allegra, et al. Potential Regional Differences for the Tolerability Profiles of Fluoropyrimidines J. Clin. Oncol., May 1, 2008; 26(13): 2118 - 2123. [Abstract] [Full Text] [PDF]

				J. L. Yen-Revollo, R. M. Goldberg, and H. L. McLeod Can Inhibiting Dihydropyrimidine Dehydrogenase Limit Hand-Foot Syndrome Caused by Fluoropyrimidines? Clin. Cancer Res., January 1, 2008; 14(1): 8 - 13. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schmoll, H.-J. Articles by Haller, D. G. Search for Related Content PubMed PubMed Citation Articles by Schmoll, H.-J. Articles by Haller, D. G.