1 Royal Marsden Hospital, London and Surrey; 2 Southampton General Hospital, Southampton and Salisbury District Hospital, Salisbury; 3 Kent Oncology Centre, Maidstone; 4 Royal Bournemouth and Poole Hospitals, Dorset; 5 St George's Hospital, London; 6 Western General Hospital, Edinburgh; 7 Brighton and Sussex University Hospital, Brighton, UK
* Correspondence to: Professor D. Cunningham, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-20-8661-3156; Fax: +44-20-8643-9414; Email: david.cunningham{at}icr.ac.uk
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients and methods: Patients with curatively resected stage II and III CRC were randomly assigned to 5-FU/LV [5-FU 425 mg/m2 intravenously (i.v.) and LV 20 mg/m2 i.v. bolus days 15 every 28 days for 6 months] or to PVI 5-FU (300 mg/m2/day for 12 weeks).
Results: Between 1993 and 2003, 801 eligible patients were randomised to 5-FU/LV (n=404) or PVI 5-FU (n=397). With a median follow-up of 5.3 years, 231 relapses and 220 deaths have been observed. Five-year relapse-free survival (RFS) was 66.7% [95% confidence interval (CI) 61.6% to 71.3%] and 73.3% (95% CI 68.4% to 77.6%) with bolus 5-FU/LV and PVI 5-FU, respectively [hazard ratio (HR) 0.8; 95% CI 0.621.04; P=0.10]. Five-year overall survival (OS) was 71.5% (95% CI 66.4% to 75.9%) and 75.7% (95% CI 70.8% to 79.9%) with bolus 5-FU/LV and PVI 5-FU, respectively (HR 0.79; 95% CI 0.611.03; P=0.083). There was a significant survival advantage for patients starting adjuvant chemotherapy within 8 weeks (P=0.044). Significantly less diarrhoea, stomatitis, nausea and vomiting, alopecia, lethargy, and neutropenia (all with P <0.0001) were seen with PVI 5-FU.
Conclusions: There was no OS difference between the two arms, although PVI 5-FU was associated with a trend towards better RFS and OS compared with bolus 5-FU/LV, as well as significantly less toxicity. Based on our results, the probability of 12 weeks of PVI 5-FU being inferior to 6 months of bolus 5-FU/LV is extremely low (P <0.005), and therefore shorter duration of adjuvant treatment should be explored further.
Key words: adjuvant therapy, colorectal cancer, fluorouracil
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Prolonged infusion of 5-FU results in less haematological toxicity and a small but statistically significant survival advantage over bolus regimens in advanced CRC [3], thus providing the rationale to investigate infused 5-FU as adjuvant therapy. Between 1993 and 2003, we conducted a multicentre prospective randomised study comparing the efficacy of protracted venous infusion (PVI) 5-FU with bolus 5-FU/LV as adjuvant therapy in patients with potentially curatively resected CRC. The initial results of this study have been published previously [4
]. Preliminary analysis on 716 patients with a median follow-up of 19.8 months suggested that PVI 5-FU was associated with a better relapse-free survival (RFS), especially in the rectal cancer subgroup, and no difference in overall survival (OS). However, there were only 218 patients with rectal cancer randomised into the study at that stage; therefore, there were insufficient patients to be certain of this observation and too few to estimate the true size of the benefit. Further rectal cancer patients were entered into the trial after the initial recruitment was reached in 1999 to confirm this preliminary observation. Here we report on 826 patients randomised between 1993 and 2003 with a median follow-up of 5.3 years.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Details of all eligible patients were forwarded to the trial office, based at the Royal Marsden Hospital, Surrey, UK, to verify eligibility criteria. Patients were then randomly assigned by an independent randomisation office to either bolus 5-FU/LV or PVI 5-FU on a 1:1 basis using random permuted blocks. Randomisation was stratified by treatment centre and in cases of rectal cancer, whether preoperative radiotherapy was given.
Patients were randomly allocated to PVI 5-FU given at a dose of 300 mg/m2/day for 12 weeks (PVI 5-FU arm) or bolus 5-FU (425 mg/m2) and LV (20 mg/m2) on days 15 every 4 weeks for six cycles (5-FU/LV arm). Patients aged >70 years and allocated to the bolus 5-FU/LV arm were treated with a reduced starting dose of 370 mg/m2. Adjuvant radiotherapy was reserved for those patients at high risk of locoregional failure (T4 tumours), and was planned to start with the fourth cycle of bolus therapy or after completion of 12 weeks of PVI 5-FU, which continued at a reduced dose of 200 mg/m2 until completion of radiotherapy.
On completion of chemotherapy, the trial protocol-specified surveillance policy was followed. Patients were seen in the outpatient clinic every 3 months for the first year, every 6 months for the second year and annually thereafter. Provided patients had remained disease-free, they could be discharged from further medical oncology follow-up after 5 years, although continued surgical surveillance was expected. Serum CEA was to be measured at baseline and at each clinic visit and CT scans of the thorax, abdomen and pelvis were to be performed at baseline, and 12 months and 24 months following initial commencement of chemotherapy. Colonoscopy was recommended 12 months after the start of chemotherapy, although subsequent frequency of colonoscopy was left to the surgeons' discretion. Quality of life (QoL) assessment was made using the European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC QLQ C-30) before randomisation, and during adjuvant treatment and follow-up.
Statistical analysis
The original sample size was calculated to detect a minimal improvement in OS from 60% to 70% after 5 years of follow-up. This would require 358 patients to be randomised per arm to provide at least 80% power in a two-sided test (=5%). The initial planned analysis in 1999, after 716 patients were randomised, suggested a better RFS in the rectal cancer subgroup. With only 218 rectal cancer patients randomised at that stage, there was insufficient sample size to be certain of this observation. By increasing the number of patients to 160 per arm (320 in total), a 5-year OS difference from 60% to 75% in the rectal cancer patients could be detected with at least 80% power (two-sided test;
=5%), and this would mean full recruitment could be completed in a realistic time frame. The primary end point in this study was OS. Secondary end points were RFS, toxicity and QoL. For RFS, an event was defined as either recurrence of cancer or a second primary tumour. Eligible patients were analysed on an intention-to-treat basis.
OS was calculated from the date of randomisation into the study to the date of death from any cause. RFS was calculated from the date of randomisation into the study to the date of either cancer recurrence or development of metachronous primary CRC. Both OS and RFS were estimated using the KaplanMeier method [5] and were compared between treatment arms using the log-rank test [6
], stratified by treatment centre.
Univariate analysis was performed using the log-rank test to identify characteristics predictive for survival. The prognostic factors analysed for effect were: treatment arms, T and N staging, performance status (PS), age, gender, site of primary tumour, tumour differentiation, the interval between surgery and commencement of adjuvant chemotherapy, baseline global health status QoL, and whether preoperative radiotherapy was given. Interval between surgery and commencement of adjuvant chemotherapy was dichotomised into 8 weeks versus >8 weeks, whereas the cut points for the global QoL score were at the median values. Multivariate survival analysis was performed using Cox's proportional hazards model [7
] and corrected for all the significant prognostic factors. Treatment toxicities in the two arms were compared using the
2-test. Two-sided P values of <0.05 were considered significant.
All analyses were performed on an intention-to-treat basis. All survival end points were updated in November 2003. Analyses were performed using SPSS package version 12 (SPSS Inc., Chicago, IL, USA).
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
|
|
|
|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The issue of shorter duration of adjuvant treatment has been addressed in the Intergroup 0089-46-51 [8], Intergroup 0089 [9
] and the Groupe d'Etude et de recherche Clinique en Oncologie Radiotherapie (GERCOR) studies [10
]. In all three studies, 6 months of adjuvant treatment was adequate, without any additional benefit with longer duration. However, our study has demonstrated that further shortening the treatment duration to 12 weeks with PVI 5-FU produced similar efficacy compared with 6 months of bolus treatment. In view of reduced incidences of toxicity and better short-term QoL with shorter duration of treatment, this therapeutic approach should be further explored in future randomised studies.
Two other studies compared infused 5-FU with bolus 5-FU regimen in the adjuvant setting. A study by GERCOR compared a bimonthly infused regimen of 5-FU/LV (LV5FU2) with a bolus schedule of 5-FU/LV given for different durations (24 versus 36 weeks) as adjuvant treatment for stage II and III colon or high rectal cancer [10]. Nine hundred and five patients were recruited in this study, with
57% of patients having stage III disease and 20% of patients having rectosigmoid and subperitoneal high rectal cancer. No differences in disease-free survival or OS were seen either between the treatment arms or between the treatment durations. This study has relatively short follow-up and only 132 deaths have occurred so far. However, LV5FU2 showed a slight excess in the number of deaths compared with 5-FU/LV regimen. Nevertheless, similar to our study, LV5FU2 produced significantly reduced incidences of neutropenia, diarrhoea and mucositis, despite the fact that the mean 5-FU dose intensities were twice the amount in LV5FU2 compared with bolus 5-FU/LV. The North American Intergroup study 0153 also compared infused with bolus administration of 5-FU and levamisole [11
]. However, this trial was halted early after an interim analysis showed a very low possibility for a significant 3-year survival difference to be detected. Given that the current studies do not support a dramatic survival benefit of bolus 5-FU/LV over infused 5-FU or vice versa, it would be reasonable to consider infused 5-FU to be used in place of bolus 5-FU/LV depending on treating clinicians' and patients' preference. Indeed, LV5FU2 has been adopted as the control arm when comparing with the addition of irinotecan or oxaliplatin to LV5FU2 in two large European studies.
Of the patients who relapsed in our study, the majority failed at distant sites. The benefit of PVI 5-FU appeared to be reducing distant metastases in patients with rectal cancer. Thirty-five out of 323 patients (10.8%) with rectal or rectosigmoid junction cancers developed local recurrences after a median follow-up of 55 months. Indeed, only 21 (6.5%) developed local-only recurrences without synchronous distant metastases, where radiotherapy is more likely to make an impact. In our study, radiotherapy was mainly reserved for patients with T4 rectal cancer, whereas patients with stage III rectal cancer did not receive routine radiotherapy. Only 10% of rectal cancer patients received post-operative adjuvant chemoradiation in our study. This local recurrence rate, therefore, compares favourably with the 8% to 14% seen in large US cooperative groups studies [12
15
]. Considering that no large randomised studies have demonstrated an OS advantage of adjuvant chemoradiation over chemotherapy alone, our results gave reassurance that radiotherapy may be safely omitted in a selected group of patients. However, one might argue that patients with locally advanced but resectable rectal cancer might be more likely to receive preoperative chemoradiation for potential downstaging, and therefore would not be recruited into our study. Given that our study commenced in 1993 and preoperative chemoradiation was not routinely considered at the participating institutions until late 1990s, this was unlikely to lead to significant referral bias. In our study, PVI 5-FU produced a significantly better RFS and a trend towards better OS compared with bolus 5-FU/LV in rectal cancer patients. With the increased number of rectal cancer patients recruited into the study, the advantage of PVI 5-FU over bolus 5-FU/LV is confirmed. Whereas O'Connell et al. [16
] demonstrated previously that infused 5-FU is superior to bolus 5-FU when used synchronously with radiation, our study added further evidence of the superiority of infused 5-FU when used as single modality adjuvant treatment, especially in reducing distant relapses.
Consistent with the pooled analysis of randomised controlled trials (RCTs), patients aged 70 years had a similar survival to those <70 years old in our study (P=0.135), thus providing further evidence that age should not be a sole contraindication to adjuvant therapy in CRC. Females have been found to experience greater 5-FU toxicity than men with CRC [17
] in a meta-analysis of five RCTs in advanced and adjuvant settings. Women and their tumours may be more sensitive to 5-FU than men, and lower doses of 5-FU may have an increased pharmacological and antitumour effect in females. However, this meta-analysis [17
] and other RCTs [10
, 15
, 18
20
] did not find any difference in survival by gender for patients receiving adjuvant therapy, in contrast to our study, where females had a better survival compared with males in multivariate analysis, although the magnitude was relatively small.
Contrary to most other recent large randomised studies in which patients were mandated to commence chemotherapy within 8 weeks of surgery [8, 10
, 20
25
], our study was more permissive in allowing patients to enter into the study up to 12 weeks after surgery. In our study, patients who commenced chemotherapy within 8 weeks had a significant survival advantage even after controlling for other prognostic variables. Indeed, this survival advantage was particularly pronounced in patients receiving PVI 5-FU. Most published studies did not explore the interval between surgery and starting adjuvant chemotherapy as a prognostic factor because of the short time interval allowed in their protocols. However, two studies have investigated this issue [10
, 26
]. The GERCOR study, which stipulated that all patients to start treatment within 7 weeks, did not find a significant association of this interval with survival [10
], whereas the pooled NORDIC study found a better survival for those who commenced treatment
8 weeks from surgery [26
]. Our data further support the belief that patients should start adjuvant chemotherapy in a timely manner after surgery, although this issue is unlikely to be ever evaluated in a randomised fashion.
Baseline QoL has been found to be a significant prognostic factor in advanced CRC [27] and other cancers [28
32
], but this did not influence the OS and RFS in our adjuvant study. QoL in a metastatic setting is more likely to be disease-related, whereas QoL is probably related more to surgery in the adjuvant setting; thus baseline QoL did not affect survival, although it is interesting that patients with PS 0 had a highly significantly improved survival compared with those with PS 12 (even though only 6% of patients had PS 2 at baseline) in our study. A more detailed account of QoL assessment and quality adjusted survival analysis will be reported in a separate publication.
Oxaliplatin and irinotecan are two agents that have made an impact in metastatic CRC in recent years. Evaluating the use of these agents in the adjuvant setting is logical. The European MOSAIC [Multicenter International Study of Oxaliplatin/5-FU/LV (FOLFOX 4) in the Adjuvant Treatment of Colon Cancer] study recruited 2248 stage II and III colon cancer patients. FOLFOX 4 significantly improved disease-free survival compared with LV5FU2, and this is the first study suggesting additional benefit of the three-drug combination in the adjuvant setting [33]. FOLFOX 4 can therefore be considered for stage III colon cancer patients, especially those with additional high-risk pathological features. However, one needs to bear in mind the safety of adjuvant treatment. The recently closed Cancer and Leukemia Group B (CALGB) C89803 compared the Roswell Park bolus 5-FU/LV regimen with irinotecan/bolus 5-FU/LV (IFL) regimen in 1263 stage III patients. The 60-day mortality rate was 2.2% in the IFL arm compared with 0.8% in the control arm [34
]. Perhaps not surprisingly, the preliminary analysis of this study did not show any survival benefit of IFL over bolus 5-FU/LV given the nearly three-fold increase in early mortality in a relatively underpowered study. In the PETACC-3 trial, LV5FU2 and irinotecan (FOLFIRI) was compared with LV5FU2 alone in 2333 patients, and no excessive treatment-related deaths have been reported to date with the substitution of an infused schedule for a bolus schedule when combined with irinotecan in this trial. Infused schedules of 5-FU/LV may represent more optimal partners when combined with oxaliplatin and irinotecan. Long-term side-effects of these agents also need to be taken into account when recommending adjuvant chemotherapy. In the MOSAIC study, 44% of patients developed grade 23 peripheral neuropathy during treatment, which decreased to 5% 1 year post-treatment. Residual functional neuropathy is much less acceptable in patients who have had a potentially curative resection. Randomised studies of neuroprotective agents are urgently required considering the roles of oxaliplatin in both adjuvant and metastatic settings.
Capecitabine simulates continuous infusion of 5-FU, which is cumbersome to use and compromises patients' independence. Moreover, the elimination of ports and pumps required for intravenous infusion and avoidance of central venous catheter-associated complications may translate into cost-saving measures for the health service. The use of capecitabine in adjuvant setting has been addressed in the X-ACT study, in which 1987 patients with stage III colon cancer were randomised between capecitabine or bolus 5-FU/LV. With a median follow-up of 3.8 years, adjuvant capecitabine for 6 months resulted in a trend towards better disease-free survival (P=0.0528) and OS (P=0.0706) than bolus 5-FU/LV [35], in addition to significantly reduced neutropenia, diarrhoea, stomatitis, nausea and alopecia [36
]. This is perhaps not surprising, given that our results showed that PVI 5-FU was also associated with a trend towards better RFS and OS compared with bolus 5-FU/LV, and the X-ACT study had a much larger sample size and included stage III colon cancer patients only. Therefore, capecitabine can be considered as a suitable substitute in the adjuvant setting to bolus intravenous 5-FU/LV for stage III colon cancer. Routine chemotherapy for stage II colon cancer is not recommended at present [37
], although recent results from the QUASAR uncertain study provided the first randomised evidence of chemotherapy producing RFS and OS advantage [38
].
In conclusion, PVI 5-FU was associated with a trend towards better RFS and OS compared with bolus 5-FU/LV, but with significantly less toxicity. Based on our results, the probability of 12 weeks of PVI 5-FU being inferior to 6 months of bolus 5-FU/LV is extremely low, and therefore shorter duration of adjuvant treatment should be explored further.
![]() |
Acknowledgements |
---|
Received for publication October 20, 2004. Revision received November 12, 2004. Accepted for publication November 15, 2004.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Chau I, Cunningham D. Adjuvant therapy in colon cancer: current status and future directions. Cancer Treat Rev 2002; 28: 223236.[CrossRef][ISI][Medline]
3. Meta-analysis Group In Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998; 16: 301308.[Abstract]
4. Saini A, Norman AR, Cunningham D et al. Twelve weeks of protracted venous infusion of fluorouracil (5-FU) is as effective as 6 months of bolus 5-FU and folinic acid as adjuvant treatment in colorectal cancer. Br J Cancer 2003; 88: 18591865.[CrossRef][ISI][Medline]
5. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457481.[ISI]
6. Peto R, Peto J. Asymptotically efficient invariant procedures. J R Stat Soc A 1972; 135: 185206.[ISI]
7. Cox DR. Regression models and life tables. J R Stat Soc A 1972; 29: 187220.
8. O'Connell MJ, Laurie JA, Kahn M et al. Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 1998; 16: 295300.[Abstract]
9. Haller D, Catalano PJ, Macdonald JS et al. Fluorouracil, leucovorin and levamisole adjuvant therapy for colon cancer: five year final report of Int-0089. Proc Am Soc Clin Oncol 1998; 17: 256a.
10. Andre T, Colin P, Louvet C et al. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol 2003; 21: 28962903.
11. Poplin E, Benedetti J, Estes N et al. Phase III randomized trial of bolus 5-FU/leucovorin/levamisole versus 5-FU continuous infusion/levamisole as adjuvant therapy for high risk colon cancer (SWOG 9415/INT-0153). Proc Am Soc Clin Oncol 2000; 19: 240a.
12. Gastrointestinal Tumor Study Group. Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med 1985; 312: 14651472.[Abstract]
13. Krook JE, Moertel CG, Gunderson LL et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991; 324: 709715.[Abstract]
14. Tepper JE, O'Connell M, Niedzwiecki D et al. Adjuvant therapy in rectal cancer: analysis of stage, sex, and local controlfinal report of Intergroup 0114. J Clin Oncol 2002; 20: 17441750.
15. Wolmark N, Wieand HS, Hyams DM et al. Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 2000; 92: 388396.
16. O'Connell MJ, Martenson JA, Wieand HS et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994; 331: 502507.
17. Sloan JA, Goldberg RM, Sargent DJ et al. Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer. J Clin Oncol 2002; 20: 14911498.
18. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) Investigators. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 1995; 345: 939944.[CrossRef][ISI][Medline]
19. Moertel CG, Fleming TR, Macdonald JS et al. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med 1995; 122: 321326.
20. 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 1997; 15: 246250.[Abstract]
21. Di Costanzo F, Sobrero A, Gasperoni S et al. Adjuvant chemotherapy in the treatment of colon cancer: randomized multicenter trial of the Italian National Intergroup of Adjuvant Chemotherapy in Colon Cancer (INTACC). Ann Oncol 2003; 14: 13651372.
22. Punt CJ, Nagy A, Douillard JY et al. Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study. Lancet 2002; 360: 671677.[CrossRef][ISI][Medline]
23. Taal BG, Van Tinteren H, Zoetmulder FA. Adjuvant 5FU plus levamisole in colonic or rectal cancer: improved survival in stage II and III. Br J Cancer 2001; 85: 14371443.[ISI][Medline]
24. Wolmark N, Fisher B, Rockette H et al. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst 1988; 80: 3036.
25. Wolmark N, Rockette H, Fisher B et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 1993; 11: 18791887.[Abstract]
26. Glimelius B, Cedermark B, Dahl O et al. Adjuvant chemotherapy in colorectal cancer: joint analyses of randomised trials by the Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Eur J Cancer 2003; 1: S318.
27. Maisey NR, Norman A, Watson M et al. Baseline quality of life predicts survival in patients with advanced colorectal cancer. Eur J Cancer 2002; 38: 13511357.[CrossRef][ISI][Medline]
28. Coates A, Porzsolt F, Osoba D. Quality of life in oncology practice: prognostic value of EORTC QLQ-C30 scores in patients with advanced malignancy. Eur J Cancer 1997; 33: 10251030.[CrossRef][ISI][Medline]
29. Dancey J, Zee B, Osoba D et al. Quality of life scores: an independent prognostic variable in a general population of cancer patients receiving chemotherapy. The National Cancer Institute of Canada Clinical Trials Group. Qual Life Res 1997; 6: 151158.[ISI][Medline]
30. Montazeri A, Milroy R, Hole D et al. Quality of life in lung cancer patients: as an important prognostic factor. Lung Cancer 2001; 31: 233240.[CrossRef][ISI][Medline]
31. Wisloff F, Hjorth M. Health-related quality of life assessed before and during chemotherapy predicts for survival in multiple myeloma. Nordic Myeloma Study Group. Br J Haematol 1997; 97: 2937.[ISI][Medline]
32. Chau I, Norman AR, Cunningham D et al. Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancerpooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol 2004; 22: 23952403.
33. Andre T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004; 350: 23432351.
34. Rothenberg ML, Meropol NJ, Poplin EA et al. Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 2001; 19: 38013807.
35. Cassidy J, Scheithauer W, McKendrick J et al. Capecitabine (X) vs bolus 5-FU/leucovorin (LV) as adjuvant therapy for colon cancer (the X-ACT study): positive efficacy results of a phase III trial. J Clin Oncol (Meeting Abstracts) 2004; 22: 3509.
36. Scheithauer W, McKendrick J, Begbie S 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 2003; 14: 17351743.
37. Benson AB 3rd, Schrag D, Somerfield MR et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004; 22: 34083419.
38. Gray RG, Barnwell J, Hills R et al. QUASAR: A randomized study of adjuvant chemotherapy (CT) vs observation including 3238 colorectal cancer patients. J Clin Oncol (Meeting Abstracts) 2004; 22: 3501.