1 University Hospital, Dresden, Germany; 2 Royal-Marsden Hospital, Sutton, UK; 3 University of Uppsala, Akademiska sjukhuset, Uppsala, Sweden; 4 Azienda Ospedale Careggi, Firence, Italy; 5 St Laurentius Hospital, Roermond, The Netherlands; 6 University Medical School, Vienna, Austria; 7 Hospital Ambroise Pare, Boulogne, France; 8 Hospital Clinico Provincial, Cordoba, Spain; 9 Medical School, Hannover, Germany
* Correspondence to:Prof. C.-H. Köhne, University Hospital Carl Gustav Carus, Medical Department, Fetscherstraße 74, 01307 Dresden, Germany. Tel: +49-351-458-4781; Fax: +49-351-458-5859; Email: claus-henning.koehne{at}uniklinikum-dresden.de
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Abstract |
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Patients and methods: We carried out a retrospective analysis using source data of 3825 patients who received 5-fluorouracil (5-FU)-containing treatment in 22 European trials and identified 629 patients with an age of 70 years.
Results: We found an equal overall survival in elderly patients [10.8 months, 95% confidence interval (CI) 9.711.8] and in younger patients (11.3 months, 95% CI 10.911.7; P=0.31). Response rate did not differ between age groups 70 and <70 years (23.9% and 21.1%; respectively; P=0.14). Progression-free survival was marginally prolonged in elderly patients (5.5 months, 95% CI 5.25.8; compared with 5.3 months, 95% CI 5.15.5; P=0.01). In both age groups, infusional 5-FU resulted in significantly increased response rates, overall survival and progression-free survival compared with bolus 5-FU.
Conclusions: Fit elderly patients benefit at least to the same extent from palliative chemotherapy with 5-FU as younger patients. Infusional 5-FU was shown to be more effective than bolus 5-FU in both age groups. Therefore, standardized palliative chemotherapy should generally be offered to elderly patients and they should not be excluded from clinical trials.
Key words: 5-FU, chemotherapy, colorectal cancer, elderly patients
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Introduction |
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Systemic chemotherapy is the treatment of choice for patients with metastatic colorectal cancer to prolong survival, and to improve symptoms and quality of life. 5-Fluorouracil (5-FU)-based treatment is generally offered to patients. Biochemical modulation of 5-FU and/or administration as a continuous infusion are achievements of the 1980s and have resulted in increased response rates and prolonged progression-free survival (PFS), while the influence on overall survival (OS) has been limited [25
]. Fortunately, the chemotherapeutic arsenal has been broadened by the introduction of new active compounds such as topoisomerase-1 inhibitors, diaminocyclohexan (DACH)-platin derivates and oral fluoropyrimidines, which improve the efficacy or the convenience of chemotherapy in metastatic colorectal cancer [6
11
].
There is still uncertainty regarding to what extent systemic palliative chemotherapy should be offered to elderly patients with colorectal cancer. This fact is related to the unfortunate underrepresentation [12, 13
] or even exclusion of elderly patients from clinical trials and also to the total lack of studies in unfit elderly patients.
Increased attention has recently been paid to the management and outcome of elderly patients with colorectal cancer. Population-based series focusing on surgery and adjuvant therapy have confirmed that older patients are more often inadequately staged and fewer elective operations are performed [14], and that they are less likely to receive adjuvant chemotherapy and/or radiotherapy [15
18
]. In contrast to these facts, a recently published meta-analysis [19
] and population-based analyses [16
, 18
, 20
] showed that elderly patients with colon or rectum cancer benefit from adjuvant chemotherapy or radiochemotherapy to the same extent as younger patients.
The reason why elderly patients are less likely to be offered adequate diagnostic procedures or treatment for their tumor is multifactorial. Advanced age is often associated with increased health problems such as declining organ functions, decreasing cognitive or socio-economic abilities and additional diseases. Although co-morbid conditions are associated with a higher operative morbidity and mortality, improvements in supportive means for anesthesia and post-operative management have reduced the mortality associated with surgical procedures. This may also be important for patients with metastatic colorectal cancer as reports are emerging on secondary resectability of metastasis following more intensive systemic chemotherapy [21].
Elderly patients with metastatic colorectal cancer are described in a report of the Royal Marsden Hospital [22] which compares efficacy and toxicity in 186 elderly patients (>70 years) with 658 younger (<70 years) patients and in a pooled analysis of four North Central Cancer Treatment Group (NCCTG) trials with 1748 patients [23
].
To gain a better understanding of the potential benefit of systemic chemotherapy in elderly patients, we undertook a retrospective analysis using original data from 22 phase II and phase III trials conducted throughout Europe and identified a total of 629 patients above 70 years of age which represents, to our knowledge, the largest cohort that has been analyzed to date.
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Patients and methods |
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For the purpose of this analysis, the regimens were classified as 5-FU treatment given as a bolus or as infusional regimen. All schedules with 5-FU administered within 2 h or less were regarded as bolus regimens, while protracted venous infusion and weekly or biweekly high-dose 5-FU was regarded as infusional 5-FU. The studies or treatment arms categorized as bolus or infusional 5-FU are shown in Table 1.
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Data were analyzed using the program SPSS, version 11.0 (SPSS, Chicago, IL). Categorical data were examined using the 2 test and laboratory data using the unpaired Student's t-test. Survival analysis was performed using the method of KaplanMeier, with the log-rank test used to examine differences in survival.
To determine the influence of age and treatment on survival, Cox regression analysis was performed with age as continuous and categorical (<70 and 70 years) variables.
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Results |
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A total of 629 patients 70 years of age were identified which represented 16.4% of the total study population. Four hundred and eighty-four patients belonged to the age group 7075 years (12.7% of the study population), 125 to the age group 7579 years (3.3%) and 20 to the age group
80 years (<1%).
Approximately 84% of patients were <70 years of age, which was quite consistent over all study groups from European countries, with the exception of two trials. While only 64% of patients from the Austrian trial where <70 years of age, the Spanish trial included <1% of patients with an age >70 years, presumably due to the fact that specific trials for elderly patients were offered in Spain.
Patients characteristics
The patient characteristics within the different age categories are listed in Table 2.
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There appeared to be no differences in the distribution of ECOG performance status or the percentage of patients with symptomatic disease. Neither the tumor load (indicated by the number of affected tumor sites) nor the distribution of metastases between liver, lung, lymph nodes or peritoneal cavity showed a significant imbalance.
About two-thirds of patients received 5-FU as a bolus and one-third as infusion. Here, less elderly patients received infusional 5-FU (28%) compared with younger patients (35%; P=0.0002).
Laboratory results before initiation of treatment are shown in Table 3. A significant difference was only seen in terms of a (clinically irrelevant) lower total serum protein in elderly patients (71.4 versus 72.7 g/l; P <0.001).
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Age-related response rates and survival
Objective tumor response was observed in 22% of the whole population. Patients in the older age group (70 years) had the same chance of response to fluoropyrimidine-based treatment as younger patients (24% and 21%; P=0.14; Table 5).
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OS in elderly patients (10.8 months; 95% CI 9.711.8 months) was not significantly different to that of younger patients who had a median OS of 11.3 months (95% CI 10.911.7 months; P=0.3; Figure 1).
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Survival and 5-FU administration
Comparing bolus and infusional 5-FU administration schedules, OS was significantly longer in patients receiving infusional 5-FU (12.3 versus 10.7 months; P <0.0001). An improvement in OS was seen in both age groups (Figure 2): In younger patients, OS increased from 10.7 months with bolus 5-FU to 12.3 months with infusional 5-FU (P <0.0001). In patients 70 years of age, OS was 10.3 and 11.9 months with bolus and infusional 5-FU, respectively (P=0.014; Table 6). In Cox regression analysis, age had no additional influence on survival when age was regarded as a continuous variable (HR 1.0, 95% CI 0.9961.003; P=0.84) or as a categorical variable (HR 1.03, 95% CI 0.941.13; P=0.52).
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Response rates were increased in patients treated with infusional 5-FU (Table 6): in younger (<70 years) patients receiving infusional 5-FU, a 7.7% difference in overall response was seen compared with younger patients treated with bolus 5-FU (26.2% versus 18.5%; P <0.0001). Elderly patients (70 years) had a 9.9% higher overall response with 5-FU infusion (31.2%) than with the 5-FU bolus regimen (21.3%; P=0.014).
Sixty day mortality was identical in the whole population and in younger patients when infusional and bolus 5-FU were compared. In patients 70 years, a trend to a reduced 60 day mortality (4.6% versus 9.2%; P=0.06) was observed in the infusional 5-FU group.
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Discussion |
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Elderly patients (70 years of age) represent 16% of the entire cohort, which is in accordance with another pooled analyses (e.g. Sargent et al. [19
]), although it reflects neither the proportion of elderly patients admitted to hospitals nor the age-specific rate of death due to colorectal cancer. A recently published analysis of National Cancer Institute (NCI)-sponsored clinical trials found the prevalence of elderly patients (
65 years) attending oncology clinics to be, in general, twice as high (61%) as that of elderly patients entering clinical trials (32%) [12
].
Elderly and younger patients in our analysis showed minor differences in their patient characteristics. A higher proportion of primary tumor site in the colon and more disease-related weight loss were observed in the age group 70 years. The higher percentage of elderly patients pretreated with adjuvant chemotherapy (also thought to adversely affect prognosis) probably reflects the selection of patients who had already tolerated a chemotherapy regimen. However, we observed an equal distribution of recently published prognostic groups (Table 3) [24
] that were developed from the same patient population, suggesting that elderly patients were not more positively selected than younger patients.
Although the age-standardized death rate due to colorectal cancer is increasing more in male than in female patients, the proportion of women dying due to colorectal cancer increases with higher age [25] because of the higher life expectation in women. However, we observed a larger proportion of male patients in the elderly group; the reason for this observation remains unclear.
Efficacy of chemotherapy did not differ when younger and elderly patients were compared. We found an equal response rate and an equal OS. The PFS was even marginally prolonged in elderly patients.
Regarding the subgroups of elderly patients, no trends in tumor response, PFS or OS were seen between patients of 7074, 7579 and 80 years of age. These data support the fact that patients fulfilling the usual inclusion criteria for clinical trials have the same chance of responding to chemotherapy without any influence of age.
The absent negative influence of age on chemotherapy efficacy is in accordance with reports from smaller cohorts. In a series of the Royal Marsden Hospital, an equal overall response and PFS was observed in 186 elderly patients compared to younger patients. However, OS was reduced in the elderly patients, which was thought to be related to an increased proportion of non-cancer deaths [22]. It may be speculated that the patients of the Royal Marsden Hospital, who were not all treated in clinical trials, had more co-morbidities than the patients included in our analysis who all fulfilled the usual inclusion criteria of clinical studies. Furthermore, a pooled analysis of two NCI-sponsored trials identified 82 patients
65 years of age. No significant differences in toxicity and in tumor response were observed between patients <65 and
65 years of age [26
]. In a multivariate analysis of 1748 patients treated within four NCCTG trials, age was not predictive of response rate, time to progression or OS [23
].
Infusional 5-FU is known to increase OS, PFS and tumor response rates compared with bolus 5-FU, as shown in randomized trials [2, 3
, 27
] and meta-analysis [28
].
Although we used source data from the different studies, only a small part of the trials was designed to compare infusional and bolus 5-FU. Nevertheless, our results confirm the (small) advantage of infusional 5-FU regarding OS, PFS and response rates reported earlier. In addition, our analysis could demonstrate that elderly patients benefit with the same gain in tumor response, PFS and OS from the more effective therapy of infusional 5-FU as younger patients.
Unfortunately, we were not able to collect and analyze toxicity data. In a retrospective analysis of a phase III trial using 5-FU, increased toxicity (leukocytopenia, diarrhea, vomiting) and more treatment-associated deaths were reported [29]. In contrast to these results, no increased grade 3/4 toxicity of 5-FU- or raltitrexed-based chemotherapy was found in elderly patients receiving palliative chemotherapy in a UK series [22
]. Interestingly, a higher incidence of stomatitis was seen in elderly patients with adjuvant chemotherapy (19% versus 11%; P < 0.02) in the same publication and a higher percentage of leukocytopenia (8% versus 4%; P < 0.05) was reported in elderly patients receiving adjuvant chemotherapy in a pooled analysis [19
].
An analysis of two randomized trials comparing capecitabine and bolus 5-FU reports an increased rate of grade 3/4 toxicity in older patients [30]. Since impaired renal function was associated with capecitabine-induced toxicity on the one hand [30
] and since renal function frequently impairs with increasing age on the other side, a regression analysis was performed with the result that no independent impact of age in addition to reduced creatinine clearance was found. 5-FU tolerability impaired in these trials at least to a similar degree as reduced renal function [30
]. This might be the cause of the increased grade 3 toxicity in elderly patients described in a pooled analysis of four NCCTG trials [23
].
We analyzed studies that were conducted before irinotecan and oxaliplatin became available as first-line therapy. During the last few years, combination chemotherapy with irinotecan and oxaliplatin has been shown to improve response rate and PFS, and also in some trials OS. Only limited data are available for the efficacy and safety of these new drugs in elderly patients.
With the combination of irinotecan and 5-FU-folinic acid (FA), a similar efficacy (response rate, PFS and OS) was seen in 92 younger and 53 elderly (>65 years) patients [31]. Beside a higher rate of febrile neutropenia (7.5% versus 1.1%), increased toxicity was not observed; in particular, there was no increase in the frequency of diarrhea (14% and 15%, respectively). This is of particular interest since the median age of patients with early therapy-induced deaths in irinotecan trials was higher (69.5 and 65 years in the C89803 and N9741 studies, respectively) than the median age of all patients in the treatment arm of the N9741 study (61 years) and the median age in most adjuvant studies (
60 years). However, patients who died early in the other treatment arms also had a higher median age: 73 years in the RPMI arm (C89803) and 66 and 68 years in the FOLFOX4 and IROX arms (N9741), respectively [32
].
In a recently published phase II trial with capecitabine and irinotecan, an increased rate of neutropenia grade 3/4 was seen in patients >65 years of age compared with those <65 years, despite a dose reduction in the elderly patients [33].
Interestingly, Saltz et al. report a prolonged PFS in patients 65 years of age in a trial comparing IFL, CPT-11 and the NCCTG regimen (HR 0.78, 95% CI 0.580.95; P=0.02) [34
].
In the randomized study comparing FOLFOX4 and LV5FU2, age had no influence on efficacy in terms of OS, PFS or tumor response [8]. A study by Giacchetti et al. [10
], investigating chronomodulated 5-FU-FA plus or minus oxaliplatin, also found there was no influence of age on OS, although age did affect tumor response (P=0.013). However, further data on elderly patients treated with combination chemotherapy are needed.
We conclude that at least elderly patients with only minor co-morbidities (fulfilling the standard inclusion criteria of clinical trials) have the same advantage from 5-FU-based chemotherapy (especially infusional 5-FU) as their younger counterparts. Therefore, elderly patients in good general condition should be offered palliative systemic chemotherapy. They should be treated with the same regimens and included in the same trials as younger patients. We recommend designing specific clinical trials that include unfit elderly patients, with reduced general condition and more co-morbidities, especially as these unfit patients seem to represent the majority of elderly patients and no valid data are available from this large subgroup of patients suffering from metastatic colorectal cancer.
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References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. de Gramont A, Bosset JF, Milan C et al. A randomized trial comparing monthly low-dose leucovorin/fluorouracil bolus with bimonthly high-dose leucovorin/fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol 1997; 15: 808815.[Abstract]
3. Weh HJ, Zschaber R, Braumann D et al. A randomized phase III study comparing weekly folinic acid (FA) and high dose 5-fluorouracil (5-FU) with monthly 5-FU/FA (days 15) in untreated patients with metastatic colorectal carinoma. Onkologie 1998; 21: 403407.[CrossRef][ISI]
4. Köhne CH, Wils J, Lorenz M et al. Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European Organization of Research and Treatment of Cancer Gastrointestinal Group study 40952. J Clin Oncol 2003; 21: 37213728.
5. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. Meta-analysis Group in Cancer. J Clin Oncol 1998; 16: 301308.[Abstract]
6. Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343: 905914.
7. Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 355: 10411047.[CrossRef][ISI][Medline]
8. de Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 29382947.
9. Köhne CH, Van Cutsem E, Wils JA et al. Irinotecan improves the activity of the AIO regimen in metastatic colorectal cancer: results of EORTC GI Group study 40986. Proc Am Soc Clin Oncol 2003; 22: 254 (Abstr 1018).
10. Giacchetti S, Perpoint B, Zidani R et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracilleucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000; 18: 136147.
11. Grothey A, Deschler B, Kroening H et al. Phase III study of bolus 5-fluorouracil (5-FU)/folinic acid (FA) (Mayo) vs weekly high-dose 24 h 5-FU infusion/FA + oxaliplatin (OXA) (FUFOX) in advanced colorectal cancer (ACRC). Proc Am Soc Clin Oncol 2002; 21: 129a (Abstr 512).
12. Lewis JH, Kilgore ML, Goldman DP et al. Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol 2003; 21: 13831389.
13. Hutchins LF, Unger JM, Crowley JJ et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999; 341: 20612067.
14. Surgery for colorectal cancer in elderly patients: a systematic review. Colorectal Cancer Collaborative Group. Lancet 2000; 356: 968974.[CrossRef][ISI][Medline]
15. Potosky AL, Harlan LC, Kaplan RS et al. Age, sex, and racial differences in the use of standard adjuvant therapy for colorectal cancer. J Clin Oncol 2002; 20: 11921202.
16. Sundararajan V, Mitra N, Jacobson JS et al. Survival associated with 5-fluorouracil-based adjuvant chemotherapy among elderly patients with node-positive colon cancer. Ann Intern Med 2002; 136: 349357.
17. Schrag D, Cramer LD, Bach PB, Begg CB. Age and adjuvant chemotherapy use after surgery for stage III colon cancer. J Natl Cancer Inst 2001; 93: 850857.
18. Neugut AI, Fleischauer AT, Sundararajan V et al. Use of adjuvant chemotherapy and radiation therapy for rectal cancer among the elderly: a population-based study. J Clin Oncol 2002; 20: 26432650.
19. Sargent DJ, Goldberg RM, Jacobson SD et al. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 2001; 345: 10911097.
20. Iwashyna TJ, Lamont EB. Effectiveness of adjuvant fluorouracil in clinical practice: a population-based cohort study of elderly patients with stage III colon cancer. J Clin Oncol 2002; 20: 39923998.
21. Giacchetti S, Itzhaki M, Gruia G et al. Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 1999; 10: 663669.[Abstract]
22. Popescu RA, Norman A, Ross PJ et al. Adjuvant or palliative chemotherapy for colorectal cancer in patients 70 years or older. J Clin Oncol 1999; 17: 24122418.
23. Jacobson SD, Cha S, Sargent DJ et al. Tolerability, dose intensity, and benefit of 5FU-based chemotherapy for advanced colorectal cancer (CRC) in the elderly. A North Central Cancer Treatment Group (NCCTG) study. Proc Am Soc Clin Oncol 2001; 20: 587 (Abstr).
24. Köhne CH, Cunningham D, Di Costanzo F et al. Clinical determinants of survival in patients with 5-fluorouracil-based treatment for metastatic colorectal cancer: results of a multivariate analysis of 3825 patients. Ann Oncol 2002; 13: 308317.
25. Bray F, Sankila R, Ferlay J et al. Estimates of cancer incidence and mortality in Europe in 1995. Eur J Cancer 2002; 38: 99106.[CrossRef][ISI][Medline]
26. Chiara S, Nobile MT, Vincenti M et al. Advanced colorectal cancer in the elderly: results of consecutive trials with 5-fluorouracil-based chemotherapy. Cancer Chemother Pharmacol 1998; 42: 336340.[CrossRef][ISI][Medline]
27. Köhne CH, Wils J, Lorenz M et al. Randomized phase III study of high dose 5-fluorouracil given as a weekly 24 hour infusion with or without leucovorin vs. bolus 5-fluorouracil plus leucovorin in advanced colorectal cancer. J Clin Oncol 2003; 21: 37213728.
28. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol 1992; 10: 896903.[Abstract]
29. Stein BN, Petrelli NJ, Douglass HO et al. Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial. Cancer 1995; 75: 1117.[ISI][Medline]
30. 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 2002; 13: 566575.
31. Rougier P, Mitry E, Cunningham D et al. Is age a prognostic factor of toxicity and efficacy in patients (pts) with metastatic colorectal cancer (MCRC) receiving irinotecan in combination with 5FU/folinic acid (FA). Proc Am Soc Clin Oncol 2003; 22: 267 (Abstr 1072).
32. Rothenberg M, Meropol NJ, Poplin EA et al. Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summery findings of an independent panel. J Clin Oncol 2001; 19: 38013807.
33. Patt Y, Lin E, Leibmann J et al. Capecitabine plus irinotecan for chemotherapy-naïve patients with metastatic colorectal cancer (MCRC): US multicenter phase II trial. Proc Am Soc Clin Oncol 2003; 22: 281 (Abstr 1130).
34. Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group [see comments]. N Engl J Med 2000; 343: 905914.
35. Scheithauer W, Kornek G, Marczell A et al. Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study. J Clin Oncol 1997; 15: 908914.[Abstract]
36. Blijham G, Wagener T, Wils J et al. Modulation of high-dose infusional fluorouracil by low-dose methotrexate in patients with advanced or metastatic colorectal cancer: final results of a randomized European Organization for Research and Treatment of Cancer Study. J Clin Oncol 1996; 14: 22662273.[Abstract]
37. Wils J, Blijham GH, Wagener T et al. High-dose 5-fluorouracil plus low dose methotrexate plus or minus low-dose PALA in advanced colorectal cancer. A randomised phase IIIII trial of the EORTC Gastrointestinal Group. Eur J Cancer 2003; 39: 346352.[CrossRef][ISI][Medline]
38. Rougier P, Paillot B, Laplanche A et al. 5-Fluorouracil (5-FU) continuous intravenous infusion compared with bolus administration. Final results of a randomised trial in metastatic colorectal cancer. Eur J Cancer 1997; 33: 17891793.[CrossRef][ISI][Medline]
39. Köhne CH, Schöffski P, Wilke H et al. Effective biomodulation by leucovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion: results of a randomized trial in patients with advanced colorectal cancer. J Clin Oncol 1998; 16: 418426.[Abstract]
40. Köhne CH, Wilke H, Hiddemann W et al. Phase II evaluation of 5-fluourouracil plus folinic acid and 2b-interferon in metastatic colorectal cancer. Oncology 1997; 54: 96101.[ISI][Medline]
41. Köhne CH, Hiddemann W, Schuller J et al. Failure of orally administered dipyridamole to enhance the antineoplastic activity of fluorouracil in combination with leucovorin in patients with advanced colorectal cancer: a prospective randomized trial. J Clin Oncol 1995; 13: 12011208.[Abstract]
42. Di-Costanzo F, Bartolucci R, Calabresi F et al. Fluorouracil-alone versus high-dose folinic acid and fluorouracil in advanced colorectal cancer: a randomized trial of the Italian Oncology Group for Clinical Research (GOIRC). Ann Oncol 1992; 3: 371376.[Abstract]
43. Di Costanzo F, Gasperoni S, Malacarne P et al. High-dose folinic acid and 5-fluorouracil alone or combined with hydroxyurea in advanced colorectal cancer: a randomized trial of the Italian Oncology Group for Clinical Research. Am J Clin Oncol 1998; 21: 369375.[CrossRef][ISI][Medline]
44. Di Costanzo F, El-Taani H, Marzola M et al. Hydroxyurea (HU), high dose folinic acid (l-FA) and 5-FU vs. HU, 5FU and interferon--2b (IFN) in advanced colorectal cancer (ACRC): a randomized trial of the Italian Oncology Group for Clinical Research (GOIRC). Proc Am Soc Clin Oncol 1995; 14: 208 (Abstr 508).
45. Graf W, Glimelius B, Pahlman L, Bergstrom R. Determinants of prognosis in advanced colorectal cancer. Eur J Cancer 1991; 27: 11191123.[ISI][Medline]
46. Graf W, Pahlman L, Bergstrom R, Glimelius B. The relationship between an objective response to chemotherapy and survival in advanced colorectal cancer. Br J Cancer 1994; 70: 559563.[ISI][Medline]
47. Glimelius B. Biochemical modulation of 5-fluorouracil: a randomized comparison of sequential methotrexate, 5-fluorouracil and leucovorin versus sequential 5-fluorouracil and leucovorin in patients with advanced symptomatic colorectal cancer. The Nordic Gastrointestinal Tumor Adjuvant Therapy Group. Ann Oncol 1993; 4: 235240.[Abstract]
48. Superiority of sequential methotrexate, fluorouracil, and leucovorin to fluorouracil alone in advanced symptomatic colorectal carcinoma: a randomized trial. The Nordic Gastrointestinal Tumor Adjuvant Therapy Group. J Clin Oncol 1989; 7: 14371446.[Abstract]
49. Expectancy or primary chemotherapy in patients with advanced asymptomatic colorectal cancer: a randomized trial. Nordic Gastrointestinal Tumor Adjuvant Therapy Group. J Clin Oncol 1992; 10: 904911.[Abstract]
50. Aranda E, Diaz-Rubio E, Cervantes A et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol 1998; 9: 727731.[Abstract]
51. Hill M, Norman A, Cunningham D et al. Royal Marsden phase III trial of fluorouracil with or without interferon -2b in advanced colorectal cancer. J Clin Oncol 1995; 13: 12971302.[Abstract]
52. Hill M, Norman A, Cunningham D et al. Impact of protracted venous infusion fluorouracil with or without interferon -2b on tumor response, survival, and quality of life in advanced colorectal cancer. J Clin Oncol 1995; 13: 23172323.[Abstract]
53. Ross P, Norman A, Cunningham D et al. A prospective randomised trial of protracted venous infusion 5-fluorouracil with or without mitomycin C in advanced colorectal cancer [see comments]. Ann Oncol 1997; 8: 9951001.[Abstract]
54. Cunningham D, Zalcberg JR, Rath U et al. Tomudex (ZD1694): results of a randomised trial in advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopenia. The Tomudex Colorectal Cancer Study Group. Eur J Cancer 1995; 31 A: 19451954.
55. Cocconi G, Cunningham D, Van Cutsem E et al. Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group. J Clin Oncol 1998; 16: 29432952.[Abstract]
56. Pazdur R, Vincent M. Raltitrexed (Tomudex) versus 5-fluorouracil and leucovorin (5-FU + LV) in patients with advanced colorectal cancer (ACC): results of a randomized, multicenter, North American trial. Proc Am Soc Clin Oncol 1997; 16: 228a (Abstr 801).