Annals of Oncology Advance Access originally published online on December 12, 2005
Annals of Oncology 2006 17(2):239-245; doi:10.1093/annonc/mdj023
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2005 European Society for Medical Oncology
A randomised cross-over trial comparing patient preference for oral capecitabine and 5-fluorouracil/leucovorin regimens in patients with advanced colorectal cancer
1 University of Leeds, Bradford NHS Trust & Beatson Oncology Centre, Glasgow; 2 North Wales Cancer Treatment Centre, Rhyl; 3 Walsgrave Hospital, Coventry; 4 Aberdeen Royal Infirmary, Aberdeen, UK
* Correspondence to: Professor C. Twelves, Tom Connors Cancer Research Centre, University of Bradford, Bradford BD7 1DP, UK. Tel: +44-1274-234280; Fax: +44-1274-235896; E-mail: c.twelves{at}bradford.ac.uk
 |
Abstract |
|---|
 Top Abstract introductionpatients and methodsresultsdiscussionReferences |
|---|
Background: Traditionally, metastatic colorectal cancer (MCRC) has been treated with intravenous (i.v.) 5-fluorouracil/leucovorin (5-FU/LV). The tumour-activated, oral fluoropyrimidine capecitabine demonstrates superior activity and favourable safety compared with the Mayo regimen, while potentially avoiding the complications and inconvenience associated with i.v. regimens.
Patients and methods: Ninety-seven patients with previously untreated advanced/MCRC were randomised to receive capecitabine followed by i.v. 5-FU/LV [Mayo Clinic, in-patient de Gramont (IPdG) or out-patient modified de Gramont (OPdG) regimens], or i.v. 5-FU/LV followed by capecitabine.
Results: Before treatment, of those patients for whom a preference was recorded, almost all (95%) preferred oral treatment (consistent across all treatment groups) and the majority retained this preference after treatment (64% overall; 86%, 63% and 50% in the Mayo, IPdG and OPdG groups, respectively). Following treatment, the principal reasons for oral treatment preference were increased convenience, home-based administration and tablet formulation. Treatment satisfaction was significantly higher with capecitabine compared with Mayo (P <0.05) and with OPdG compared with capecitabine (P <0.05). Quality of life (QoL) was largely constant across the regimens, although it appeared better with OPdG than capecitabine (P <0.05). Grade 3/4 adverse events were uncommon in all arms.
Conclusions: This study confirmed that the majority of patients with MCRC prefer oral to i.v. therapy, although the OPdG regimen appears to be the most popular i.v. option. Capecitabine clearly represents an effective, well-tolerated oral alternative to i.v. 5-FU/LV.
Key words: 5-FU/LV, capecitabine, colorectal cancer, patient preference, quality of life, treatment satisfaction
|
introduction |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
The outcomes of cancer therapy are traditionally evaluated using objective response and survival criteria. There is, however, increasing emphasis on assessment of quality of life (QoL), convenience and patient preference. For many years, metastatic colorectal cancer (CRC) has been treated primarily with either bolus or infused intravenous (i.v.) 5-fluorouracil (5-FU), with or without leucovorin (LV). As well as impacting significantly on often over-stretched resources, i.v. chemotherapy is inconvenient for patients and may be associated with pain, discomfort and complications such as thrombosis, bleeding and infection [1
–8], particularly with regimens requiring indwelling i.v. catheters for continuous or protracted infusion. In addition, i.v. chemotherapy may be associated with significant psychological distress, prolonged hospital stays and financial burden [9].
Home-based treatment may improve QoL, decrease analgesic requirements and reduce psychosocial morbidity compared with hospital-based therapy in patients with advanced cancer [9–11]. However, the ambulatory pumps used to facilitate home-based administration of i.v. 5-FU regimens still require indwelling i.v. catheters with the potential for discomfort and significant complications [2]. Indeed, a recent literature review showed that symptomatic central venous catheter (CVC)-related deep-vein thrombosis (DVT) occurred in up to 28% of patients receiving chemotherapy via CVCs [7].
Oral chemotherapy offers several potential advantages, with improved convenience and less impact on the patient's lifestyle compared with i.v. treatment. Capecitabine has become a well-established alternative to i.v. 5-FU/LV in the treatment of metastatic CRC. An oral fluoropyrimidine, it is designed to generate 5-FU preferentially in tumour tissue, exploiting the increased expression of thymidine phosphorylase in tumours compared with healthy tissue [12, 13].
Two large, phase III studies (n = 1207) demonstrated that, as first-line therapy for metastatic CRC, capecitabine achieves superior antitumour activity with a favourable safety profile compared to i.v. 5-FU/LV (Mayo Clinic regimen) [14, 15]. The improved efficacy and safety profiles of capecitabine were also mirrored in the adjuvant setting, where capecitabine showed a consistent (
4%) improvement in disease-free, relapse-free and overall survival compared with 5-FU/LV (Mayo Clinic regimen) [16, 17]. Furthermore, medical resource use is reduced with oral capecitabine when compared with i.v. 5-FU/LV (Mayo Clinic regimen) in both the adjuvant and metastatic settings, with reduced costs for management of adverse events and fewer ambulatory visits [18, 19]. A recent pharmacoeconomic analysis showed that capecitabine is a ‘dominant strategy’ compared with i.v. 5FU/LV in the adjuvant treatment of colon cancer, providing superior outcomes with cost savings versus the Mayo Clinic Regimen [20]. Capecitabine also saves staff time compared with infused 5-FU. A UK time-and-motion audit showed that combined staff time for administration and consultation was more than 10-fold greater with the modified de Gramont 5-FU/LV regimen than with capecitabine (mean time per course of treatment: 669 min versus 60 min, respectively) [21].
In a recent study, patients who had received both the Mayo Clinic regimen and the oral fluoropyrimidine UFT expressed a strong preference for oral treatment [22], while a previous questionnaire-based study showed that oral treatment was strongly preferred provided that this was not at the expense of efficacy [23]. However, in the metastatic setting, infusional 5-FU regimens have largely replaced bolus 5-FU/LV, especially in Europe, and patients' preference for oral treatment compared with an infusion regimen has not previously been evaluated.
The current open-label, randomised, cross-over study was conducted to determine patient preference for treatment with capecitabine or an i.v. 5-FU/LV regimen (the bolus Mayo Clinic regimen or the infusional de Gramont regimen, administered on either an in- or out-patient basis) in patients with advanced CRC. Secondary objectives of the study were toxicity, QoL and patient satisfaction with treatment, which may underpin or influence preference for a particular regimen.
|
patients and methods |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
patients
Male and female patients aged between 18 and 75 years with previously untreated advanced or metastatic CRC were eligible for the study. In addition, they were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of
2 and life expectancy of at least 3 months. Any prior adjuvant chemotherapy was to have been completed at least 6 months before enrolment. Patients were required to have an absolute neutrophil count 
1.5 x 109/l, platelet count 100 x 109/l, haemoglobin >8 g/dl, corrected serum calcium <2.80 mmol/l and bilirubin 1.5x upper normal limit.
The following patients were excluded from study: pregnant or lactating patients, those who had previously experienced a severe and unexpected reaction to fluoropyrimidine therapy or with known hypersensitivity to 5-FU, patients with severe renal impairment (creatinine clearance 30 ml/min according to the Cockcroft–Gault formula), central nervous system disorders or psychiatric disability, clinically significant cardiac disease, arrhythmias or angina pectoris. Patients with serious, uncontrolled, intercurrent infection and those known to have hepatitis B or C, or human immunodeficiency virus infection were also ineligible. Patients with malabsorption syndromes or a history of previous gastrointestinal surgery affecting oral absorption were also excluded from study, as were patients with a history of another malignancy within the previous 5 years, except successfully treated basal cancer of the skin or carcinoma in situ of the uterine cervix. Participation in any study of an investigational drug within the 4 weeks prior to study also precluded enrolment.
The study was conducted in accordance with local ethical and regulatory requirements and all patients provided written informed consent.
study treatment
In this study, treatment with capecitabine was compared with the i.v. 5-FU/LV treatment regimen that was used routinely in each participating centre (Mayo Clinic and in- or out-patient de Gramont regimens) to reflect standard clinical practice. The treatment scheme for the study is shown in Figure 1. Each course of treatment consisted of one cycle of capecitabine, one cycle of the Mayo Clinic regimen, or two cycles (commencing on days 1 and 14) of the de Gramont regimen. At the end of the second treatment period, patients could continue to receive their chosen therapy, as appropriate.
|
Capecitabine 1250 mg/m2 was administered twice daily (morning and evening within 30 min of ingestion of food) on days 1–14 of a 3-week treatment cycle. The capecitabine dose was reduced to 75% of full dose in patients entering the study with moderate renal impairment (creatinine clearance 30–50 ml/min according to the Cockcroft–Gault formula). The Mayo Clinic regimen was administered according to local practice, but typically comprised LV 20 mg/m2 administered as a rapid i.v. infusion followed by a bolus injection of 5-FU 370–425 mg/m2 administered daily on days 1–5 of a 28-day treatment cycle. The de Gramont regimen was administered on an in- or out-patient basis. The in-patient regimen (IPdG) typically comprised LV 200 mg/m2 as a 2-h i.v. infusion followed by a bolus injection of 5-FU 400 mg/m2 then 5-FU 600 mg/m2 administered in two 22-h i.v. infusions on days 1 and 2 of a 14-day treatment cycle. The out-patient regimen (OPdG) typically comprised the modified de Gramont regimen of LV 175 mg/m2 as a 2-h i.v. infusion followed by a bolus injection of 5-FU 400 mg/m2 then 5-FU 2800 mg/m2 administered as an i.v. infusion over 46 h [24
]. Dose modification for management of adverse events was conducted according to the local practice of the participating centres and capecitabine dose modification guidelines [15]. Administration of additional cytotoxic agents or investigational drugs was prohibited during study. Patients received supportive therapy according to standard practice at their centre.
patient evaluation
Patient preference was assessed using a questionnaire designed specifically for this study. The preference questionnaire was distributed by clinic staff and completed by each patient, without assistance, prior to the first dose of study drug and on the last day of the second course of treatment (Table 1). Results from the patient preference questionnaire were analysed using the Hills–Armitage approach [25], which excludes patients who expressed ‘no preference’ from the analysis. A 2 x 2 table of association was then constructed and the associations of treatment sequence and preferences tested using Fisher's exact test.
|
Patient satisfaction with treatment was assessed using a questionnaire designed for use in this study and completed by each patient on the final day of the second course of treatment. Patients were asked to rate, on a scale of 1 (very dissatisfied) to 10 (very satisfied), both the regimens in terms of overall satisfaction, convenience and how they felt after treatment. For each patient, the difference in the ratings for each period was calculated and all patients were ranked in order. The Mann–Whitney U-test was applied to the period differences in overall satisfaction between the oral and i.v. regimens. A positive estimated score indicated increased overall satisfaction with oral compared with i.v. therapy and a negative score indicated increased overall satisfaction for i.v. compared with oral therapy.
QoL was assessed using the validated FACT-C questionnaire [26] prior to randomisation, and on the final days of the first and second courses of treatment. Overall QoL scores were evaluated using an analysis of variance and estimates of treatment effects were presented for each group adjusting for sequence group, treatment and period. A positive score indicated increased QoL with oral compared with i.v. therapy and a negative score demonstrated increased QoL with i.v. compared with oral therapy.
Safety was evaluated in all patients receiving at least one dose of study treatment. Adverse events were graded according to the National Institute of Cancer (NCI) Common Toxicity Criteria (CTC) version 2 until 4 weeks after last study drug administration.
|
results |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
patient population and disposition
In total, 97 patients from 13 centres in the UK were enrolled and of these, 94 were evaluable (prior to receiving treatment one patient died, one had no i.v. access and was excluded, and one withdrew from the study). The uneven weighting in the IPdG arm, shown in Figure 2, was due to a randomisation error in a single centre (of the 44 patients on the IPdG arm, 26 received the oral/i.v. sequence and 18 the i.v./oral sequence; four patients were allocated to the sequence different from that to which they were originally randomised). Recruitment to this arm of the study was increased in an attempt to redress the imbalance. All patients were analysed according to the regimen/sequence actually received.
|
The baseline characteristics of patients are shown in Table 2, including initial treatment preferences in the three arms. A higher proportion of patients in the Mayo Clinic regimen arm had an ECOG performance score of 0 compared with those in the de Gramont regimen arms (58% versus 30% and 37% for the IPdG and OPdG arms, respectively). Also, a higher proportion of males (81%) received the OPdG regimen compared with the other 5-FU/LV regimens (58% in both the Mayo and IPdG regimen arms). The median age of patients receiving the de Gramont regimens was older than in the Mayo Clinic group.
|
treatment preferences before and after treatment
The results of the treatment preference questionnaires are shown in Table 3. Almost all patients (98%) completed the patient preference questionnaire prior to the first dose of study drug. Overall, before treatment, 78% of patients completing questionnaires expressed a preference for oral therapy, 4% for i.v. and 18% were undecided. Therefore, of those patients who expressed a particular preference, 95% preferred oral and 5% preferred i.v. regimens prior to treatment. Patient preference questionnaires were completed by 76% of patients after treatment course 2 (Table 3). For patients who did not complete post-treatment questionnaires, the principal causes (80% of cases) were early death or withdrawal due to adverse events.
|
Figure 3 shows that, after receiving both treatment courses, the preference for oral therapy was maintained by the majority of patients. Overall, 57% of patients expressed a preference for capecitabine and 32% for 5-FU/LV. Again, of those for whom a preference was recorded, 64% preferred oral and 36% preferred i.v. therapy. The type of i.v. regimen administered did, however, influence this preference to a large degree. Following treatment, of those who expressed a preference, an equal proportion (50%) of patients receiving the OPdG regimen preferred i.v. and oral treatment; a higher proportion of patients preferred capecitabine to IPdG (63%) or Mayo Clinic (86%) regimens (Table 3, Figure 3). In the Mayo Clinic and IPdG groups, the three patients who expressed a preference for i.v. administration before treatment reported a preference for oral administration after the second treatment period.
|
The principal reasons given by patients for preferring a particular regimen after treatment are illustrated in Figure 4. For the 42 patients who preferred capecitabine after treatment, the convenience of tablet administration at home was the dominant rationale. Where i.v. therapy was preferred (24 patients), the principal reason was that it caused fewer side-effects. The order in which treatment was received did not appear to influence treatment preference (data not shown).
|
treatment satisfaction
Patient satisfaction with treatment was assessed on the last day of treatment course 2. A positive score indicates increased satisfaction with oral compared with i.v. therapy and a negative score indicates increased satisfaction for i.v. compared with oral therapy.
Overall, there was no difference in patient satisfaction with oral or i.v. therapy (Table 4). However, results varied across the different i.v. regimens. Although the number of patients analysed was small, it appeared that treatment satisfaction with capecitabine was higher than with the Mayo Clinic regimen (P <0.05). No significant difference in patients' median treatment satisfaction scores was observed between capecitabine and the IPdG regimen. In contrast, treatment satisfaction with the OPdG regimen appeared higher than with capecitabine (P <0.05).
|
impact of treatment on QoL
Overall, mean QoL scores were maintained throughout the study period in all groups. Although the number of patients analysed was small and time over which the assessment was made was short, no differences in estimated QoL scores were observed between patients receiving capecitabine and those receiving the Mayo Clinic or IPdG regimens (Table 5). Mean QoL scores appeared higher with the OPdG regimen compared with oral therapy (P <0.05).
|
toxicity
The small number of patients in the individual i.v. treatment groups precluded formal comparison of toxicity in each arm. Treatment-related adverse events (all grades) were observed in 60% of patients when receiving both capecitabine and i.v. 5-FU/LV. In all arms, treatment-related adverse events were typical fluoropyrimidine toxicities. Grade 3/4 adverse events were uncommon in all treatment arms, occurring in 12% and 7% of patients during treatment with capecitabine and i.v. 5-FU/LV, respectively (Figure 5). No substantial differences in the safety profiles of the regimens were observed with the different treatment sequences.
|
|
discussion |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
The improved antitumour activity, favourable tolerability, improved medical resource utilisation and pharmacoeconomics of capecitabine compared with 5-FU/LV lend support to its increasing use for the treatment of advanced CRC [20
, 27]. Capecitabine also appears more convenient for patients, but it is important to confirm this by analysing patient preference and treatment satisfaction. Although previous studies have demonstrated that patients prefer oral compared with i.v. chemotherapy [22, 23], the current study represents the first formal evaluation of patient preference for oral capecitabine versus both bolus and infusional i.v. 5-FU/LV regimens.
Before treatment, the majority of patients expressed a preference for the oral therapy, citing increased convenience, administration at home and an oral administration route as the main reasons for their initial preference. These reasons were also prominent in a study by Liu et al. [23], which also demonstrated that patients are unwilling to accept a reduction in efficacy. The current study was not designed to compare efficacy; however, capecitabine has been shown to achieve significantly higher response rates than bolus 5-FU/LV as first-line therapy for metastatic CRC [14]. Infusional 5-FU/LV also achieved higher response rates than bolus 5-FU/LV [28], but neither capecitabine nor infusional 5-FU/LV significantly prolonged survival. It is most likely, therefore, that capecitabine and infusional 5-FU/LV have very similar activity and are both at least as effective as bolus 5-FU/LV [27].
In the current study, the majority of patients who preferred oral therapy before treatment maintained their preference after treatment, usually because of the greater convenience of treatment at home. Following treatment, the preference for oral therapy (86%) was strongest in patients for whom the alternative was bolus 5-FU/LV, with only two patients preferring the Mayo Clinic regimen over capecitabine. There was also a clear, though less marked, preference for capecitabine (63%) over the IPdG infusion regimen. Those patients receiving oral capecitabine and the OPdG infusion regimen were equally split in terms of their preference. The variation in expressed preference for oral therapy in relation to the nature of the i.v. treatment may be due to a variety of factors. The Mayo Clinic regimen requires frequent hospital visits and is less well tolerated than the IPdG regimen in terms of toxicity profile [28]. The OPdG regimen has the advantage to the patient that disconnection of the 46-h 5-FU infusional pump and the second week central line flush can be carried out in the patient's home, with less inconvenience for the patient and only one hospital visit every 14 days. Nearly half the patients in the OPdG arm who initially expressed a preference for oral treatment later changed that preference, with most stating that i.v. therapy caused few side-effects. The OpdG regimen is clearly a reasonable option for many patients. However, it also emphasises the importance of educating patients and healthcare staff in the prevention of toxicity associated with capecitabine if patients are to benefit from the convenience of oral therapy.
Patients appeared least satisfied with the Mayo Clinic regimen versus oral treatment, particularly when they received oral therapy first. This is consistent with previous studies demonstrating increased levels of treatment satisfaction from home-based compared with hospital-based therapy [29, 30]. There was a trend towards increased satisfaction with the IPdG regimen and a statistically significant increase in satisfaction with the OPdG regimen over capecitabine. This may be explained by the low toxicity and increased convenience of the OPdG regimen or may conceivably be a consequence of the poorer baseline performance status and greater age of patients receiving the de Gramont regimens. A higher percentage of patients in the de Gramont arms had ECOG performance status of 1/2, and their median age was higher than those receiving the Mayo Clinic regimen. It is possible that more frail patients may appreciate close and immediate access to medical support and prefer the responsibility for administration of i.v. chemotherapy to rest in the hands of their health professionals.
The QoL analysis failed to demonstrate any statistically significant difference between capecitabine and either Mayo Clinic or IPdG regimens. In contrast, the OPdG regimen showed a statistically increased QoL benefit compared with capecitabine (P < 0.05). The apparent preference for the OPdG regimen compared with capecitabine in terms of patient satisfaction estimates and QoL is perhaps surprising given that the results from the patient preference assessments showed an equal split between OPdG and capecitabine.
The apparent differences between the different i.v. regimens in terms of patient satisfaction and QoL scores should, however, be interpreted with caution because of the small and variable proportion of patients completing questionnaires and the limited period over which the data were collected. Nevertheless, the demonstrated benefit of patient choice in the cancer treatment decision-making process supports an option for patient choice in the management of advanced CRC [31]. These data indicate that, prior to receiving chemotherapy, oral treatment is the preferred choice for the majority of patients with advanced CRC, mirroring the results of a previous study [23]. After experiencing both capecitabine and a variety of i.v. regimens, at least half the patients retained this preference, again in line with previous experience with another oral fluoropyrimidine [22]. It would appear, however, that the strength of this preference for oral capecitabine depends on which i.v. regimen is used as the comparator, being strongest in relation to the IPdG and Mayo Clinic regimens but weaker in relation to the OPdG regimen. The present study supports the principle that capecitabine represents a highly effective, convenient and well-tolerated alternative to i.v. 5-FU/LV regimens in the metastatic setting. It is interesting to speculate that these benefits in terms of patient preference may also apply in the adjuvant setting, where 5-FU/LV (Mayo Clinic regimen) has been standard therapy, but capecitabine recently showed a consistent, approximately 4% improvement in disease-free, relapse-free and overall survival [17].
|
Acknowledgements |
|---|
We thank the following, who also entered patients: Dr S. Anwad (Chelmsford), Dr R. Glynne-Jones (Northwood), Dr F. Lofts (London), Dr A. Robinson (Shrewsbury), Dr M. Saunders (Northampton), Dr J. Stewart (Northampton) and Dr Tahir (Manchester).
Received for publication May 27, 2005. Revision received August 25, 2005. Accepted for publication August 26, 2005.
|
References |
|---|
|
TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
|---|
1. Hansen RM, Ryan L, Anderson T et al. Phase III study of bolus versus infusion fluorouracil with or without cisplatin in advanced colorectal cancer. J Natl Cancer Inst 1996; 88: 668–674.
2. Poorter RL, Lauw FN, Bemelman WA et al. Complications of an implantable venous access device (Port-a-Cath) during intermittent continuous infusion of chemotherapy. Eur J Cancer 1996; 32A: 2262–2266.[CrossRef]
3. Schwarz RE, Coit DG, Groeger JS. Transcutaneously tunneled central venous lines in cancer patients: an analysis of device-related morbidity factors based on prospective data collection. Ann Surg Oncol 2000; 7: 441–449.[Abstract]
4. Frank JL, Garb JL, Halla B, Reed WP Jr. Ionic implantation of silicone chronic venous access devices does not alter thrombotic complications: a double-blinded, randomized clinical trial. Surgery 2001; 129: 547–551.[CrossRef][ISI][Medline]
5. Hartkamp A, van Boxtel AJ, Zonnenberg BA, Witteveen PO. Totally implantable venous access devices: evaluation of complications and a prospective comparative study of two different port systems. Neth J Med 2000; 57: 215–223.[CrossRef][ISI][Medline]
6. Nightingale CE, Norman A, Cunningham D et al. A prospective analysis of 949 long-term central venous access catheters for ambulatory chemotherapy in patients with gastrointestinal malignancy. Eur J Cancer 1997; 33: 398–403.[CrossRef][ISI][Medline]
7. Verso M, Agnelli G. Venous thromboembolism associated with long-term use of central venous catheters in cancer patients. J Clin Oncol 2003; 21: 3665–3675.
8. Kuter DJ. Thrombotic complications of central venous catheters in cancer patients. Oncologist 2004; 9: 207–216.
9. Payne SA. A study of quality of life in cancer patients receiving palliative chemotherapy. Soc Sci Med 1992; 35: 1505–1509.[CrossRef][ISI][Medline]
10. Rischin D, White MA, Matthews JP et al. A randomised crossover trial of chemotherapy in the home: patient preferences and cost analysis. Med J Aust 2000; 173: 125–127.[ISI][Medline]
11. Wilson A, Wynn A, Parker H. Patient and carer satisfaction with ‘hospital at home’: quantitative and qualitative results from a randomised controlled trial. Br J Gen Pract 2002; 52: 9–13.[ISI][Medline]
12. Miwa M, Ura M, Nishida M et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998; 34: 1274–1281.[CrossRef][ISI][Medline]
13. Schüller J, Cassidy J, Dumont E et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 2000; 45: 291–297.[CrossRef][ISI][Medline]
14. 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 2004; 90: 1190–1197.[CrossRef][ISI][Medline]
15. 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: 566–575.
16. 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: 1735–1743.
17. Twelves C, Wong A, Nowacki M et al. Oral capecitabine (Xeloda®) as a replacement for i.v. 5-FU-based adjuvant therapy for colon cancer: efficacy results of a large phase III trial (the X-ACT trial). N Engl J Med; in press.
18. 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 2001; 37: 597–604.[CrossRef][ISI][Medline]
19. McKendrick J, Cassidy J, Chakrapee-Sirisuk S et al. Capecitabine (X) is resource saving compared with i.v. bolus 5-FU/LV in adjuvant chemotherapy for Dukes' C colon cancer patients: Medical resource utilization (MRU) data from a large phase III trial (X-ACT). J Clin Oncol 2004; 22: 264s (Abstr 3578).
20. Douillard J-Y, Twelves C, McKendrick J et al. Pharmacoeconomic analysis of capecitabine in the adjuvant setting. Results from the X-ACT trial comparing capecitabine with 5-FU/LV in patients with Dukes' C colon cancer. Ann Oncol 2004; 15: iii73 (Abstr 274P).
21. James R, Blanco C, Farina C. Savings in staff time as a result of switching from de Gramont to oral capecitabine for patients with advanced colorectal cancer. Eur J Cancer 2003; 1: S83 (Abstr 271).
22. Borner MM, Schöffski P, de Wit R et al. Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer. Eur J Cancer 2002; 38: 349–358.[CrossRef][ISI][Medline]
23. Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997; 15: 110–115.
24. Seymour M. Optimising the use and sequencing of fluorouracil, irinotecan and oxaliplatin in advanced colorectal cancer (ACRC): The UK MRC FOCUS (CR08) trial. Ann Oncol 2004; 15: iii2 (Abstr 5IN).
25. Hills M, Armitage P. The two-period cross-over clinical trial. Br J Clin Pharmacol 1979; 8: 7–20.[ISI][Medline]
26. Ward WL, Hahn EA, Mo F et al. Reliability and validity of the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) quality of life instrument. Qual Life Res 1999; 8: 181–195.[CrossRef][ISI][Medline]
27. Twelves CJ, Cassidy J. Which endpoints should we use in evaluating the use of novel fluoropyrimidine regimens in colorectal cancer? Br J Cancer 2002; 86: 1670–1676.[CrossRef][ISI][Medline]
28. de Gramont A, Bosset JF, Milan C et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study. J Clin Oncol 1997; 15: 808–815.
29. Borras JM, Sanchez-Hernandez A, Navarro M et al. Compliance, satisfaction, and quality of life of patients with colorectal cancer receiving home chemotherapy or outpatient treatment: a randomised controlled trial. Br Med J 2001; 322: 826.
30. King MT, Hall J, Caleo S et al. Home or hospital? An evaluation of the costs, preferences, and outcomes of domiciliary chemotherapy. Int J Health Serv 2000; 30: 557–579.[CrossRef][ISI][Medline]
31. Deadman JM, Leinster SJ, Owens RG et al. Taking responsibility for cancer treatment. Soc Sci Med 2001; 53: 669–677.[CrossRef][ISI][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  I. M. Hennig, J. D. Naik, S. Brown, A. Szubert, D. A. Anthoney, D. P. Jackson, A. M. Melcher, S. M. Crawford, C. Bradley, J. M.B. Brown, et al. Severe Sequence-Specific Toxicity When Capecitabine Is Given After Fluorouracil and Leucovorin J. Clin. Oncol., July 10, 2008; 26(20): 3411 - 3417. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Findlay, G. von Minckwitz, and A. Wardley Effective oral chemotherapy for breast cancer: pillars of strength Ann. Onc., February 1, 2008; 19(2): 212 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Mayer Should Capecitabine Replace Infusional Fluorouracil and Leucovorin When Combined With Oxaliplatin in Metastatic Colorectal Cancer? J. Clin. Oncol., September 20, 2007; 25(27): 4165 - 4167. [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Kohne and G. Folprecht On prejudice and facts and choices Ann. Onc., February 1, 2006; 17(2): 185 - 187. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||