Annals of Oncology Advance Access originally published online on May 9, 2006
Annals of Oncology 2006 17(9):1469-1471; doi:10.1093/annonc/mdl082
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© 2006 European Society for Medical Oncology
letters to the editor |
In response to: ‘On prejudice and facts and choices’, an editorial by Köhne and Folprecht
Cancer Research UK, Department of Medical Oncology, University of Glasgow, Scotland
*(E-mail: j.cassidy{at}beatson.gla.ac.uk)
I read with interest the recent editorial ‘On prejudice and facts and choices’ by Köhne and Folprecht [1], in which they discussed the increasing use of oral compounds in colorectal cancer. The authors raise some thought-provoking points, although I feel that many of their comments are premature and, in some cases, inaccurate.
Overall, the article leaves you with the impression that the oral fluoropyrimidine capecitabine is less effective than i.v. 5-fluorouracil (FU)/LV, although there is no evidence to support this view. Data from two large phase III trials in metastatic colorectal cancer (MCRC) show that first-line capecitabine results in superior response rates, better safety and improved convenience compared with the Mayo regimen [2]. With 600 patients in each trial, both were sufficiently powered to show non-inferiority in response rate and were the biggest trials ever performed in first-line at the time. The prospectively planned protocol-defined pooled analysis was sufficiently powered to show non-inferiority in time to progression (or death), illustrating that the two treatments were indeed equivalent. These data were convincing to the regulatory authorities on both sides of the Atlantic, leading to approval in 2001 of capecitabine as first-line treatment for MCRC. In addition to these data in the metastatic setting, there is compelling evidence in stage III colon cancer that capecitabine results in at least equivalent disease-free survival (DFS), superior relapse-free survival (RFS) and similar overall survival (OS), with trends towards superior DFS and OS compared with the Mayo regimen [3]. This has led to the recent approval of capecitabine as adjuvant therapy for early colon cancer.
The authors correctly point out that the choice of the Mayo Clinic regimen as the comparator for oral fluoropyrimidines in phase III trials was indeed at the request of regulatory authorities. Since capecitabine was first approved, treatment standards have changed so that most patients receive combination regimens instead of single-agent therapy. Consequently, the only direct comparisons we have of capecitabine versus infusional 5-FU are as part of combination trials. However, we are now close to having comparative data from a large registration trial of capecitabine plus 3-weekly oxaliplatin (XELOX) versus FOLFOX ± bevacizumab, and several other randomised phase III/IV trials comparing capecitabine with infusional regimens of 5-FU plus oxaliplatin [4–7] or irinotecan [8, 9]. Interim findings from these studies have been presented at recent large oncology congresses. Considering the capecitabine/oxaliplatin studies first, Köhne and Folprecht mention the TREE1 study, which initially compared the bFOL (bolus 5-FU), FOLOX (infusional 5-FU) and XELOX regimens in first-line MCRC, and was subsequently amended to include bevacizumab in all arms (TREE2 study). One can only assume that their editorial was written before the most recent findings were reported at the ASCO GI meeting in January this year. Compared with either of the 5-FU-based regimens (bFOL or FOLOX) plus bevacizumab, XELOX plus bevacizumab demonstrated the longest median TTP in the trial. One can conclude that reducing the capecitabine dose to 850 mg/m2 twice daily in combination with oxaliplatin and bevacizumab appears to have resulted in a very well tolerated and highly effective regimen in this setting.
The authors of the editorial then single out the German AIO trial, in which infusional 5-FU/LV plus oxaliplatin (FUFOX) was compared with capecitabine plus weekly oxaliplatin (CAPOX) as first-line therapy. While CAPOX appeared to be slightly better tolerated than FUFOX overall and both regimens were basically identical in terms of response rate (48% versus 54%), median progression-free survival (PFS, 7.1 versus 8.0 months) appeared to favour FUFOX. However, there were restaging issues that may have favoured the FUFOX arm and caused the PFS curves to separate at week 21 [6]. Survival data are yet to mature in this study. Finally, it is important to note that the capecitabine/oxaliplatin regimen used in this trial is not the standard 3-weekly XELOX regimen, which has the benefit of being developed formally within a large-scale clinical trials programme.
Moving on to the capecitabine/irinotecan studies, Köhne and Folprecht first discuss the abandoned EORTC 40015 randomized phase III study of XELIRI versus FOLFIRI ± celecoxib in first-line MCRC, which at first glance appears to indicate that 3-weekly XELIRI is not feasible in a multicentre setting. While there were only 39 XELIRI- and 29 FOLFIRI-treated patients evaluable when the data were presented at ASCO 05 [8], the findings suggest a possible interaction between celecoxib and XELIRI. These factors should be taken into account when interpreting the limited findings from this study. The authors then mention the CAIRO study, which is the largest conducted with XELIRI (n = 820) and compares sequential versus combination therapy (capecitabine with either irinotecan or oxaliplatin), although their comments fail to reflect the most recently presented findings at ASCO GI 06 [9]. Nevertheless, current safety data from the CAIRO study do not confirm the issues observed in the EORTC study (perhaps because celecoxib was not included?). Efficacy data from this important study are expected later this year. Overall, while the combination of irinotecan and capecitabine has been shown to be feasible and effective in multiple phase II trials, findings generally indicate that lower doses of irinotecan and/or capecitabine are likely to be necessary in any context where there might be a risk (e.g. in patients >65 years of age).
To summarise the clinical trial situation, over the next 12–18 months we are expecting a huge amount of data from ongoing phase III studies of capecitabine plus either oxaliplatin or irinotecan (± biological agents) versus infusional 5-FU-based combinations. While we await these data, I believe the statement made by Köhne and Folprecht that ‘capecitabine and oxaliplatin or irinotecan may have a somewhat lower efficacy than infusional 5-FU-based regimens’ is both premature and misleading.
Throughout their editorial, the authors also question the rationale for using oral versus i.v. treatment. They doubt that capecitabine can play a role in patients receiving complex regimens including weekly or bi-weekly i.v. infusions of cetuximab or bevacizumab in combination with a chemotherapy backbone. Given that these patients would require i.v. infusion of these biologicals anyway, why not simply base their treatment around i.v. 5-FU, as we have done for so many years? Many readers of this journal will be familiar with the huge body of evidence showing that, rather than spend time in hospital receiving i.v. chemotherapy, patients prefer outpatient treatment, particularly in the form of an oral agent like capecitabine [10, 11]. We know from the large phase III monotherapy trials that capecitabine-treated patients spent fewer days in hospital for the management of adverse events compared with those receiving 5-FU/LV [12]. In addition, capecitabine was associated with substantially fewer hospital visits for drug administration and a reduction in medical resource usage [13]. Furthermore, evidence from the UK shows that switching patients with advanced disease from a modified de Gramont regimen to oral capecitabine results in significant savings in staff time, increasing the capacity to treat more patients [14]. These pharmacoeconomic benefits are also seen when capecitabine is given alongside oxaliplatin or irinotecan in first-line, with XELOX or XELIRI saving money compared with FOLFOX or FOLFIRI because of the reduced cost of managing adverse events and less time required for treatment administration [15–17]. While the addition of new biological agents will undoubtedly make administration schedules more complicated, cost and time savings are still expected with capecitabine-based regimens compared with those based on infusional 5-FU.
With all of these issues in mind, I urge the authors of this editorial and readers of Annals of Oncology not to lose sight of the bigger picture. Significant and meaningful gains in the survival of patients with colorectal cancer have been made through the addition of new compounds. Clearly, we are still trying to determine which regimens offer the best outcome to various patients. Capecitabine and other oral agents are all part of this mix. No-one would argue that oral agents can meet the needs of all patients, even if they offer equivalent, or even better, efficacy than their i.v. counterparts. However, they do offer patients more choices than ever before, even when administered with other i.v. agents. The large number of ongoing trials of capecitabine versus 5-FU-based combination regimens with oxaliplatin, irinotecan with or without the new biologicals reflects new treatment strategies and has nothing to do with one successful pharmaceutical company having a number of highly effective drugs on the market! Rather than worrying about who manufactures our most highly active drugs, we should revel in the progress made and look forward to seeing the exciting data from ongoing trials looking at combinations of biological agents and fluoropyrimidine-based regimens (whether they be oral or i.v.-based).
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 Top References |
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1. Köhne C-H and Folprecht G. (2006) On prejudice and facts and choices. Ann Oncol 17:185–187.
2. Van Cutsem E, Hoff PM, Harper P, et al. (2004) Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer 90:1190–1197.[CrossRef][Web of Science][Medline]
3. Twelves C, Wong A, Nowacki MP, et al. (2005) Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 352:2696–2704.
4. Anon.FOCUS2. Drug treatment for bowel cancer—making the best choice when a milder treatment is needed. http://www.controlled-trials.com/isrctn/trial/%7C/0/21221452.html (23 February 2006, date last accessed).
5. Bennouna J, Lledo G, Ychou M, et al. (2005) Initial safety findings from a phase III study of capecitabine (X) plus oxaliplatin (XELOX) vs. infusional 5-FU/LV plus oxaliplatin (FOLFOX-6) in first-line treatment of patients (pts) with metastatic colorectal cancer (MCRC). Proc ECCO Abstr 636.
6. Kubicka S, Arkenau HT, Grothey A, et al. (2006) Randomized trial of infusional 5-FU/LV plus oxaliplatin (FUFOX) vs. capecitabine plus oxaliplatin (CAPOX) as first-line treatment of metastatic colorectal cancer (MCRC): updated results of the safety and efficacy analysis. Proc Am Soc Clin Oncol GI Symposium Abstr 277.
7. Sastre J, Massuti B, Tabernero JM, et al. (2005) Preliminary results of a randomized phase III trial of the TTD Group comparing capecitabine and oxaliplatin (CapeOx) vs. oxaliplatin and 5-fluorouracil in continuous infusion (5-FU CI) as first line treatment in advanced or metastatic colorectal cancer (CRC). Proc Am Soc Clin Oncol Abstr 3524.
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9. Punt C, Koopman M, Honkoop A, et al. (2006) Randomized study of sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (ACC), an interim safety analysis: A Dutch Colorectal Cancer Group (DCCG) phase III study. Proc Am Soc Clin Oncol GI Symposium Abstr 282A.
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