Worldwide, oral fluoropyrimidines have become attractive options in the treatment of patients with colorectal cancer. Capecitabine (Xeloda), the only commercially available oral fluorouracil (5-FU) analog in the United States, was rationally designed to provide prolonged exposure to 5-FU and to generate 5-FU preferentially within tumor tissue. Capecitabine is absorbed unchanged through the gastrointestinal wall and is converted to 5-FU via a three-step enzymatic cascade. It is first hydrolyzed in the liver by carboxylesterase to 5'-deoxy-5-fluorocytidine (5'-DFCR). The next step occurs in the liver and tumor tissue, where cytidine deaminase converts 5'-DFCR to 5'-deoxy-5-fluorouridine (5'-DFUR). Finally, 5'-DFUR is converted to 5-FU by thymidine phosphorylase, which is preferentially expressed in tumors.
Biological and Clinical Considerations With Capecitabine
Although the higher thymidine phosphorylase levels found in tumor tissue convey the potential advantage of tumor-selective generation of 5-FU, and higher levels of 5-FU have been found in tumor tissue than in plasma in patients administered capecitabine, the clinical importance of this finding is not clear. Fluorouracil is further catabolized to 5,6-dihydro-5- fluorouracil (FUH2), alpha-fluorobeta- ureido propionic acid (FUPA) and ultimately alpha-fluoro-beta-alanine (FBAL), which is excreted in urine. Dihydropyrimidine dehydrogenase is the rate-limiting enzyme in the catabolic pathway of 5-FU. Capecitabine does not inhibit dihydropyrimidine dehydrogenase, and this sets it apart from other newly developed oral fluoropyrimidines such as S-1, UFT (uracil/tegafur), and BOF-A2.
As might be expected, the handfoot syndrome associated with infusional 5-FU is also the most frequently observed toxicity of capecitabine. Drs. Scheithauer and Blum provide an excellent overview of capecitabineinduced hand-foot syndrome. The overall incidence of hand-foot syndrome in patients treated with capecitabine monotherapy at the US Food and Drug Administration-approved dose (1,250 mg/m2 twice daily for 14 days followed by a 7-day rest period) is approximately 45%. This raises two important questions: "Is this rate acceptable?" and "Do all drugs that deliver prolonged exposure to 5-FU produce this same rate of hand-foot syndrome?"
Interpretation of Adverse Events
Regarding the first question, it is important to recognize that the system used to grade hand-foot syndrome in the two pivotal trials[2,3] was not version 3 of the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), but rather version 1 (when they were known as Common Toxicity Criteria). In that version, there were no specific criteria for hand-foot syndrome, and severity was evaluated according to the study-specific criteria, in which grade 1 toxicity was defined as numbness, dysesthesia/ paresthesia, tingling, painless swelling, or erythema not disrupting normal activities; grade 2 was defined as painful erythema with swelling or disruption of normal activities; and grade 3 was defined as moist desquamation, ulceration, blistering, severe pain, or any symptoms leading to the inability to perform daily activities.
Patients who experienced painful erythema sufficient to interfere with normal daily activities were categorized as grade 2 in the original single- agent studies but would be considered grade 3 under CTCAE version 3. This is not a trivial issue since, along with diarrhea and myelosuppression, hand-foot syndrome is one of the most common reasons for dose interruption and dose reduction in patients treated with cape citabine. Dose reduction for toxicity was required in 40.5% and 27.3% of patients in the capecitabine arm of two phase III studies in patients with metastatic colorectal cancer.[2,3] Similarly, dose reduction for toxicity was required in 42% of patients treated with capecitabine as adjuvant therapy in a recently reported phase III trial.
The fact that dose modification is frequently required due to severe toxicity (including hand-foot syndrome) when capecitabine is administered at 1,250 mg/m2 twice daily leads us to question whether this should be considered the optimal starting dose. A retrospective multivariate analysis demonstrated that dose modification had no significant effect on efficacy and prevents the recurrence of severe toxicity. There seems to be a possibility that we can treat patients with a lower starting dose without decreasing efficacy. When the starting dose of capecitabine is set at 25% below the standard dose (ie, 950- 1,000 mg/m2 twice daily), the incidence of grade 2 hand-foot syndrome is estimated to be 7.5%. However, prospective trials would be needed to confirm that the activity of capecitabine is not compromised.
Another factor that may contribute to the clinical impact of hand-foot syndrome is inadequate awareness and/or education of physicians and patients. Clinicians may underestimate the impact of hand-foot syndrome because the syndrome is not considered life-threatening, may not be associated with dramatic findings on physical examination, and is reversible when the causative agent is interrupted. However, hand-foot syndrome can compromise quality of life and lead to more serious toxicities if dosing is continued. It is important to recognize the need to interrupt capecitabine if grade 2 hand-foot syndrome or diarrhea is encountered. Because capecitabine is mainly administered on an outpatient basis, we must ensure that patients are educated sufficiently and understand the criteria for contacting medical personnel and interrupting capecitabine until resolution of symptoms.
Hand-Foot Syndrome and Other Oral 5-FU Analogs
The second question regards whether hand-foot syndrome is inherent to all forms of oral 5-FU administration. Interestingly, although hand-foot syndrome has been reported to occur with other oral fluoropyrimidines including UFT, S-1, and oral 5-FU plus eniluracil (776C85), the incidence and severity of handfoot syndrome with these agents appears to be somewhat lower than that reported for capecitabine, ranging from 0% to 10% (Table 1).[6-23]
Why the difference? One possible reason is that these agents do not undergo the same multistep enzymatic process that is required to convert capecitabine to 5-FU. Another possible reason is that UFT, S-1, and 5-FU/eniluracil all contain dihydropyrimidine dehydrogenase inhibitors. It is tempting to speculate that one of the activation intermediates of capecitabine, such as 5'-DFCR or 5- DFUR, or any one of the dihydropyrimidine dehydrogenase-related catabolites may be in some way related to the incidence and severity of hand-foot syndrome.
Unfortunately, there is no direct evidence to show that these metabolites play a causative role in hand-foot syndrome. In fact, population plasma pharmacokinetic studies show that there are broad overlaps in systemic exposure to capecitabine and its metabolites (5'-DFUR, 5-FU, and FBAL) for all patients regardless of safety outcome, and these are poorly predictive of safety and/or hand-foot syndrome.[ 24] Because capecitabine is metabolized or catabolized through multiple enzymatic steps, drug delivery to systemic organs is complex and may depend on the enzymatic activity within a particular organ or tissue.
Lastly, wide variation in the incidence and severity of hand-foot syndrome suggests that normal genetic variants (ie, genetic polymorphisms) may also contribute to this toxicity. Clearly, further study is needed in this area.
Phase III studies performed in the advanced disease and now adjuvant settings indicate that capecitabine is a very promising and suitable candidate to replace 5-FU in the treatment of colorectal cancer. In addition to the studies performed several years ago in patients with metastatic colorectal cancer cited above,[2,3] Cassidy and colleagues have reported that in patients with stage III colon cancer, capecitabine was at least equivalent to bolus 5-FU and leucovorin in terms of disease-free and overall survival.[ 25] Other phase III trials are comparing the capecitabine-plusoxaliplatin (Eloxatin) combination to the FOLFOX4 regimen (5-FU, leucovorin, oxaliplatin) as first- and second- line treatment of patients with metastatic colorectal cancer. We believe that the results of these trials, combined with patient education and aggressive management of hand-foot syndrome, will help to improve the optimal utilization of this very useful drug.
1. Takebayashi Y, Yamada K, Miyadera K,
et al: The activity and expression of thymidine
phosphorylase in human solid tumours. Eur J
Cancer 32A:1227-1232, 1996.
2. Hoff PM, Ansari R, Batist G, et al: Comparison
of oral capecitabine versus intravenous
fluorouracil plus leucovorin as first-line treatment
in 605 patients with metastatic colorectal
cancer: Results of a randomized phase III study.
J Clin Oncol 19:2282-2292, 2001.
3. Van Cutsem E, Twelves C, Cassidy J, et
al: Oral capecitabine compared with intravenous
fluorouracil plus leucovorin in patients
with metastatic colorectal cancer: Results of a
large phase III study. J Clin Oncol 19:4097-
4. Cassidy J, Twelves C, Van Cutsem E, et
al: First-line oral capecitabine therapy in metastatic
colorectal cancer: A favorable safety profile
compared with intravenous 5-fluorouracil/
leucovorin. Ann Oncol 13:566-575, 2002.
5. Scheithauer W, McKendrick J, Begbie
S, et al: Oral capecitabine as an alternative to
IV 5-fluorouracil-based adjuvant therapy for
colon cancer: Safety results of a randomized,
phase III trial. Ann Oncol 14:1735-1743,
6. Mani S, Schiano T, Garcia JC, et al: Phase
II trial of uracil/tegafur (UFT) plus leucovorin
in patients with advanced hepatocellular
carcinoma. Invest New Drugs 16:279-283,
7.Mani S, Kugler JW, Sciortino DF, et al:
Phase II trial of uracil/tegafur (UFT) plus leucovorin
in patients with advanced pancreatic
carcinoma: A University of Chicago phase
II consortium study. Ann Oncol 9:1035-1037,
8. Ravaud A, Borner M, Schellens JH, et
al: UFT and leucovorin in first-line chemotherapy
for patients with metastatic gastric
cancer. An Early Clinical Studies Group
(ECSG)/European Organization for Research
and Treatment of Cancer (EORTC) phase II
trial. Eur J Cancer 37:1642-1647, 2001.
9. Colevas AD, Amrein PC, Gomolin H,
et al: A phase II study of combined oral uracil
and ftorafur with leucovorin for patients with
squamous cell carcinoma of the head and
neck. Cancer 92:326-331, 2001.
10. Carmichael J, Popiela T, Radstone D,
et al: Randomized comparative study of
tegafur/uracil and oral leucovorin versus
parenteral fluorouracil and leucovorin in patients
with previously untreated metastatic
colorectal cancer. J Clin Oncol 20:3617-
11. Douillard JY, Hoff PM, Skillings JR,
et al: Multicenter phase III study of uracil/
tegafur and oral leucovorin versus fluorouracil
and leucovorin in patients with previously
untreated metastatic colorectal cancer.
J Clin Oncol 20:3605-3616,2002
12. Sakata Y, Ohtsu A, Horikoshi N, et al:
Late phase II study of novel oral
fluoropyrimidine anticancer drug S-1 (1 M
tegafur-0.4 M gimestat-1 M otastat potassium)
in advanced gastric cancer patients.
Eur J Cancer 34:1715-1720, 1998.
13. Chollet P, Schoffski P, Weigang-
Kohler K, et al: Phase II trial with S-1 in chemotherapy-
naive patients with gastric cancer.
A trial performed by the EORTC Early
Clinical Studies Group (ECSG). Eur J Cancer
14. Van den Brande J, Schoffski P,
Schellens JH, et al: EORTC Early Clinical
Studies Group early phase II trial of S-1 in
patients with advanced or metastatic
colorectal cancer. Br J Cancer 88:648-653,
15. Marsh JC, Catalano P, Huang J, et al:
Eastern Cooperative Oncology Group phase
II trial (E4296) of oral 5-fluorouracil and
eniluracil as a 28-day regimen in metastatic
colorectal cancer. Clin Colorectal Cancer
16. Schilsky RL, Levin J, West WH, et al:
Randomized, open-label, phase III study of
a 28-day oral regimen of eniluracil plus fluorouracil
versus intravenous fluorouracil plus
leucovorin as first-line therapy in patients
with metastatic/advanced colorectal cancer.
J Clin Oncol 20:1519-1526, 2002.
17. Llovet JM, Ruff P, Tassopoulos N, et
al: A phase II trial of oral eniluracil/5-fluorouracil
in patients with inoperable hepatocellular
carcinoma. Eur J Cancer 37:1352-
18. Schilsky RL, Bukowski R, Burris H
3rd, et al: A multicenter phase II study of a
five-day regimen of oral 5-fluorouracil plus
eniluracil with or without leucovorin in patients
with metastatic colorectal cancer. Ann
Oncol 11:415-420, 2000.
19. Rivera E, Sutton L, Colwell B, et al:
Multicenter phase II study of a 28-day regimen
of orally administered eniluracil and
fluorouracil in the treatment of patients with
anthracycline- and taxane-resistant advanced
breast cancer. J Clin Oncol 20:987-
20. Mani S, Hochster H, Beck T, et al:
Multicenter phase II study to evaluate a 28-
day regimen of oral fluorouracil plus
eniluracil in the treatment of patients with
previously untreated metastatic colorectal
cancer. J Clin Oncol 18:2894-2901, 2000.
21. Knowling M, Browman G, Siu L,
Khoo K, et al: A National Cancer Institute
of Canada clinical trials group phase II study
of eniluracil (776C85) and oral 5-fluorouracil
in patients with advanced squamous cell
head and neck cancer. Ann Oncol 12:919-
22. Skovsgaard T, Davidson NG, Piccart
MJ, et al: A phase II study of oral eniluracil/
fluorouracil in patients with anthracyclinerefractory
or anthracycline- and taxane-refractory
advanced breast cancer. Ann Oncol
23. Smith IE, Johnston SR, O'Brien ME,
et al: Low-dose oral fluorouracil with
eniluracil as first-line chemotherapy against
advanced breast cancer: A phase II study. J
Clin Oncol 18:2378-2384, 2000.
24. Gieschke R, Burger HU, Reigner B,
et al: Population pharmacokinetics and concentration-
effect relationships of
capecitabine metabolites in colorectal cancer
patients. Br J Clin Pharmacol 55:252-
25. 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):
Efficacy results of a phase III trial (abstract
3509). Proceedings of the 40th annual meeting
of the American Society of Clinical
Oncology, New Orleans, June 5–8, 2004,
Late Breaking Abstracts Booklet, p 14.