- Email: [email protected]
Benefits and Drawbacks of the Use of Oral Fluoropyrimidines as Single-Agent Therapy in Advanced Colorectal Cancer
Benefits and Drawbacks of the Use of Oral Fluoropyrimidines as Single-Agent Therapy in Advanced Colorectal Cancer Jim Cassidy Abstract One of the most widely used cytotoxic agents is 5-fluorouracil.The use of infusional regimens has become commonplace and with this has come a realization of the limitations of this mode of administration. A number of oral fluoropyrimidines have been developed. Of these, capecitabine is the most established, with registrations in most countries for breast and colorectal cancer. The trials with this agent have mainly attempted to show equivalence with a “standard” intravenous comparator. In most cases, this endpoint has been met or exceeded. In addition, the trials have demonstrated reduced toxicity (except for hand-foot syndrome), and aspects of patient acceptability and cost-effectiveness have been integrated into these studies. Patients seem to prefer oral therapy but not at the expense of anticancer activity. However, the absence of intravenous access devices and complications associated with their use is a major bonus for oral therapy.The drawbacks are somewhat less obvious. Some patients are concerned that oral therapy is in some way inferior (ie, soft option) to intravenous chemotherapy. Compliance with oral therapy is always questionable.Although very few trials in which compliance has been formally assessed have been performed, the issue of overcompliance has not been addressed; in other words, there may be a problem of patients continuing to take the medication even in the face of toxicity and advice to stop treatment. Oral chemotherapy requires just as much care as intravenous chemotherapy and probably requires more attention to patient education and involvement in care decisions. Clinical Colorectal Cancer, Vol. 5, Suppl. 1, 47-50, 2005 Key words: Capecitabine, 5-Fluorouracil, Leucovorin,Toxicity
Introduction Cytotoxic chemotherapy is most often administered as an intravenous (I.V.) infusion or bolus. There are some drugs, such as chlorambucil, that are administered orally, but these are a minority in standard practice. This situation has arisen for many practical and scientific reasons. Many cytotoxins are poorly and variably absorbed by the gut, so I.V. administration gets around this limitation. Because most drugs are used at doses that are close to the limit of tolerance by employing the parenteral route, one can be sure that the “full” dose has been delivered. Cytotoxins have unpleasant side effects, which could suggest patient compliance with oral therapy would be impaired.
Beatson Oncology Centre, Glasgow, United Kingdom Submitted: Mar 25, 2005; Revised: Apr 11, 2005; Accepted: Apr 15, 2005 Address for correspondence: Jim Cassidy, MD, FRCP, Beatson Oncology Centre, Glasgow G11 6NT, UK Fax: 44-141-330-4063; e-mail: [email protected]
Although these and other reasons are often quoted for the use of I.V. cytotoxins, there can be no doubt that patients in most clinical situations would prefer not to have I.V. medications. Even the subcutaneous administration of a life-saving medication, such as insulin, is problematic in some diabetic patients. In addition, the I.V. route has some serious limitations in terms of cost, complications of access devices, and introduction of a portal of entry for infection in patients whose immune system is likely to be significantly compromised. The development and use of oral compounds for cancer therapy are now becoming more common and have found widespread acceptance with patients. One particular area of clinical utility has been the introduction of oral fluoropyrimidines in the therapy of colorectal cancer (CRC). This was driven by the realization that infusional regimens of fluoropyrimidines are more active but have serious logistic and convenience drawbacks. Several oral fluoropyrimidines or drugs have been developed (uracil/tegafur, Furtulon, and S1) and licensed for use in some countries. In clinical terms, the most advanced of these is capecitabine, which will be the focus of this review.
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Colorectal Cancer Supplement April 2005
• S47
Oral Fluoropyrimidines in Advanced Colorectal Cancer Figure 1
Enzymatic Activation of Capecitabine
Figure 2
Intestine 100
Capecitabine
80
Tumor → Normal Tissue Carboxylesterase 5'-DFCR
Carboxylesterase 5'-DFCR
Cytidine deaminase 5'-DFUR
Cytidine deaminase 5'-DFUR Thymidine phosphorylase 5-FU
Survival Probability (%)
Capecitabine
Liver
Early Studies of Capecitabine Capecitabine is an oral prodrug of 5-fluorouracil (5-FU). It was initially developed as a logically designed compound as part of a long-term project to develop oral fluoropyrimidines. Its metabolism is shown in Figure 1. The agent is partially broken down in the gastrointestinal tract and then converted to 5-FU in the tumor by the enzyme thymidine phosphorylase (TP; also known as platelet-derived endothelial cell growth factor, an angiogenic molecule). It has been shown that TP is overexpressed in many human solid cancers, including CRC. In early phase trials, this agent demonstrated activity and a toxicity profile reminiscent of infusional regimens of 5-FU. A variety of dose schedules that also included the addition of leucovorin (LV) were investigated, because this agent was and still is commonly used as a modulator of 5-FU and has been shown to improve response rates to fluoropyrimidinebased therapy in CRC. A particular goal of the early-phase studies was to demonstrate that the mechanism of activation actually occurred in human cancer. Schuller et al administered capecitabine preoperatively to patients scheduled for resection of liver metastases and/or primary CRCs.1 Tissue and blood were taken and analyzed for content of 5-FU and all the intermediary metabolites of capecitabine as well as the critical enzymes in its catabolic pathway. This trial confirmed that 5-FU is preferentially formed in cancer tissue. The tumor-toplasma ratio of 5-FU was > 20 fold, and the tumor to adjacent normal tissue concentrations were > 3 fold higher. This selective concentration in the tumor has never been demonstrated with the parent 5-FU drug. Because 5-FU was the backbone of all therapy in CRC at the time, it was decided to focus clinical development on that indication initially; however, it was always assumed that the agent would eventually find clinical utility in all the established fluoropyrimidine-sensitive cancers. A dose and schedule that were convenient, simple, active, and least toxic were chosen from the phase I/II trial program to take further for registration purposes.
S48 • Clinical Colorectal Cancer Supplement April 2005
Capecitabine (n = 603) 5-FU/LV (n = 604) Hazard Ratio = 0.96
60 40 20
0 Abbreviations: 5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine
Time to Progression and Overall Survival of Capecitabine and Intravenous 5-FU/LV
5
10
15
20
25
30
35
40
45
Months
Capecitabine in Advanced Colorectal Cancer Two large-scale, randomized trials were performed in the setting of first-line CRC therapy. The standard arm was selected to be the 5-FU/LV combination, known as the Mayo Clinic regimen.2 The intention was that the prospective design and performance of these 2 studies would allow for the results to be combined for future analyses. The trials were also designed to demonstrate equivalence in overall survival (OS) between the test regimens rather than the more usual design that seeks to demonstrate one regimen is superior to another. The rationale for this is that if we could show equivalent efficacy and hopefully less toxicity and more “convenience” for patients then capecitabine therapy would be seen as a step forward. The results of the primary endpoint are shown in Figure 2. It is clear that capecitabine is equivalent in OS but is actually somewhat superior in terms of the secondary endpoint of response rate (Figure 3). In addition, toxicity was reduced using capecitabine compared with the Mayo Clinic regimen (Figure 4). The exception is hand-foot syndrome, which is characterized by dryness and tenderness of the hands and feet that progresses to moist desquamation unless appropriate and timely dose reductions are implemented. As an integral part of the clinical development program, a dose-reduction schema for capecitabine was developed and prospectively tested. This schema (see package insert for details), when applied correctly, results in reduction in all major side effects. Although the Mayo Clinic regimen was a suitable control arm at the time of the design of these trials, the therapy of CRC has moved on since then. It is now commonplace for patients to be offered therapy that incorporates fluoropyrimidine plus irinotecan or oxaliplatin. These combinations are more toxic than single-agent fluoropyrimidine but have shown convincing improvements in efficacy outcomes in multiple randomized controlled trials. Combination trials of capecitabine
Jim Cassidy Figure 3
Figure 4
Safety Profile of Capecitabine
100
25 Capecitabine (n = 596) 5-FU/LV (n = 593) *P < 0.0001
*
15 10 5 *
*
* * *
* cia pe Alo
a/v
Na u
se
tro p
en
om itin g
ia
me Ne u
dro yn
d-f oo Ha n
Feb
rile
ne
ts
a
ma titi s Sto
he Dia rr
g
sea
Vo mi tin
ia/ en op
Na u
sis Sto ma titi s Dia rrh ea
sep
nia pe tr o utr
dr o
me
Ne u
yn ts oo
* 40
0
d- f Ha n
*P < 0.001
60
20
*
0
Capecitabine (n = 993) Bolus 5-FU/LV (n = 974)
80 Patients (%)
*
20 Patients (%)
Treatment-Related Adverse Events with Capecitabine
plus oxaliplatin or irinotecan have been performed, and the results of large-scale comparisons are awaited.3 Small-scale exploratory studies have been published that seem to indicate that substitution of capecitabine can be performed without detrement to the activity of the combination in question. Capecitabine is also now being used as the fluoropyrimidine base for combination regimens with a diverse range of other cytotoxins in other clinical indications. It remains to be proven whether this substitution will always be beneficial; however, one could intuitively expect this to be the case. More recently, the targeted therapies of cetuximab and bevacizumab have also shown benefits when added to the therapy of advanced CRC. Trials that integrate these agents with capecitabine are under way. Capecitabine has not been formally compared with the multitude of infusional regimens of 5-FU/LV that are in common use. There is no consensus as to which of these regimens is the best, and, in any case, as stated earlier, the use of combination therapy seems likely to replace these in everyday practice. Nonetheless, the use of single-agent fluoropyrimidines as a palliative and well-tolerated therapy in patients with advanced disease continues at present. Not all patients are candidates for multiple-agent therapy, and because CRC predominantly affects an elderly population, there are often comorbidities that limit tolerance to more aggressive cytotoxic regimens. Data derived from market research sources indicate that this situation pertains to a significant minority of patients in normal practice outside the large academic cooperative institutions.
Benefits Capecitabine is an active therapy with respectable response rates as a single agent. It is well tolerated and has a predictable side-effect profile. In addition, the published dose-reduction criteria and rules have been shown to allow continuation of therapy in a safe manner. Patients express a prefer-
ence for oral therapy as long as the efficacy of therapy is not compromised. Compared with I.V. infusional regimens, there are also cost savings if therapy is switched to capecitabine (see the National Institute for Health and Clinical Excellence [NICE] guidance Web site at http://www.nice.org.uk). Recently, we have also demonstrated that it is possible to safely oversee this therapy in a clinic that is staffed with nurses and pharmacists, thereby saving physician consultation time (data in press). In our health care system, capacity is a major problem, so the use of capecitabine also frees time for pharmacy technicians, I.V. team nurses, and phlebotomists, and these staff can then be redeployed to other patient groups.
Drawbacks Single-agent capecitabine is unlikely to be as active as modern combination therapies. This will be offset by the lesser toxicity profile of single-agent therapy. Some patients perceive the use of oral chemotherapy as “second best” to I.V. therapy. This prejudice seems restricted to cancer therapy, and, with the use of oral agents becoming more common, one could expect this to diminish in the future. Even though single-agent capecitabine is probably less active than combination therapy, it is still likely to be used in clinical practice for those patients who are not suited to more aggressive (more toxic) therapy. This could include patients who are older, have more comorbidities, or choose to have a simpler, more convenient therapy for the palliation of their disease. We performed careful compliance checks in the early studies of capecitabine and found no real problems. However, the issue of overcompliance is of concern; patients have the opportunity to reduce the dose or stop taking the tablets in mid-course with capecitabine (which is not possible with I.V. therapy) but could feel disinclined to do so if they believe this could have an adverse effect on the response of the cancer. This requires patient education so that the situation of worsening toxicity can be avoided. In our practice, we give patients written and verbal instructions and a contact phone number for advice on dose and toxicity.
Clinical Colorectal Cancer Supplement April 2005
• S49
Oral Fluoropyrimidines in Advanced Colorectal Cancer Table 1
Tumor Response Rates with Capecitabine and 5-Fluorouracil/Leucovorin
Response
Capecitabine, % (n = 603)
5-FU/LV, % (n = 604)
P Value
PR + CR (95% CI)
26 (22-30)
17 (14-20)
< 0.0002
and it is particularly important to make them aware of the side-effect profile and the appropriate dose adjustment schema. Capecitabine is likely to become a common fluoropyrimidine base on which to build combination therapy. In addition, it has recently been shown to be an active agent in the adjuvant setting.4
References A further issue that arises in some health care systems is that reimbursement policies favor I.V. chemotherapy. It is hoped that this situation will be remedied, because many other novel agents coming to the clinic in oncology will be oral and will require chronic administration schedules.
Conclusion Oral fluoropyrimidines have a place as single-agent therapy in advanced CRC. Capecitabine offers significant advantages over bolus type regimens (Table 1). Patients need adequate education and support through their treatment with all oral chemotherapy,
S50 • Clinical Colorectal Cancer Supplement April 2005
1. Schuller 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. 2. Van Cutsem E, Hoff PM, Harper P, et al. Oral capecitabine versus 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. 3. Cassidy J, Tabernero J, Twelves C, et al. XELOX (capecitabine plus oxailplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 2004; 22:2084-2091. 4. Cassidy J, Scheithauer WJ, McKendrick H, et al, on behalf of the X-ACT study investigators. Capecitabine (X) versus bolus 5FU/leucovorin (LV) as adjuvant therapy for colon cancer (the X-ACT study): efficacy results of a phase III trial. Late-breaking abstract from the 2004 ASCO Annual Meeting, J Clin Oncol 2004; 22(suppl):3509.
Introduction Cytotoxic chemotherapy is most often administered as an intravenous (I.V.) infusion or bolus. There are some drugs, such as chlorambucil, that are administered orally, but these are a minority in standard practice. This situation has arisen for many practical and scientific reasons. Many cytotoxins are poorly and variably absorbed by the gut, so I.V. administration gets around this limitation. Because most drugs are used at doses that are close to the limit of tolerance by employing the parenteral route, one can be sure that the “full” dose has been delivered. Cytotoxins have unpleasant side effects, which could suggest patient compliance with oral therapy would be impaired.
Beatson Oncology Centre, Glasgow, United Kingdom Submitted: Mar 25, 2005; Revised: Apr 11, 2005; Accepted: Apr 15, 2005 Address for correspondence: Jim Cassidy, MD, FRCP, Beatson Oncology Centre, Glasgow G11 6NT, UK Fax: 44-141-330-4063; e-mail: [email protected]
Although these and other reasons are often quoted for the use of I.V. cytotoxins, there can be no doubt that patients in most clinical situations would prefer not to have I.V. medications. Even the subcutaneous administration of a life-saving medication, such as insulin, is problematic in some diabetic patients. In addition, the I.V. route has some serious limitations in terms of cost, complications of access devices, and introduction of a portal of entry for infection in patients whose immune system is likely to be significantly compromised. The development and use of oral compounds for cancer therapy are now becoming more common and have found widespread acceptance with patients. One particular area of clinical utility has been the introduction of oral fluoropyrimidines in the therapy of colorectal cancer (CRC). This was driven by the realization that infusional regimens of fluoropyrimidines are more active but have serious logistic and convenience drawbacks. Several oral fluoropyrimidines or drugs have been developed (uracil/tegafur, Furtulon, and S1) and licensed for use in some countries. In clinical terms, the most advanced of these is capecitabine, which will be the focus of this review.
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cancer Information Group, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Colorectal Cancer Supplement April 2005
• S47
Oral Fluoropyrimidines in Advanced Colorectal Cancer Figure 1
Enzymatic Activation of Capecitabine
Figure 2
Intestine 100
Capecitabine
80
Tumor → Normal Tissue Carboxylesterase 5'-DFCR
Carboxylesterase 5'-DFCR
Cytidine deaminase 5'-DFUR
Cytidine deaminase 5'-DFUR Thymidine phosphorylase 5-FU
Survival Probability (%)
Capecitabine
Liver
Early Studies of Capecitabine Capecitabine is an oral prodrug of 5-fluorouracil (5-FU). It was initially developed as a logically designed compound as part of a long-term project to develop oral fluoropyrimidines. Its metabolism is shown in Figure 1. The agent is partially broken down in the gastrointestinal tract and then converted to 5-FU in the tumor by the enzyme thymidine phosphorylase (TP; also known as platelet-derived endothelial cell growth factor, an angiogenic molecule). It has been shown that TP is overexpressed in many human solid cancers, including CRC. In early phase trials, this agent demonstrated activity and a toxicity profile reminiscent of infusional regimens of 5-FU. A variety of dose schedules that also included the addition of leucovorin (LV) were investigated, because this agent was and still is commonly used as a modulator of 5-FU and has been shown to improve response rates to fluoropyrimidinebased therapy in CRC. A particular goal of the early-phase studies was to demonstrate that the mechanism of activation actually occurred in human cancer. Schuller et al administered capecitabine preoperatively to patients scheduled for resection of liver metastases and/or primary CRCs.1 Tissue and blood were taken and analyzed for content of 5-FU and all the intermediary metabolites of capecitabine as well as the critical enzymes in its catabolic pathway. This trial confirmed that 5-FU is preferentially formed in cancer tissue. The tumor-toplasma ratio of 5-FU was > 20 fold, and the tumor to adjacent normal tissue concentrations were > 3 fold higher. This selective concentration in the tumor has never been demonstrated with the parent 5-FU drug. Because 5-FU was the backbone of all therapy in CRC at the time, it was decided to focus clinical development on that indication initially; however, it was always assumed that the agent would eventually find clinical utility in all the established fluoropyrimidine-sensitive cancers. A dose and schedule that were convenient, simple, active, and least toxic were chosen from the phase I/II trial program to take further for registration purposes.
S48 • Clinical Colorectal Cancer Supplement April 2005
Capecitabine (n = 603) 5-FU/LV (n = 604) Hazard Ratio = 0.96
60 40 20
0 Abbreviations: 5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine
Time to Progression and Overall Survival of Capecitabine and Intravenous 5-FU/LV
5
10
15
20
25
30
35
40
45
Months
Capecitabine in Advanced Colorectal Cancer Two large-scale, randomized trials were performed in the setting of first-line CRC therapy. The standard arm was selected to be the 5-FU/LV combination, known as the Mayo Clinic regimen.2 The intention was that the prospective design and performance of these 2 studies would allow for the results to be combined for future analyses. The trials were also designed to demonstrate equivalence in overall survival (OS) between the test regimens rather than the more usual design that seeks to demonstrate one regimen is superior to another. The rationale for this is that if we could show equivalent efficacy and hopefully less toxicity and more “convenience” for patients then capecitabine therapy would be seen as a step forward. The results of the primary endpoint are shown in Figure 2. It is clear that capecitabine is equivalent in OS but is actually somewhat superior in terms of the secondary endpoint of response rate (Figure 3). In addition, toxicity was reduced using capecitabine compared with the Mayo Clinic regimen (Figure 4). The exception is hand-foot syndrome, which is characterized by dryness and tenderness of the hands and feet that progresses to moist desquamation unless appropriate and timely dose reductions are implemented. As an integral part of the clinical development program, a dose-reduction schema for capecitabine was developed and prospectively tested. This schema (see package insert for details), when applied correctly, results in reduction in all major side effects. Although the Mayo Clinic regimen was a suitable control arm at the time of the design of these trials, the therapy of CRC has moved on since then. It is now commonplace for patients to be offered therapy that incorporates fluoropyrimidine plus irinotecan or oxaliplatin. These combinations are more toxic than single-agent fluoropyrimidine but have shown convincing improvements in efficacy outcomes in multiple randomized controlled trials. Combination trials of capecitabine
Jim Cassidy Figure 3
Figure 4
Safety Profile of Capecitabine
100
25 Capecitabine (n = 596) 5-FU/LV (n = 593) *P < 0.0001
*
15 10 5 *
*
* * *
* cia pe Alo
a/v
Na u
se
tro p
en
om itin g
ia
me Ne u
dro yn
d-f oo Ha n
Feb
rile
ne
ts
a
ma titi s Sto
he Dia rr
g
sea
Vo mi tin
ia/ en op
Na u
sis Sto ma titi s Dia rrh ea
sep
nia pe tr o utr
dr o
me
Ne u
yn ts oo
* 40
0
d- f Ha n
*P < 0.001
60
20
*
0
Capecitabine (n = 993) Bolus 5-FU/LV (n = 974)
80 Patients (%)
*
20 Patients (%)
Treatment-Related Adverse Events with Capecitabine
plus oxaliplatin or irinotecan have been performed, and the results of large-scale comparisons are awaited.3 Small-scale exploratory studies have been published that seem to indicate that substitution of capecitabine can be performed without detrement to the activity of the combination in question. Capecitabine is also now being used as the fluoropyrimidine base for combination regimens with a diverse range of other cytotoxins in other clinical indications. It remains to be proven whether this substitution will always be beneficial; however, one could intuitively expect this to be the case. More recently, the targeted therapies of cetuximab and bevacizumab have also shown benefits when added to the therapy of advanced CRC. Trials that integrate these agents with capecitabine are under way. Capecitabine has not been formally compared with the multitude of infusional regimens of 5-FU/LV that are in common use. There is no consensus as to which of these regimens is the best, and, in any case, as stated earlier, the use of combination therapy seems likely to replace these in everyday practice. Nonetheless, the use of single-agent fluoropyrimidines as a palliative and well-tolerated therapy in patients with advanced disease continues at present. Not all patients are candidates for multiple-agent therapy, and because CRC predominantly affects an elderly population, there are often comorbidities that limit tolerance to more aggressive cytotoxic regimens. Data derived from market research sources indicate that this situation pertains to a significant minority of patients in normal practice outside the large academic cooperative institutions.
Benefits Capecitabine is an active therapy with respectable response rates as a single agent. It is well tolerated and has a predictable side-effect profile. In addition, the published dose-reduction criteria and rules have been shown to allow continuation of therapy in a safe manner. Patients express a prefer-
ence for oral therapy as long as the efficacy of therapy is not compromised. Compared with I.V. infusional regimens, there are also cost savings if therapy is switched to capecitabine (see the National Institute for Health and Clinical Excellence [NICE] guidance Web site at http://www.nice.org.uk). Recently, we have also demonstrated that it is possible to safely oversee this therapy in a clinic that is staffed with nurses and pharmacists, thereby saving physician consultation time (data in press). In our health care system, capacity is a major problem, so the use of capecitabine also frees time for pharmacy technicians, I.V. team nurses, and phlebotomists, and these staff can then be redeployed to other patient groups.
Drawbacks Single-agent capecitabine is unlikely to be as active as modern combination therapies. This will be offset by the lesser toxicity profile of single-agent therapy. Some patients perceive the use of oral chemotherapy as “second best” to I.V. therapy. This prejudice seems restricted to cancer therapy, and, with the use of oral agents becoming more common, one could expect this to diminish in the future. Even though single-agent capecitabine is probably less active than combination therapy, it is still likely to be used in clinical practice for those patients who are not suited to more aggressive (more toxic) therapy. This could include patients who are older, have more comorbidities, or choose to have a simpler, more convenient therapy for the palliation of their disease. We performed careful compliance checks in the early studies of capecitabine and found no real problems. However, the issue of overcompliance is of concern; patients have the opportunity to reduce the dose or stop taking the tablets in mid-course with capecitabine (which is not possible with I.V. therapy) but could feel disinclined to do so if they believe this could have an adverse effect on the response of the cancer. This requires patient education so that the situation of worsening toxicity can be avoided. In our practice, we give patients written and verbal instructions and a contact phone number for advice on dose and toxicity.
Clinical Colorectal Cancer Supplement April 2005
• S49
Oral Fluoropyrimidines in Advanced Colorectal Cancer Table 1
Tumor Response Rates with Capecitabine and 5-Fluorouracil/Leucovorin
Response
Capecitabine, % (n = 603)
5-FU/LV, % (n = 604)
P Value
PR + CR (95% CI)
26 (22-30)
17 (14-20)
< 0.0002
and it is particularly important to make them aware of the side-effect profile and the appropriate dose adjustment schema. Capecitabine is likely to become a common fluoropyrimidine base on which to build combination therapy. In addition, it has recently been shown to be an active agent in the adjuvant setting.4
References A further issue that arises in some health care systems is that reimbursement policies favor I.V. chemotherapy. It is hoped that this situation will be remedied, because many other novel agents coming to the clinic in oncology will be oral and will require chronic administration schedules.
Conclusion Oral fluoropyrimidines have a place as single-agent therapy in advanced CRC. Capecitabine offers significant advantages over bolus type regimens (Table 1). Patients need adequate education and support through their treatment with all oral chemotherapy,
S50 • Clinical Colorectal Cancer Supplement April 2005
1. Schuller 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. 2. Van Cutsem E, Hoff PM, Harper P, et al. Oral capecitabine versus 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. 3. Cassidy J, Tabernero J, Twelves C, et al. XELOX (capecitabine plus oxailplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 2004; 22:2084-2091. 4. Cassidy J, Scheithauer WJ, McKendrick H, et al, on behalf of the X-ACT study investigators. Capecitabine (X) versus bolus 5FU/leucovorin (LV) as adjuvant therapy for colon cancer (the X-ACT study): efficacy results of a phase III trial. Late-breaking abstract from the 2004 ASCO Annual Meeting, J Clin Oncol 2004; 22(suppl):3509.