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Current Status of Oral Chemotherapy for Colorectal Cancer

Current Status of Oral Chemotherapy for Colorectal Cancer

ABSTRACT: The treatment of advanced colorectal cancer over the past 4 decades has required the use of intravenous chemotherapy, most typically fluorouracil (5-FU). The possibility of providing an alternative to intravenous delivery while at the same time improving the quality of life of patients who require fluorouracil for advanced or adjuvant therapy has provided the stimulus for the development of oral fluoropyrimidine drugs. Five oral fluoropyrimidine drugs have recently entered clinical trials in the United States. These include capecitabine (Xeloda), UFT (uracil and tegafur) or UFT/leucovorin (Orzel), eniluracil (ethynyluracil), S-1, and BOF A-2. At least two of these drugs have demonstrated survival equivalent to the standard intravenous fluorouracil and leucovorin regimens used to treat advanced colorectal cancer. This, together with less severe toxicity and potential increased quality of life, should lead to approval of one or more of these oral agents in the near future. Based on both patient and physician acceptance of oral fluoropyrimidines, other oral drugs from classes other than fluoropyrimidines will likely be developed in the near future. [ONCOLOGY 15(Suppl 5):16-20, 2001]

Introduction

For over 40 years, the primary therapy for the treatment of
colorectal cancer has been intravenous fluorouracil (5-FU), administered as an
intravenous bolus, 5-day infusion, or protracted infusion over several weeks.[1]
Intravenous 5-FU has also been used in adjuvant regimens for newly diagnosed
colorectal cancer, typically as a bolus injection.[2]

As with other therapeutic drug classes, there has been an effort
to develop oral dose formulations of drugs used in oncology. The appeal of oral
drugs for oncology, as for other disease areas, is for the most part obvious.
This includes ease of administration—patients may not need to visit a
healthcare facility (eg, a physician’s office or hospital) in order to receive
treatment. For the advanced-disease patient, this may allow more meaningful time
with family and less time spent in a healthcare facility. For the newly
diagnosed patient receiving adjuvant chemotherapy, the availability of oral
therapy often permits patients at an early stage of disease to receive treatment
while continuing full-time employment. Studies by Liu et al demonstrated that
cancer patients preferred oral drugs to their intravenous counterparts as long
as they were assured that efficacy was maintained with the oral formulation.[3]

However, several pharmacologic requirements must be met in
developing an oral formulation.[4] These include demonstrated stability of the
medication in the gastrointestinal tract and ability to be absorbed from the
gastrointestinal tract with sufficient bioavailability to assure dosing
decisions. Other factors, eg, lack of interaction with other orally administered
drugs that the patient may be taking, also are important. Additional
considerations can limit enthusiasm for oral drugs, including concern about
patients’ mental status that may result in inappropriate dosing, or overdosing
in situations when chemotherapy should be stopped because of side effects. Other
related issues include patient compliance and the difficulty in adequately
assessing how much of, and when, the drug was taken.

In oncology, increasing clinical experience with oral
chemotherapy agents has been accumulated[5] and includes oral mercaptopurines,
nitrosoureas, hydroxyurea, and methotrexate. Several other new oral chemotherapy
agents are currently under investigation. Thus, more orally administered agents
for the treatment of cancer are likely to be available in the future.

In particular, five oral fluoropyrimidine drugs have recently
entered clinical trials in the United States. These include capecitabine
(Xeloda), UFT (uracil and tegafur) or the combination of UFT and leucovorin
(Orzel), eniluracil (ethynyluracil), S-1, and BOF A-2. BOF A-2 was associated
with severe toxicity, hence clinical studies have been terminated. The other
four agents are still under clinical evaluation. The details are described
herein.

Capecitabine

Capecitabine is a third-generation fluoropyrimidine drug that
was designed to be a selectively activated prodrug that would release 5-FU
preferentially within the tumor (Figure 1A).[6] Capecitabine, when administered
orally, is absorbed from the gastrointestinal tract into the bloodstream and has
excellent bioavailability.[7] This agent is activated by a series of three
enzymes in the liver and tumor to eventually release 5-FU within the tumor (Figure
1B
). The last of these enzymes—thymidine phosphorylase, localized
mainly in the tumor—is responsible for selective activation of the metabolite
5´-DFUR to 5-FU.[8]

Capecitabine was approved by the US Food and Drug Administration
(FDA) in April 1998 as third-line therapy for patients with paclitaxel (Taxol)-
or anthracycline-resistant metastatic breast cancer (or for patients for whom
anthracycline was not indicated).[9] In approving this oral fluoropyrimidine, it
was noted that there was less severe myelotoxicity and, in particular, less
febrile-associated leukopenia than with intravenous infusion of 5-FU. The only
toxicity that appeared more prominent with capecitabine was the occurrence of
hand/foot syndrome, which was often severe (grade 3). This toxicity, while
uncomfortable, is not life threatening and can be managed by withholding therapy
for several days or by decreasing the daily dose (typically from the recommended
dose of 2,500 to 2,000 mg/m2/d).

Capecitabine has also been evaluated in colorectal cancer. Two
large phase III studies compared a capecitabine regimen with a standard Mayo
Clinic regimen of 5-FU plus leucovorin. In both trials the capecitabine regimen
produced a greater response rate, with survival and time to progression
equivalent to that achieved with the Mayo Clinic regimen, but with much less
severe toxicity and with potential quality-of-life benefits.[10,11]

At present, capecitabine is not scheduled for a further Oncology
Drug Advisory Committee (ODAC) review; approval of this agent for the treatment
of advanced colorectal cancer is expected this year. Capecitabine may also have
other roles, including acting as a radiosensitizer in rectal cancer and as noted
above as adjuvant therapy in colorectal cancer. These studies are currently
underway.

UFT and UFT/Leucovorin

In the 1970s, tegafur—a prodrug of 5-FU—was synthesized in
the hope of having an oral dose form of 5-FU.[12] This drug, however, was
associated with many undesirable side effects, and despite being approved in
Japan and many other Asian countries, it failed to obtain approval in the United
States. In the late 1970s, an attempt was made to improve tegafur by combining
it with the naturally occurring pyrimidine uracil, to modulate the metabolism,
and in turn the pharmacology, of tegafur. This two-component drug, known as UFT,
is composed of uracil and tegafur in a 4:1 ratio (Figure
2
).[13]

UFT is currently approved for clinical use in many areas
worldwide, including Japan, Asia, South America, and Spain. It is also being
evaluated with oral leucovorin as a two-pill combination known as Orzel in an
attempt to improve further on the efficacy of the 5-FU formed from UFT.[14]

Mechanism of Action

The mechanism of action of UFT and the combination drug UFT plus
leucovorin is summarized in Figure 3. Figure 3A demonstrates that the uracil in
the UFT combination functions as an "inhibitor" of the important
pyrimidine catabolic enzyme dihydropyrimidine dehydrogenase (DPD), which is an
important regulatory step in 5-FU metabolism.[15] Uracil is, in fact, a
competitive inhibitor of DPD, resulting in 5-FU levels being elevated and
sustained for a longer time with the theoretical opportunity for more 5-FU to be
anabolized. Because it is a competitive inhibitor, the effect is transient and
reverses rapidly once the uracil levels have sufficiently decreased. Figure 3B
demonstrates the additional biomodulation produced by leucovorin with UFT plus
leucovorin, showing that leucovorin expands the 5,10 methylene tetrahydrofolate
pool resulting theoretically in the formation of more ternary complex required
for effective inhibition of the synthesis of thymidylate needed for DNA
synthesis.

There is extensive experience in the clinical evaluation of UFT
worldwide, as it has been approved and used extensively in many countries.[16]
UFT plus leucovorin has recently undergone extensive evaluation in clinical
trials
in phase III studies demonstrating equivalence to the Mayo Clinic regimen of
5-FU plus leucovorin with less severe toxicity.[17,18] In September 1999, the
Oncology Drug Advisory Committee of the FDA reviewed the clinical data on UFT
plus leucovorin and voted unanimously to approve the drug application. However,
the FDA has continued to have concerns about approving either UFT alone or
combined with leucovorin. Thus, approvals of both UFT and the combination of UFT
with leucovorin are currently on hold.

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