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
ABSTRACT: The treatment of advanced colorectal cancer over the past 4decades has required the use of intravenous chemotherapy, most typicallyfluorouracil (5-FU). The possibility of providing an alternative to intravenousdelivery while at the same time improving the quality of life of patients whorequire fluorouracil for advanced or adjuvant therapy has provided the stimulusfor the development of oral fluoropyrimidine drugs. Five oral fluoropyrimidinedrugs have recently entered clinical trials in the United States. These includecapecitabine (Xeloda), UFT (uracil and tegafur) or UFT/leucovorin (Orzel),eniluracil (ethynyluracil), S-1, and BOF A-2. At least two of these drugs havedemonstrated survival equivalent to the standard intravenous fluorouracil andleucovorin regimens used to treat advanced colorectal cancer. This, togetherwith less severe toxicity and potential increased quality of life, should leadto approval of one or more of these oral agents in the near future. Based onboth patient and physician acceptance of oral fluoropyrimidines, other oraldrugs from classes other than fluoropyrimidines will likely be developed in thenear future. [ONCOLOGY 15(Suppl 5):16-20, 2001]
For over 40 years, the primary therapy for the treatment ofcolorectal cancer has been intravenous fluorouracil (5-FU), administered as anintravenous bolus, 5-day infusion, or protracted infusion over several weeks.Intravenous 5-FU has also been used in adjuvant regimens for newly diagnosedcolorectal cancer, typically as a bolus injection.
As with other therapeutic drug classes, there has been an effortto develop oral dose formulations of drugs used in oncology. The appeal of oraldrugs for oncology, as for other disease areas, is for the most part obvious.This includes ease of administrationpatients may not need to visit ahealthcare facility (eg, a physician’s office or hospital) in order to receivetreatment. For the advanced-disease patient, this may allow more meaningful timewith family and less time spent in a healthcare facility. For the newlydiagnosed patient receiving adjuvant chemotherapy, the availability of oraltherapy often permits patients at an early stage of disease to receive treatmentwhile continuing full-time employment. Studies by Liu et al demonstrated thatcancer patients preferred oral drugs to their intravenous counterparts as longas they were assured that efficacy was maintained with the oral formulation.
However, several pharmacologic requirements must be met indeveloping an oral formulation. These include demonstrated stability of themedication in the gastrointestinal tract and ability to be absorbed from thegastrointestinal tract with sufficient bioavailability to assure dosingdecisions. Other factors, eg, lack of interaction with other orally administereddrugs that the patient may be taking, also are important. Additionalconsiderations can limit enthusiasm for oral drugs, including concern aboutpatients’ mental status that may result in inappropriate dosing, or overdosingin situations when chemotherapy should be stopped because of side effects. Otherrelated issues include patient compliance and the difficulty in adequatelyassessing how much of, and when, the drug was taken.
In oncology, increasing clinical experience with oralchemotherapy agents has been accumulated and includes oral mercaptopurines,nitrosoureas, hydroxyurea, and methotrexate. Several other new oral chemotherapyagents are currently under investigation. Thus, more orally administered agentsfor the treatment of cancer are likely to be available in the future.
In particular, five oral fluoropyrimidine drugs have recentlyentered 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 associatedwith severe toxicity, hence clinical studies have been terminated. The otherfour agents are still under clinical evaluation. The details are describedherein.
Capecitabine is a third-generation fluoropyrimidine drug thatwas designed to be a selectively activated prodrug that would release 5-FUpreferentially within the tumor (Figure 1A). Capecitabine, when administeredorally, is absorbed from the gastrointestinal tract into the bloodstream and hasexcellent bioavailability. This agent is activated by a series of threeenzymes in the liver and tumor to eventually release 5-FU within the tumor (Figure1B). The last of these enzymesthymidine phosphorylase, localizedmainly in the tumoris responsible for selective activation of the metabolite5´-DFUR to 5-FU.
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 whomanthracycline was not indicated). In approving this oral fluoropyrimidine, itwas noted that there was less severe myelotoxicity and, in particular, lessfebrile-associated leukopenia than with intravenous infusion of 5-FU. The onlytoxicity that appeared more prominent with capecitabine was the occurrence ofhand/foot syndrome, which was often severe (grade 3). This toxicity, whileuncomfortable, is not life threatening and can be managed by withholding therapyfor several days or by decreasing the daily dose (typically from the recommendeddose of 2,500 to 2,000 mg/m2/d).
Capecitabine has also been evaluated in colorectal cancer. Twolarge phase III studies compared a capecitabine regimen with a standard MayoClinic regimen of 5-FU plus leucovorin. In both trials the capecitabine regimenproduced a greater response rate, with survival and time to progressionequivalent to that achieved with the Mayo Clinic regimen, but with much lesssevere toxicity and with potential quality-of-life benefits.[10,11]
At present, capecitabine is not scheduled for a further OncologyDrug Advisory Committee (ODAC) review; approval of this agent for the treatmentof advanced colorectal cancer is expected this year. Capecitabine may also haveother roles, including acting as a radiosensitizer in rectal cancer and as notedabove as adjuvant therapy in colorectal cancer. These studies are currentlyunderway.
In the 1970s, tegafura prodrug of 5-FUwas synthesized inthe hope of having an oral dose form of 5-FU. This drug, however, wasassociated with many undesirable side effects, and despite being approved inJapan and many other Asian countries, it failed to obtain approval in the UnitedStates. In the late 1970s, an attempt was made to improve tegafur by combiningit 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 (Figure2).
UFT is currently approved for clinical use in many areasworldwide, including Japan, Asia, South America, and Spain. It is also beingevaluated with oral leucovorin as a two-pill combination known as Orzel in anattempt to improve further on the efficacy of the 5-FU formed from UFT.
Mechanism of Action
The mechanism of action of UFT and the combination drug UFT plusleucovorin is summarized in Figure 3. Figure 3A demonstrates that the uracil inthe UFT combination functions as an "inhibitor" of the importantpyrimidine catabolic enzyme dihydropyrimidine dehydrogenase (DPD), which is animportant regulatory step in 5-FU metabolism. Uracil is, in fact, acompetitive inhibitor of DPD, resulting in 5-FU levels being elevated andsustained for a longer time with the theoretical opportunity for more 5-FU to beanabolized. Because it is a competitive inhibitor, the effect is transient andreverses rapidly once the uracil levels have sufficiently decreased. Figure 3Bdemonstrates the additional biomodulation produced by leucovorin with UFT plusleucovorin, showing that leucovorin expands the 5,10 methylene tetrahydrofolatepool resulting theoretically in the formation of more ternary complex requiredfor effective inhibition of the synthesis of thymidylate needed for DNAsynthesis.
There is extensive experience in the clinical evaluation of UFTworldwide, as it has been approved and used extensively in many countries.UFT plus leucovorin has recently undergone extensive evaluation in clinicaltrialsin phase III studies demonstrating equivalence to the Mayo Clinic regimen of5-FU plus leucovorin with less severe toxicity.[17,18] In September 1999, theOncology Drug Advisory Committee of the FDA reviewed the clinical data on UFTplus leucovorin and voted unanimously to approve the drug application. However,the FDA has continued to have concerns about approving either UFT alone orcombined with leucovorin. Thus, approvals of both UFT and the combination of UFTwith leucovorin are currently on hold.
It should also be noted that there has been considerableinterest in the potential use of UFT as a radiosensitizer for radiotherapy ofrectal cancer, as a substitute for continuous-infusion 5-FU. Also, use of UFTplus leucovorin has been evaluated as adjuvant therapy for colorectal cancer ina large multi-institutional study conducted by the National Surgical AdjuvantBreast and Bowel Project (NSABP). This study was designed to compare UFT plusleucovorin with a more traditional 5-FU plus leucovorin adjuvant regimen.Accrual has been completed and mature survival data are awaited.
Eniluracil (ethynyluracil, GW776) is another type of DPDinhibitory fluoropyrimidine (DIF) that was synthesized and demonstrated to be apotent inactivator of DPD. The structure of eniluracil, as shown in Figure4, is similar to that of both uracil and 5-FU. Following interaction with thecofactor NADPH (nicotinamide adenine dinucleotide phosphate) and the enzyme DPD,a covalent bond is formed between eniluracil and DPD that leads toconformational change in the enzyme with complete loss of enzyme activity.Enzyme activity does not return until new enzyme is synthesized.
Because of the interpatient variability in DPD levels, which hasbeen demonstrated to be responsible for much of the variability in themetabolism and pharmacology of 5-FU, it has been suggested that totalinactivation of DPD would be desirable. Thus, variability in pharmacokineticsand bioavailability could be decreased, and it may even be possible to useeniluracil to reverse the resistance to fluoropyrimidines due to DPDoverexpression in the tumor.
Many of the clinical studies with eniluracil have beencompleted. Two large phase III studies comparing an eniluracil plus 5-FU oralregimen to a Mayo Clinic regimen of 5-FU plus leucovorin will be presented atthe American Society of Clinical Oncology Conference in May 2001. Based on thepreliminary results, this drug has been withdrawn by the sponsor (GlaxoWellcome).
S-1 is made up of three separate component drugs: the 5-FUprodrug tegafur, the DPD inhibitor 5-chloro-2,4-dihydroxypyridine, and thecompound potassium oxonate, which has been shown to inhibit orotatephosphoribosyltransferase, the enzyme responsible for the conversion of 5-FU tothe nucleotide fluorouridylate monophosphate in the gastrointestinal tract.These components are constituted in a ratio of 1:0.4:1, as shown in Figure5. Ithas been suggested that potassium oxonate will be useful in preventing diarrhea,a toxicity that often accompanies fluoropyrimidine drug use.
S-1 has been examined in clinical studies in Japan where it isapproved for use in gastric cancer. The Japanese experience suggests that S-1 isassociated with decreased gastrointestinal toxicity and diarrhea. Clinicalstudies of S-1 were recently started in the United States and western Europe.Unfortunately, the dose-limiting toxicity of S-1 in these studies has beendiarrhea. It has been suggested that this may reflect a genetic difference inthe patient populations, although no objective data supporting this hypothesisare available at present.
The expected availability in the near future of an oralfluoropyrimidine approved for the treatment of advancedand potentially newlydiagnosed (as adjuvant treatment)colorectal cancer provides motivation fordeveloping oral agents. Since irinotecan (Camptosar, CPT-11) was approved forfront-line treatment of patients with advanced colorectal cancer, there has beeninterest in developing an oral dosage form of camptothecin. Similarly, Europeanstudies have demonstrated a role for oxaliplatin (Eloxatin), which hasstimulated interest in developing an oral formulation of a platinum analog forpotential use in colorectal cancer.
Undoubtedly, as more effective agents for treatment ofcolorectal cancer are developed, interest in synthesizing oral formulations willincrease. This will particularly be true if the oral fluoropyrimidines areapproved and demonstrate utility in the clinical practice setting.
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