new drugs in the treatment of colorectal carcinoma

New Drugs in the Treatment of Colorectal Carcinoma

Cornelis J. A. Punt, M.D., Ph.D.

Department of Medical Oncology, University Hos-pital Nijmegen, Nijmegen, The Netherlands.

Address for reprints: Cornelis J. A. Punt, M.D.,Ph.D., Department of Medical Oncology, UniversityHospital Nijmegen, P.O. Box 9101, 6500 HB Nij-megen, The Netherlands.

Received November 1, 1997; revision receivedFebruary 4, 1998; accepted February 4, 1998.

BACKGROUND. Treatment with 5-fluorouracil (5-FU) plus leucovorin has been the

unofficial standard therapy for patients with colorectal carcinoma (CRC) for more

than a decade; however, the optimal dose and schedule remain a matter of debate.

Recently several new drugs have shown activity in this disease. These include

irinotecan (CPT-11); oxaliplatin; the thymidylate synthase inhibitors raltitrexed,

uracil/tegafur (UFT), capecitabine, and S-1; the biochemical modulators trimetrex-

ate and 5-ethynyluracil; and the monoclonal antibody 17–1A.

METHODS. The results of clinical trials with these and other new agents, as well as

their current status and main characteristics, were reviewed.

RESULTS. Several of these agents, some with a novel mechanism of action, show

promising activity in CRC. In combination with 5-FU and leucovorin, trimetrexate

showed encouraging response rates in Phase II studies. Other interesting agents

include capecitabine, UFT, and S-1. The biochemical modulator 5-ethynyluracil

may allow the oral administration of 5-FU; however, results of Phase II clinical

trials are not yet available. CPT-11 is in the most advanced stage of development

and, based on consistent data generated in extensive Phase II studies, currently

appears to be a reasonable choice for 5-FU-resistant or refractory disease. Another

promising agent is oxaliplatin, which showed activity as first-line and second-line

treatment.

CONCLUSIONS. Several new agents have shown promise in the treatment of CRC,

and changes in the standard treatment of advanced or high risk CRC appear likely

in the near future. Cancer 1998;83:679 – 89. © 1998 American Cancer Society.

KEYWORDS: colorectal carcinoma, chemotherapy, review, irinotecan (CPT-11), ox-aliplatin, raltitrexed, uracil/tegafur, capecitabine, S-1, 5-ethynyluracil, 17–1A mono-clonal antibody.

Colorectal carcinoma (CRC) accounts for 10 –12% of all cancers andis the second leading cause of cancer deaths in Western countries.

The incidence of CRC in the U. S. and Europe is estimated at 300,000new cases per year. Approximately 50% of patients who have under-gone surgery eventually will develop metastatic disease.1

Treatment with a 5-fluorouracil (5-FU)-containing regimen hasbeen the only available option for systemic treatment for many years,and most likely increases the life expectancy of patients with meta-static CRC by several months, although this question has never beenaddressed adequately in randomized trials. Leucovorin enhances theactivity of 5-FU, and a bolus regimen with a daily times five scheduleof 5-FU and low dose leucovorin currently is preferred in most coun-tries and results in response rates of approximately 20% and a medianoverall survival of approximately 12 months.2 Enormous efforts havebeen made to improve on this outcome by changing the method of5-FU administration and/or the biochemical modulation of 5-FU.These efforts have been inspired by new insights into the biochemicalpharmacology of 5-FU and the identification of agents that effectively

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© 1998 American Cancer Society

enhance the antitumor activity of 5-FU in preclinicalmodels. Improved tumor control and a more favorabletoxicity pattern may be achieved by continuous infu-sion schedules, either at a flat rate3,4 or at a circadianrythm,5 and regional hepatic delivery of 5-FU.6 Meta-analyses have shown a statistically significant survivaladvantage for both the biochemical modulation of5-FU by methotrexate over 5-FU alone7 and the con-tinuous infusion of 5-FU over bolus 5-FU infusion.8

However, this advantage was small. Clearly the lack ofactive agents other than 5-FU has hampered signifi-cant progress in the treatment of advanced CRC. Inthe last few years several new drugs have been testedthat show activity in CRC. The purpose of this articlewas to review new developments in the treatmentof CRC.

Chemotherapeutic AgentsIrinotecanIrinotecan (CPT-11) is a semisynthetic soluble deriva-tive of the plant alkaloid camptothecin, and is metab-olized in the liver to its active metabolite, SN-38.9

Camptothecins inhibit the action of topoisomerase I,an enzyme responsible for variations in the topologicform of DNA during replication and transcription.10,11

Inactivation of topoisomerase I by CPT-11 causes ir-reversible single strand breaks in DNA that ultimatelylead to cell death.

The pharmacokinetics of CPT-11 have been inves-tigated in a number of studies.12,13 The terminalplasma half-life for CPT-11 and SN-38 were approxi-mately 8 hours and 13 hours, respectively. Althoughmarked interindividual variations were reported in the

metabolic ratio, significant correlations were reportedbetween the areas under the concentration timecurves of both CPT-11 and SN-38 and the severity ofneutropenia and diarrhea. Phase I studies with CPT-11involving . 400 patients have been conducted in Eu-rope, Japan, and the U. S. In Europe, a dosage sched-ule of 350 mg/m2 once every 3 weeks was selected forPhase II studies because this was associated with thehighest dose intensity and tolerability, and also wasthe most convenient.14 –19 In the U. S. a dosage sched-ule of 125–150 mg/m2 every week for 4 weeks followedby a 2-week rest was selected for Phase II trials. TheJapanese investigators used CPT-11 at 100 mg/m2

weekly or 150 mg/m2 biweekly. The dose-limiting tox-icities (DLT) for CPT-11 are delayed diarrhea and neu-tropenia.20 However, strict adherence to a regimen ofloperamide significantly reduced the incidence of di-arrhea.21 Other possible toxicities include nausea/emesis, alopecia, and an early cholinergic-like syn-drome that also may include diarrhea. Phase II trialswith CPT-11 as first-line therapy for CRC showed re-sponse rates between 19 –32% (Table 1).13,22,23 UsingCPT-11 as second-line therapy resulted in responserates of 13–25% (Table 2)24 –26 as well as durable dis-ease stabilizations in a significant percentage of pa-tients. Median survival times for first-line and second-line treatment have been in the range of 9 –12 months.Comparison of results from studies using the weeklyand 3-weekly schedules do not suggest a significantdifference in terms of toxicity or efficacy in second-line therapy. However, it should be noted that thedifferent regimens have not been compared in a pro-spective randomized setting. Two European Phase III

TABLE 1CPT-11 as First-Line Treatment of CRC

Authors (ref) Schedule Patients (no.) Response (95% CI) Median survival (mos)

Conti et al.13 125 mg/m2 weekly 3 4 every 6 weeks 41 32% (18%–46%) 12Pitot et al.22 125 mg/m2 weekly 3 4 every 6 weeks 31 26% (12%–45%) 12Rougier et al.23 350 mg/m2 every 3 weeks 48 19% (9%–33%) 10

CPT-11: irinotecan; CRC: colorectal carcinoma; 95% CI: 95% confidence interval.

TABLE 2CPT-11 as Second-Line Treatment of 5-FU-Resistant CRC

Authors (ref) Schedule Patients (no.) Response (95% CI) Median survival (mos)

Shimada et al.24 100 mg/m2 weekly or 150 mg/m2 twice weekly 52 25% (14%–39%) NAVon Hoff et al.25 100–150 mg/m2 weekly 3 4, every 6 weeks 304 13% 9Van Cutsem et al.26 350 mg/m2 every 3 weeks 455 13% (10%–17%) 9.5

CPT-11: irinotecan; 5-FU: 5-fluorouracil; CRC: colorectal carcinoma; 95% CI: 95% confidence interval; NA: not available.

680 CANCER August 15, 1998 / Volume 83 / Number 4

trials of CPT-11 in second-line therapy recently havebeen completed: CPT-11 versus best supportive careand CPT-11 versus the best estimated 5-FU regimen.These results have not yet been published.

There clearly is much interest in the combinationof CPT-11 and 5-FU. In vitro data indicate synergybetween CPT-11 and 5-FU, particularly when CPT-11is added to the test system first.27 In a Phase I study,coadminstration of 5-FU was reported to have no sub-stantial effect on the pharmacokinetics of eitherCPT-11 or SN-38.28 Various combinations of CPT-11and 5-FU currently are under investigation.28 –31 Pre-liminary results show that both CPT-11 and 5-FU canbe administered near or at the maximum tolerateddose (MTD), and response rates are promising. PhaseIII trials with CPT-11 plus 5-FU as first-line treatmentof advanced CRC are underway.

Topotecan and 9-aminocamptothecinThe results mentioned earlier with CPT-11 obviouslyaroused interest in studies using other camptothecinsin the treatment of CRC. Topotecan is a water-solublecamptothecin derivative with activity in a wide varietyof preclinical models. Its activity is schedule-depen-dent, with a greater therapeutic index using repeatedor prolonged dosage schedules.32 Its main toxicity ismyelosuppression. In studies using topotecan at 1.0 –2.0 mg/m2/day as weekly 24-hour infusions,32 at 1.5mg/m2/day as 30-minute infusions for 5 days,33 or at0.5 mg/m2/day as a continuous infusion for 21 days34

only minor activity was demonstrated in patients withCRC, with response rates of # 10%.

The topoisomerase I inhibitor 9-aminocamptothe-cin (9-AC) was shown to have excellent activity inhuman colon tumor xenografts.35 Unlike CPT-11, it ispoorly water-soluble and requires a lipophilic formu-lation. Based on its pharmacokinetic profile a pro-longed infusion is preferred over bolus infusion.36

Neutropenia is the DLT and correlates with the dose of9-AC and with steady-state plasma concentra-tions.36,37 In a Phase II study using a schedule of 840mg/m2/day (35 mg/m2/hour) by continuous infusionfor 3 days every 2 weeks, no responses were noted in17 previously untreated patients with CRC.38 Phase IIstudies using schedules of longer duration and a PhaseI study with an oral polyethylene glycol 1000 formu-lation39 are ongoing.

OxaliplatinOxaliplatin is a third-generation platinum complexthat has increased therapeutic activity and reducedtoxicity compared with cisplatin.40,41 It binds to spe-cific points in single strand DNA where it blocks rep-lication by inter- and intrastrand crosslinks, resulting

in cell death. 5-FU and oxaliplatin act synergistically;after stabilization of the intracellular 5-FU–thymidy-late synthase (TS) complex by leucovorin, oxaliplatinmakes tumor cells more susceptible to injury by5-FU.42 Oxaliplatin follows a bicompartmental distri-bution and linearity when infused over 2 hours.43

Collective safety data for oxaliplatin as a singleagent or in combination with 5-FU have been com-piled from 682 patients.44 The most frequent DLT wasa cumulative peripheral sensory neuropathy that isreversible after oxaliplatin withdrawal.45 Addition ofoxaliplatin to 5-FU/leucovorin increased the inci-dence and severity of several toxicities.46

Oxaliplatin at 130 mg/m2 infused over 2 hoursevery 3 weeks is being evaluated as a single agent forfirst-line treatment of patients with advanced CRC intwo Phase II European studies, and preliminary re-sponse rates are in the range of 21–24%.47,48 Resultsfrom two Phase II studies in second-line therapy in-volving a total of 106 patients show response rates of10% and a median survival of 8.2 months.49 In a fur-ther dose-escalating study with oxaliplatin at 150 –200mg/m2 in a 5-day continuous infusion schedule, aresponse rate of 12% was observed in second-linetreatment in 25 patients.50

Given the synergistic effects of oxaliplatin and5-FU, emphasis rapidly was placed on the develop-ment of oxaliplatin in combination with 5-FU/leuco-vorin. Phase II studies that investigated differentschedules of oxaliplatin/5-FU/leucovorin, includingchronomodulated infusion of 5-FU, in both pretreatedand chemotherapy-naıve patients have produced re-sponse rates of 46 –58% and median survival times of15–18 months.7,42,45,51,52 Preliminary data from a largePhase III study of 5-FU/ leucovorin with or withoutoxaliplatin in first-line indicated that oxaliplatin sig-nificantly increases the response rate (12% vs. 34%).46

Data on survival are not yet available.

Thymidylate Synthase InhibitorsRaltitrexedRaltitrexed, a water-soluble antifolate agent, is a spe-cific inhibitor of thymidylate synthase (TS). The cyto-toxic activity of raltitrexed is dependent on active up-take into cells via the reduced folate carrier.53,54

Raltitrexed is rapidly and extensively polyglutamatedintracellularly, which accounts for its potency and re-tention. Pharmacokinetic studies indicate a triphasicelimination of raltitrexed with a wide range in themean terminal half-life (8.2–105 hours).55 There is alinear relation between the dose and both the areaunder the curve and the maximum concentration,although there is no clear association between theseparameters and either clinical response or toxicity.

New Drugs in Colorectal Carcinoma/Punt 681

Phase I studies in Europe55 and the U. S.56 recom-mended a starting dose of 3– 4 mg/m2 by short intra-venous (i.v.) infusion once every 3 weeks for Phase IIevaluation. However a dose of 4 mg/m2 subsequentlywas shown to be too toxic in a Phase III trial.57 Themost frequently reported toxicities for raltitrexed inPhase III studies were asthenia, leukopenia, diarrhea,nausea, and emesis.57,58 Diarrhea, leukopenia, andmucositis occurred less frequently in patients treatedwith raltitrexed compared with patients treated with5-FU/leucovorin. Conversely, raltitrexed was associ-ated with a higher incidence of anemia and hepato-toxicity, although the latter was not clinically signifi-cant.

There are no data that show activity for raltitrexedin patients previously treated with 5-FU. In a Phase IIstudy with 177 chemotherapy-naıve patients withmetastatic CRC, a response rate of 26% (95% confi-dence interval, 19%–33%) and a median survival timeof 9.6 months were reported with a schedule of 3mg/m2 given as a 15-minute infusion every 3 weeks.59

Three large Phase III trials involving previously un-treated patients with advanced disease are now com-plete (Table 3).57,58,60 The European trial comparedraltitrexed with 5-FU/leucovorin administered usingthe Mayo clinic schedule.60 In 439 patients this studyshowed no significant difference between the 2 treat-ments in terms of response rate (19% vs. 17%), mediansurvival (10.3 months), or time to disease progression(4.7 months vs. 3.6 months). The North American trialalso compared raltitrexed with the Mayo clinic regi-men of 5-FU/leucovorin in 459 patients.57 The re-sponse rates for the 2 treatments at 12 months’ fol-low-up were comparable (14% and 15%, respectively),although the median survival time was significantlyshorter for the raltitrexed treatment group (9.7 monthsvs. 12.7 months). The international trial that com-pared raltitrexed with 5-FU/ leucovorin (Machover

dosage schedule) in 495 patients reported comparableresponse rates (19% vs. 18%, respectively) and mediansurvival rates (10.7 months vs. 11.8 months) for thetwo treatments.58 A European trial of adjuvant therapywith raltitrexed versus 5-FU/leucovorin in patientswith Dukes Stage C colon carcinoma is ongoing.

CapecitabineCapecitabine is an orally administered prodrug of5-FU. It passes through the intestinal mucosal mem-brane as an intact molecule and then is activated by acascade of three enzymes that results in the intratu-moral release of 5-FU.61 This tumor specific activationenables higher concentrations of 5-FU to be achievedin the tumor compared with normal tissues. Pharma-cokinetic analyses showed good gastrointestinal ab-sorption of capecitabine with extensive conversion tothe main metabolite (59-deoxy-59fluorouridine).61 Theantitumor activity of capecitabine has been demon-strated in vivo in 5-FU-sensitive and 5-FU-resistantmurine tumor models.62 Capecitabine showed im-proved efficacy in human cancer xenografts over 5-FUand uracil/tegafur (UFT).63

In 2 Phase I studies using a continuous adminis-tration for 6 weeks different MTDs of capecitabinewere found (1657 and 2510 mg/m2/day, respective-ly).64,65 The MTD when given intermittently for 2weeks followed by a 1-week rest was 3514 mg/m2/day.66 Side effects were similar to those observed withinfusional 5-FU, including the hand-foot syndrome.DLT were diarrhea, nausea, emesis, mucositis, andneutropenia. Capecitabine also has been investigatedin combination with oral leucovorin in a Phase Istudy.67 In a Phase II study 3 dosage schedules of oralcapecitabine were investigated in 109 patients withadvanced CRC (first-line therapy): 1331 mg/m2/daycontinuous, 2510 mg/m2/day intermittent, and 1657mg/m2/day plus oral leucovorin, 60 mg/day, intermit-

TABLE 3Phase III Studies with Raltitrexed in CRC

Authors (ref) Schedule Patients (no.) Response Median survival (mos)

Pazdur et al.57 5-FU, 425 mg/m2 1LV, 20 mg/m2 daily 3 5, every 4 weeks 210 15% 12.7NS (P 5 0.01)

Raltitrexed, 3–4 mg/m2 every 3 weeks 249 14% 9.7

Harper et al.58 5-FU, 400 mg/m2 1LV, 200 mg/m2 daily 3 5, every 4 weeks 18% 11.8455 NS NS

Raltitrexed, 3 mg/m2 every 3 weeks 19% 10.7 m

Cunningham et al.60 5-FU, 425 mg/m2 1LV, 20 mg/m2 daily 3 5, every 4 weeks 216 17% 10.3NS NS

Raltitrexed, 3 mg/m2 every 3 weeks 223 19% 10.3

CRC: colorectal carcinoma; 5-FU: 5-fluorouracil; LV: leucovorin; NS: not significant.


tent.68 At 12 weeks, the response rates in evaluablepatients were 19%, 28%, and 24%, respectively. Toxic-ity was most frequent in the combination schedule.The intermittent single agent schedule was preferredfor further evaluation.

UFTUFT is a combination of uracil and tegafur. Tegafur isan orally active prodrug of 5-FU. Slow hydroxylationand conversion of tegafur to 5-FU was predicted tomaintain 5-FU levels in the tumor. However, clinicaldevelopment of tegafur as a single agent was discon-tinued in the U. S. because of toxic effects and equiv-alent efficacy compared with 5-FU.69,70 Further re-search has shown that after activation of tegafur to5-FU, uracil may inhibit the activity of hepatic dihy-dropyrimidine dehydrogenase (DPD), thus leading toincreased 5-FU levels. This inhibition occurs predom-inantly in tumor cells, and results in an increase inintratumoral 5-FU concentration. Preclinical studiesin rats have shown the optimal ratio of uracil andtegafur to be a 4:1 molar concentration.71

Results of a Phase I study of oral UFT at 300 –500mg/m2/day showed that UFT at 400 mg/m2/day in 3divided doses in 28-day courses was the optimalschedule.72 UFT showed steep, linear dose-dependentpharmacokinetics with a half-life of 6 –7 hours. Intol-erance to a single daily dose was overcome by using asplit-dosage regimen. The toxicities observed withUFT are typical for the fluoropyrimidines. Responsesin patients failing prior 5-FU treatment were noted.72

In other Phase I studies the recommended UFT dosesfor Phase II testing were 800 mg/m2/day for 5 days and360 mg/m2/day for 28 days, with granulocytopeniaand diarrhea, respectively, occurring as the DLT.73

Pharmacokinetic analyses show the parameters

for UFT plus leucovorin to be comparable to UFTalone, suggesting that leucovorin does not alter thekinetics of tegafur, uracil, or 5-FU.74 In Phase I studieswith UFT plus leucovorin, the MTD of UFT was 390mg/m2/day in a 14-day schedule,75 and 350 mg/m2/day in a 28-day schedule.76 The results of Phase IItrials of UFT/leucovorin69,77-79 are summarized in Ta-ble 4. The overall response rates were 25– 42% in pre-viously untreated patients with a median survival ofapproximately 12–13 months. The complete responserates in these studies ranged between 2% and 9%.Randomized Phase III trials comparing a UFT/leuco-vorin regimen with 5-FU/leucovorin in both the adju-vant setting and in patients with advanced disease areongoing in the U. S.

S-1S-1 is an orally active therapeutic agent combiningtegafur with two modulators: 5-chloro-2,4-dihydroxy-pyridine, an inactivator of DPD, and oxonic acid, aninhibitor of 5-FU phosphorylation in the gastrointes-tinal tract. These agents are used at a molar ratio of1.0:0.4:1.0, respectively.80,81 As with UFT, the aim ofS-1 is to mimic 5-FU prolonged continuous infusion.In human colonic tumor models, S-1 had a higherantitumor activity than either 5-FU or UFT82,83 andwas shown to be highly synergistic with cisplatin.84

Preliminary results from a Phase I study showeffective inhibition of DPD, with diarrhea as the maintoxicity.81 In this study the MTD was 45 mg/m2 givenin 2 daily doses for 4 weeks followed by a 1-week rest.In a Phase II study that used a schedule of 100 mg/dayfor 4 weeks, the response rate was 17% in 30 patientswith CRC.85

TABLE 4Phase I–II trials with UFT/LV in CRC

Authors (ref) SchedulePatients(no.)

Response(95% CI)

Mediansurvival(mos)

Pazdur et al.69 UFT, 300–350 mg/m2 day orallya LV, 150 mg/day orallya for 28 days, every 5 weeks 45 42% (28%–8%) 71Saltz et al.77 UFT, 350 mg/m2/day orallya and LV, 15 mg/day orallya for 28 days, every 5 weeks 20 25% (6%–44%) 121Gonzalez-Baron et al.78 UFT, 390 mg/m2/day i.v. on Days 1–14 and LV, 500 mg i.v. on Day 1 and 15 mg/12 hours on

Days 2–14, every 4 weeks75 39% (28%–51%) 13.5

Feliu et al.79 UFT, 390 mg/m2 day orally on Days 1–14b and LV, 500 mg i.v. on Day 1 and 15 mg/12 hourson Days 2–14, every 4 weeks

38c 29% (15%–46%) 12.5

UFT: uracil/tegafur; LU: leucouorin; CRC: colorectal carcinoma; 95% CI: 95% confidence interval; i.v.: intravenously.a In three daily doses.b In two daily doses.c All patients were age . 70 years.


Biochemical ModulatorsTrimetrexateTrimetrexate (TMTX) is a dihydrofolate reductase in-hibitor. In contrast to methotrexate, TMTX does notrequire enzymatic activation, does not undergo intra-cellular polyglutamation, and does not compete withleucovorin for cellular uptake. Rather it enters cells bypassive diffusion.86,87

As a single agent for advanced CRC, TMTX wasnot or only marginally active.88,89 The most commontoxicities are myelosuppression, diarrhea, and derma-titis.90 Because TMTX enhances the cytotoxic effects of5-FU 91 and those of 5-FU plus leucovorin,87 the se-quential use of TMTX and 5-FU/leucovorin was eval-uated in a Phase I study.92 The main toxicities re-ported for this drug combination were diarrhea andhypersensitivity reactions. The response rate in pre-treated CRC patients was 20%. Based on these resultsa Phase II study was performed in CRC patients usingthe following weekly regimen given for 6 weeks fol-lowed by a 2-week rest: TMTX at 110 mg/m2 i.v. onDay 1, and leucovorin at 200 mg/m2 i.v. and 5-FU at500 mg/m2 i.v. bolus on Day 2 followed by oral leuco-vorin at 7 3 15 mg every 6 hours.93 In 30 evaluablepatients the response rate was 50%, including com-plete responses in 7% of patients. The median survivaltime was 53 weeks. Severe gastrointestinal toxicities(nausea and diarrhea) were common. Preliminary re-sults from a Phase II study using the same regimen in29 untreated CRC patients showed a response rate of38%.94 The true benefit of TMTX/5-FU/ leucovorinversus 5-FU/leucovorin currently is being evaluated intwo randomized multicenter Phase III trials, one in theU. S. and the other in Europe. A Phase II study withTMTX/5-FU/leucovorin in CRC patients with 5-FU re-sistant disease is ongoing.

5-ethynyluracil5-ethynyluracil is a potent irreversible inactivator ofDPD, the rate-limiting enzyme in 5-FU metabolismthat accounts for the elimination of . 80% of theadministered 5-FU dose. Substantial interpatient vari-ability in DPD activity accounts in part for the largeinterpatient differences in the systemic clearance anderratic bioavailability of oral 5-FU. 5-ethynyluracil hasbeen shown to increase the antitumor efficacyand therapeutic index of 5-FU in animal tumormodels.95,96

In a Phase I study of oral 5-ethynyluracil plus i.v.5-FU with or without oral leucovorin the DLT wereneutropenia and diarrhea.97 Clinical responses in CRCpatients were noted. Pharmacokinetic data showedthat 5-ethynyluracil decreases the clearance and pro-

longs the half-life of 5-FU. Another Phase I trial as-sessed several regimens of oral 5-ethynyluracil plusoral 5-FU.98 In this study, 5-ethynyluracil was shownto be nontoxic when administered as a single agent,and it greatly increased the bioavailability of oral 5-FUwith a marked decrease in interindividual variability.Renal excretion appeared to be the principal mecha-nism for 5-FU elimination when given in combinationwith 5-ethynyluracil. The DLT for the combinationwas neutropenia, and this precluded escalation of oral5-FU to doses . 25 mg/m2/day for 5 days in combi-nation with 5-ethynyluracil given at 3.7 mg/m2/day onDays 1–7, every 4 weeks. With this oral 5-FU dose thesystemic exposure achieved was comparable to thatobserved using 5-FU doses of 1000 mg/m2/day for 5days given as a continuous infusion.

Biologic Agents17–1a monoclonal antibodyThe murine IgG2a monoclonal antibody (MoAb)17–1A specifically binds to a cell surface glycoproteinthat is expressed preferentially on adenocarcinomasbut also is found on normal epithelial cells. Preclinicaldata support the view that 17–1A MoAb induces anti-body-dependent cellular cytotoxicity.99 In addition,clinical data support its immunologic activity by theinduction of an antiidiotypic response.100,101 In pa-tients with CRC the antiidiotypic response can be aug-mented further by the addition of granulocyte-mac-rophage-colony stimulating factor, and completeresponses have been demonstrated.102,103 The meanplasma half-life of 17–1A MoAb is between 14.4 and25.3 hours, and the human antimurine antibody re-sponse that occurs in varying degrees was not found toinfluence its pharmacokinetics.104

A randomized trial of 17–1A MoAb versus obser-vation was performed in 189 patients with resectedDukes Stage C CRC.105 17–1A MoAb was administeredat an initial dose of 500 mg i.v. followed by 4 monthlyinfusions of 100 mg. After a median follow-up of 7years adjuvant therapy with 17–1A MoAb significantlyreduced the overall death rate by 32% and the recur-rence rate by 23%.106 Treatment with 17–1A MoAb wasmost effective in the prevention of distant metastases.Toxic effects of 17–1A MoAb were infrequent, with themost common toxic effects being mild gastrointestinalsymptoms. Controllable anaphylactic reactions werereported in only a minority of patients. Two largePhase III adjuvant studies, one comparing 5-FU/le-vamisole versus 5-FU/levamisole/17–1A MoAb andthe other comparing 5-FU/leucovorin versus 17–1AMoAb versus the combination currently are beingconducted in patients with Dukes Stage C colon car-cinoma.


Other DrugsThe thymidine analogue zidovudine was tested in aPhase I-II study in combination with weekly bolusinjections of 5-FU (500 mg/m2) and 2-hour infusionsof leucovorin (250 mg/m2).107 The rationale for thisstudy was provided by the observation that 5-FU-induced inhibition of TS enhances the cytotoxicity ofzidovudine. Among 34 evaluable patients, the re-sponse rate was 44% with 5 complete responses. How-ever, these results need to be confirmed, and furtherstudies with this combination are ongoing.

Other drugs recently have been tested in patientswith CRC, but with negative results. These include thesomatostatin analogue octreotide108; tallimustine, anovel DNA minor groove binder109; edatrexate, amethotrexate analogue110; the addition of interferon-ßto 5-FU111; and several new drugs that have showndefinite activity in other types of cancer such as pac-litaxel,112 docetaxel,113,114 and gemcitabine.115

DISCUSSIONUntil recently, 5-FU has been the only available drugwith consistent activity, albeit moderate, against CRC.Hence, clinical research focused mainly on biochem-ical modulation and new administration schedules of5-FU. Although these developments occasionally haveled to improved response rates or a more favorabletoxicity pattern, to date they have not resulted in ameaningful increase in survival.

Several new TS inhibitors have come available. Ofthese, raltitrexed does not appear to be more effectivethan 5-FU/leucovorin in first-line therapy, but its tox-icity profile and more convenient schedule suggest arole in combination treatment or in the adjuvant set-ting. Studies regarding this use are underway. In com-bination with 5-FU and leucovorin, TMTX showedencouraging response rates in Phase II studies, andPhase III studies currently are ongoing. Other inter-esting TS inhibitors are capecitabine, UFT, and S-1,and responses in CRC have been observed with theseagents. Further studies are necessary to define theirrole in the treatment of CRC. The biochemical modu-lator 5-ethynyluracil may allow the oral administra-tion of 5-FU; however, results of Phase II clinical trialsare not yet available. Because all these new agentshave TS inhibition as their primary target, and eventhe most optimal TS inhibition is likely to have itslimitations in terms of clinical efficacy, studies regard-ing combination treatment with agents that have adifferent mechanism of action appear to be a logicalapproach.

In recent years several such drugs with activity inCRC have become available. Of these, CPT-11 is in the

most advanced stage of development. Based on con-sistent data generated in extensive Phase II studies,CPT-11 currently appears to be a reasonable choicefor 5-FU-resistant or refractory disease. OngoingPhase III studies are evaluating CPT-11 as both first-line and second-line therapy for metastatic CRC. An-other promising agent is oxaliplatin, which showedactivity as first-line and second-line therapy. Futurestudies will address the question of whether drugssuch as CPT-11 or oxaliplatin should be given con-comitantly or sequentially with a 5-FU regimen asfirst-line treatment of CRC.

The 17–1A MoAb showed a survival advantageover no treatment in a randomized trial in patientswith Dukes Stage C CRC. The limited number of pa-tients allowed no conclusions to be reached for thesubgroups of colon and rectal carcinoma patients. Thevalue of this biologic agent currently is being evalu-ated in two large randomized trials in patients withDukes Stage C colon carcinoma. It is expected thatnew immunogenic epitopes in CRC will be identifiedin the future and this will allow further clinical re-search on biologic therapy.

In conclusion, several new agents have showninteresting promise for the treatment of CRC, andchanges in the standard treatment of patients withadvanced or high risk disease appear likely in the nearfuture.

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