VIEWS & REVIEWS

Coloredal cancer: old challenges, new issues

·Jul ie Daniels -

Although modulated Ouorouracil is still the mainstay of antineoplastic treatment for colorectal cancer, it is DOW

j oined by newer therapeutic approaches, including the use of topoisomerase I Inhibitors and spttmc thymidylatesynthase inhibitors. Recent pbase m data on the thymidylate synthase inhibitor Tomudex«l[ZD-1694] have shownthat the efficacy of this agent is comparable to that oftbe Mayo regimen (fluorouracil + calcium foUnate). Theresults of this study, and other news relating to improved therapy for colorectel cancer, were presented at a Zeneca·sponsored symposium held at the 8th European Cancer Confe rence [ECCO 8; Paris, Fran ce; November 1995].

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O>Ioredal cancer- the dJaDmgeColoreceal cancer is the second-most common

malignancy in the Western world. Over the last 30years, improved surgical techniques and early diag­nosis have markedly increased the S-year survival ratefor this malignancy from 43% in the early 1960s. to61% in the 19805. Further advances have also beenmade with the introduction of adjuvant treatment,which has demonstrated significant survival benefitsin Dukes stage B and C disease.': 2.'

More re cently, the benefit s of ch emotherapy inthe tre atment of advanced disease in terms of survival,palliative benefits and qu ality of life have beenrea lised.· ·5 However, Professor H Bleiburg from theInsti tut Jules Bordet, Brusse ls, Belgium. explainedthat. despite these advances, further progress isneeded in the treatment of this disease. focusing onthe implementation of a multidisciplinary approachto patient care, increased patient referral, and thedevelopment of new drugs.

Jnaeasing the eIJicacy oCOuorouradlFluorouracil is current ly the mai n antineoplastic

agent used in the treatment of colorectal cancer.However, Dr R La bianca fro m San Carlo BorromeoHospital. Milan. Ital y. ex plained that the re spon serate typ ically achieved with bolus fluorouracil mono­the rapy in the treatment of advanced disease islimited. at on ly 10%, with an overall survival of< 12 months.

Thi s has led to the use of biochemical modulatingagents. such as calcium folinare [folinic acid:leucovorin], interferon-a and methotrexate to increasethe efficacy of fluorouracil. It has also led to theinvestigation of different do sing schedules.

The most widely investigated regimen isfluorouracil plus calcium folinate, which was shownto be significantly superior to fluorouracil alone interms of respon se rate (23 % for the combi ned ann),but not overa ll survival. in a met a-analysis. However.the best adminis tratio n sched ule is still undefined,and the dose of calcium fo Hnate ne cessary for optimalfluorouracil mod ulation is currently a co ntentiousissue.

Ibmudex"'-larg<Uing thymidylate syntha5eFollowing on from the promising phase II study

results reported with the direct thymidylate synthaseinhibitor Tomudex· [ZD-1694; zenecaj ' in advanced: olorectal cancer,ooProfessor D Kerr from the CRC

- Tomudo!' if~ ill IN UKfor thejim.W I1rQImnfI if"""'='-~

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Institute for Cancer Studies, Birmingham, UK.reponed the results of a large, randomised, phase IIIcomparative study.

'Thble r.F.fIlcacy or Tomudu~ in advancedcoIorectaI cancer (p base ill data)

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• Odd& ratio 1.7 (O~.81 1: D.. 0.059

IV Tomudex'" 3 mg/m2 for IS minutes every3 weeks was compared with the Mayo regimen(bolus fluorouracil plus low-dose ca lcium foli natefor 5 days, repeated every 4--5 weeks). All patientsentered into the srudy had previously untreatedadvanced colorectal cancer. According to the studyresults:• Tomudex· was at least as effective as the Mayo

regime n in terms of overall response rate [seetable 1]

• both treatment cohorts showed improvements inquality-of-life scores and palli ative benefits ( I S vs12% for weight gain, and 34 vs 25% for performancestatus, in the Tomude x· and Mayo regimen groups,respectively)

• the time spent in the healthcare facility for treatmentadministration was markedly shorter with Tomudex·(0.7 vs 3 days. for the Tomudex· and Mayo regimens.respectively)

• patients treated with Tomudex· experienced asignificantly lower incidence of grade 314 mucositis(2 vs 22%) and leucopenia (10 vs 26%) comparedwith the Mayo regimen-treated patients

• theTomudex· cohort ex perienced a significantlyhigher incidence ofelevated liver transaminaseactivity (10 vs 0%) compared with Mayo regimenrecipients, but this effect was usual ly reversibleand asymptomatic .

Alook at health economic ........ ..In the field of co lorectal cancer there is a need

for economic evaluation an d the measurement ofeconomic parameters in multicentre. randomisedtrials. to establish the pote ntial impact of new treat­ments on resource utilisation. With thi s aim in mind.Mr K Torfs from the European Organisation for theResearch and Treatment of Cancer (fORTe) HealthEconomics Unit, Brussels, Belgium. described thepreliminary results of a study designed to gai n insightinto the overall resource ut ilisation for the treatmentof advanced co lorectal cancer.

4 V IE WS & R E VI EWS

Colorectal cancer: old challenges, new issues - continued

The study is based upon the retrospective cell­ection of resource utilisation data from 200 consec­utive patients in 10 European hospitals. and will beaccompanied by a pro spective: study focusing on theec onomic burden of me: di sease from the: patients'perspective:. The key preliminary findings fo r 140patients in 7 hospitals indicate that there is:• a lack of unifo rm treatment panerns• a wide variation in the use of chemotherapy,

with 50% of patients receiving no chemotherapy• a high rate of hospitalisation (mean 42 days)• potential for improved efficiency.

••• and auditA study has been conducted at the Royal Marsden

Hospital, London and Surrey, UK. to determinethe tota l cost of fluorouraci l-based chemothera pyregimens in th e treatment of advanced co lorectalcancer at a major oncology centre. Dr P Ros s ex ­plained that the case records and prescription chartsof selected pati ents were: audited retrospectively, andtha t 3 regimens were studied .

• Mayo regimen.• De Gramont regimen (bolus fluorouracil plus

high-dose calcium folinate followed by a 22-hoorinfusioo of fluorouracil for 2 days. repeated every2 weeks).

• Continuous infusion fluorouracil.For all 3 treatment regimens. drug costs were a

relatively smal l proportion of total treatment costs(see table 2].

Table 2. Monthly total costs (medJan in £)Cor various fluorouracU regimens

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~drug$ " 386 96

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A glimpse of the future:nooalIDJlllI'll studies •••

Dr H Schmoll from the Medical University.Hannover. Germany, described several approachesthat are currently being investigated for the tr eatmentof co lorectal cancer in phase 11 studies .

lrinotecan [CPT. 1I I' produces objective re pon serates of 2 1% in chemptberepy-nelve patients andabout 18% in pretreated patien ts refractory tofluorou racil with or witho ut ca lcium folinate .However, the high incidence of severe neutropenia

t Jrinot«:otlhas~ launc:NxJ ill!Frona ar aSit!ICmd-1ine~foradvmctJc:oIorec:rol (l!lrIQ!T

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and delayed diarrhoea. and the risk of infectiousco mplications with irinotecan, are problematic - strictsupporti ve measures are required to manage theseadverse events.

Efficacy levels that are significantly higher thanthose associated with bol us fluorouracil have beenachieved using high-dose continuous infusionsof fluorouracil + calcium folinate . However. nosignificant differences in survival benefit have beenseen. Clinical studies are ongoing to furthe r investi­gate the impact on survival of continuous infusiontherapy.

Oxaliplatin has produced promising results in co m­bination with fluorouracil plus calcium folin ate asfirst- line the rapy. A range of dos es and admi ni strationschedules have been investigated. Response ra teshave varied be tween 40 and 70 %. The combinationhas also shown som e efficacy as second-line therapyin patients refractory to fluorouracil plus calciumIclmere, with a respoose rate of approximately 50% .

•••and new diredion<;

The spec trum of new developments for the treat­ment of colorecrel cancer is wide and promising.according to Dr E van Cutsem from UniversityHospital Gasthuisberg. Leuven, Belgium. and shou ldlead to better patient care together with improvedprognosis and survival. The thymidylate synth aseinhibitors, for example, Tcmudexs , LY-231514.AG-33 ] and AO-337. have demonstrated a widespectrum of activity against a number of cancer ce llline s. and will hopefull y be active agai nst a range ofhuman cancers.

Interesting ac tivity has also been reported withtopoisomerase I inhibitors, most notably irin otecan•and also 9·ami nocamptomecin and 0 1- ]4721] .Strategies aimed at enhancing the therapeu tic efficacyand improving the selectivity of fluorouracil have ledto the development of the dehydrogenase inhibitor5-ethi nyluracil. and the fluorou racil prodrugs. tegafur[norafur] and capecitabine.

Immunotherapy is also being investigated. withthe monoclonal antibody 17·1A currently underfurther investigatio n for the adjuvant treatmentof colon cancer, Additional in vestigations are alsoongoing to evaluate the use of antibody-directedprodrug therapy (AD EPT) to generate a cytotox icagent from a nontoxic prodrug at the tumoursite.

L MocrId.co. e.aI.f"Iuon:uvjJ plus~ • elra:tioc adju-. lbcnp)' aftao.-.:lioIl of aap m cob>~ alillll rq:ut. AIlPllIs ofll=mil MedC>c122: 321-326, I M¥ IWS 1. \\\::lllrwlr.N, etal. lbcbcndilol~IJIOdWalcd fb.Ioro\lr3ciI ..~\'Cadju~~ \bInpy b primary "'*'"~ fallhs fu:m NarionalSWJic&l Adj u~..n BTa.SI and Bowel~pt:ltoX<Il c.m.Journalol Oinital 0Iw;01oD I I: 1879-1&87, Oct 1993

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