Current Strategies in Previously Untreated Advanced Colorectal Cancer

In the past 5 years, the treatment ofmetastatic colorectal cancer hasseen unparalleled advances. Medianoverall survivals reported inphase III trials have almost doubledand are poised to break the 2-yearbarrier very soon, perhaps as early asthis year. This has been made possiblethrough the introduction of a varietyof active agents into the treatmentof this disease.These active agents are classic cytotoxicdrugs such as irinotecan(Camptosar) and oxaliplatin (Eloxatin),but also novel biologics that targetspecific molecular structuresassociated with tumor growth. In fact,colorectal cancer is the first malignantdisease in which the 30-year-oldhypothesis that antiangiogenesis canbe exploited as a therapeutic tool incancer has finally been validated.However, the rapid development inthe medical treatment of colorectalcancer after decades of stasis mightleave some oncologists confused inview of all the available therapeuticoptions.Several Key Points
The article by Drs. Penland andGoldberg outlines the most importantsteps in the development of chemotherapyin advanced colorectal cancerover the past 10 years. All thepivotal trials that added significantknowledge to our understanding ofthe medical treatment of this diseaseare presented in detail. The only shortcomingthe article might have is thatit does not fully discuss the implicationsof the results of those trials forclinical practice. The following keypoints are meant to summarize guidelinesfor everyday practice and highlightcurrent challenges in the treatmentof advanced colorectal cancer.

• Combination regimens with5-FU/leucovorin plus either irinotecanor oxaliplatin have emerged asstandard of care for first-line chemotherapy.There is truly no need to discussthis further.

• Bolus 5-FU/leucovorin protocolsare obsolete.[1] It has been clearlyshown that both the Mayo Clinic andRoswell Park protocols are associatedwith inferior safety profile and lowerefficacy compared with infusional5-FU/leucovorin or capecitabine (Xeloda),in particular when used as thebackbone for combination protocolswith irinotecan and oxaliplatin. ThusIFL, the combination of bolus 5-FU/leucovorin plus irinotecan, should beabandoned in clinical practice and replacedby FOLFIRI. Based on theavailable data, it is conceivable thatpurely infusional oxaliplatin- or irinotecan-based regimens, ie, protocolsthat omit any bolus 5-FU applicationcompletely, confer an even better safetyprofile.

• While capecitabine can alreadybe considered a superior substitute forbolus 5-FU/ leucovorin, it is not yetclear if it can replace infusional 5-FU/leucovorin in combination regimens.The results of ongoing clinical trialswill clarify if capecitabine/irinotecanand capecitabine/oxaliplatin regimenswill be able to replace FOLFIRI andFOLFOX in the future.
• Patients should receive all availableactive drugs in the course of theirdisease to maximize their overall survival.While the optimal sequence ofchemotherapy regimens is debatable,it is clear that patients benefit fromactive second- and presumably thirdlinetherapies.[2]
• The high efficacy associated withmodern combination protocols hasturned advanced colorectal cancer intoa chemosensitive disease in which innovativetherapeutic strategies withcurative intent have emerged. In patientswith disease limited to the liver(perhaps even with additional potentiallyresectable lung metastases), secondarysurgery for metastases afterdownstaging should be considered anintegral part of the therapeutic strategy.No patient should be denied the onlypotentially curative chance he mighthave in the course of his disease.[3]
• Bevacizumab (Avastin) andcetuximab (Erbitux), the two monoclonalantibodies both approved forthe treatment of advanced colorectalcancer in February 2004, constitute agreat challenge. What is the best wayto integrate these agents into currentclinical practice? Fortunately for now,both drugs are approved for very differentclinical settings.

Cetuximab

Because cetuximab was mainlydeveloped as salvage therapy for patientsthat have progressed on conventional,irinotecan-based therapy,the approval follows this label exactly.It has to be emphasized, however,that the actual clinical activity ofcetuximab is quite impressive. Asmonotherapy, it is able to generate aresponse rate of around 10% in patientsrefractory to irinotecan-

and

oxaliplatin-based therapy. In combinationwith irinotecan, the responserate is in the range of 20%. This comparesvery favorably to the efficacyreported for FOLFOX after IFL (10%response rate).[4,5]

Bevacizumab

Based on the convincing proof ofefficacy when added to IFL and bolus5-FU/leucovorin as first-line treatment,bevacizumab has been approvedfor the use in the first-line setting incombination with any intravenous5-FU-based therapy.[6] This labelopens the door for a combination thathas not yet been tested in first line:FOLFOX plus bevacizumab.While safety data on FOLFOX plusbevacizumab have become availablethrough an interim analysis of the second-line Eastern Cooperative OncologyGroup trial E3200, it is an openquestion if bevacizumab will add significantefficacy to FOLFOX in thesame way it did to less active cytotoxicregimens (IFL and bolus 5-FU/leucovorin).However, not least basedon the molecular mechanism of actionof bevacizumab, it is conceivableits enhancement of activity is independentof the cytotoxic combinationpartner used. Thus, the clinical approachto combine the best availablecytotoxic protocol with the best availablebiologic agent in the first-linesetting makes sense. In fact, as of thetime of this writing (April 2004), about40% of all bevacizumab is used incombination with FOLFOX-in theabsence of confirmatory data!If we postulate that bevacizumabwill add a similar incremental benefitto FOLFOX as it did to IFL-in particular,in terms of time to tumor progression-a distinct clinical problememerges: Hypothetically, the mediantime on treatment could now exceed 12months. However, 12 months of therapywith FOLFOX would mean a cumulativeoxaliplatin dose of over 2,000mg/m

²

if FOLFOX were used continuously.It is quite obvious that this cumulativedose is not tolerable by mostpatients. Thus, innovative treatmentstrategies have to be developed.The most promising approach tosolve this problem has already beenstudied in the OPTIMOX trial.[7] Ithas been shown that it is clinically feasible,and does not compromise overallefficacy, to stop oxaliplatin after a certainnumber of induction cycles up to apredefined cumulative oxaliplatin dose.The achieved response or stable diseasecan then be maintained by a non-oxaliplatin-containing regimen. Thisconcept, though, will have to be validatedin a randomized trial under inclusionof bevacizumab.

Conclusions

In view of the great variety of therapeuticoptions in advanced colorectalcancer, the key question for allclinical trials has moved from, "Whatis the best X (first-, second-, etc)-linetherapy?" to "What is the best overalltreatment strategy?" If we make useof all available resources and treatmentmodalities, we will turn metastaticcolorectal cancer into a chronicdisease; there will be significant (positive)implications for patients, but alsopharmacoeconomic consequences thatwe are only beginning to understand.Along this way, we as medical oncologistswill have a lot to learn-for thebenefit of our patients.

Disclosures:

The author receivesresearch support from Sanofi-Synthelabo andRoche. He is on the speaker's bureaus of Sanofi-Synthelabo, Genentech, Roche, and Bristol-Myers Squibb.

References:

1.

Saltz LB: Another study of how to givefluorouracil? J Clin Oncol 21:3711-2, 2003

2.

Grothey A, Sargent D, Goldberg RM, etal: Survival of patients with advancedcolorectal cancer improves with the availabilityof fluorouracil-leucovorin, irinotecan, andoxaliplatin in the course of treatment. J ClinOncol 22:1209-1214, 2004.

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Adam R: Chemotherapy and surgery: Newperspectives on the treatment of unresectableliver metastases. Ann Oncol 14(suppl 2ii):13-16, 2003.

4.

Cunningham D, Humblet Y, Siena S, etal: Cetuximab (C225) alone or in combinationwith irinotecan (CPT-11) in patients with epidermalgrowth factor receptor (EGFR)-positive,irinotecan-refractory metastatic colorectal cancer(MCRC) (abstract 1012). Proc Am Soc ClinOncol 22:252, 2003.

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Rothenberg ML, Oza AM, Bigelow RH,et al: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapyalone in patients with progressive colorectalcancer after irinotecan and fluorouracil-leucovorin:Interim results of a phase III trial. J ClinOncol 21:2059-2069, 2003.

6.

Hurwitz H, Fehrenbacher L, CartwrightT, et al: Bevacizumab (a monoclonal antibodyto vascular endothelial growth factor) prolongssurvival in first-line colorectal cancer (CRC):Results of a phase III trial of bevacizumab incombination with bolus IFL (irinotecan, 5-fluorouracil,leucovorin) as first-line therapy insubjects with metastatic CRC (abstract 3646).Proc Am Soc Clin Oncol 22, 2003.

7.

Andre T, Figer A, Cervantes A, et al:FOLFOX7 compared to FOLFOX4. Preliminaryresults of the randomized optimox study(abstract 1016). Proc Am Soc Clin Oncol22:253, 2003.