Dr. O’Connell has done a remarkablejob of discussingmodalities available for patientswith intermediate- to high-riskfully resected large bowel malignancies.Indeed, the title “Current Statusof Adjuvant Therapy for ColorectalCancer” is an underestimate of thearticle’s contents, as he nicely detailsthe past development of standard-ofcareadjuvant (and neoadjuvant, whenappropriate) treatments as well. As isclearly pointed out in the article, adjuvanttherapy works. Adding fluorouracil(5-FU) with or without radiationto surgery already saves thousandsof lives each year, and the enticing possibilityof throwing newer chemotherapeuticagents (eg, oxaliplatin)and/or targeted therapies (bevacizumab[Avastin]) into the mix makespotential future successes even greater.
Dr. O'Connell has done a remarkablejob of discussingmodalities available for patientswith intermediate- to high-riskfully resected large bowel malignancies.Indeed, the title "Current Statusof Adjuvant Therapy for ColorectalCancer" is an underestimate of thearticle's contents, as he nicely detailsthe past development of standard-ofcareadjuvant (and neoadjuvant, whenappropriate) treatments as well. As isclearly pointed out in the article, adjuvanttherapy works. Adding fluorouracil(5-FU) with or without radiationto surgery already saves thousandsof lives each year, and the enticing possibilityof throwing newer chemotherapeuticagents (eg, oxaliplatin)and/or targeted therapies (bevacizumab[Avastin]) into the mix makespotential future successes even greater.While it thoroughly reviews thelandmark adjuvant trials and reliablydiscusses the general outcomes by arm(eg, "This study [MOSAIC] demonstrateda significant improvement in3-year disease-free survival for patientswho received...FOLFOX comparedto...5-FU plus leucovorin"), space precludesa discussion of the magnitude ofbenefits in Dr. O'Connell's article.Thus, readers should pull the referencesand read the original publicationsthemselves. This will likely lead to aneven greater appreciation for what hasbeen achieved by investigators overthe past 20 or so years.Dose and Scheduleof 5-FU and Leucovorin
Dr. O'Connell addresses many ofthe controversies in adjuvant therapyfor colorectal malignancy, such aswhether or not to offer treatment toresected stage II colon cancer patients.However, there are several remainingquestions. One concerns the appropriatedose of leucovorin. Leucovorinis an excellent 5-FU modulator, andDr. O'Connell states that the additionof leucovorin to 5-FU improves efficacy(response) in metastatic disease.Indeed, a recent update of the meta analysis he references suggests a survivalimprovement as well.Currently, 5-FU plus leucovorin isalso the standard-of-care colon canceradjuvant regimen. However, thebest dose and schedule of leucovorinfollowing resection of colon cancerare rarely discussed by American authorsand editorialists. In general, leucovorin(given with 5-FU) can begiven at a low (usually 20 mg/m2) orhigher (175 to 500 mg/m2) dose, andit can be administered on a weekly ordaily * 5 (usually every 4 to 5 weeks)basis.In metastatic disease, there are nooverall survival differences when oneuses 5-FU with weekly low-dose leucovorin,weekly high-dose leucovorin(Roswell Park regimen), or daily* 5 low-dose leucovorin (the Mayoregimen). However, due to severe toxicitiesassociated with that dosingschedule, the Mayo regimen is essentiallyno longer used to treat eithermetastatic or micrometastatic (ie, adjuvant)disease. There is also no reasonto use the Roswell Park regimenfor advanced disease, as the higherleucovorin dose is not more efficacious,but it is more expensive; it isalso associated with higher rates ofsevere diarrhea. Strangely, NorthAmerican cooperative groups havetested Mayo against Roswell Park inadjuvant trials (thus changing bothdose and scheduling of theleucovorin), demonstrating equivalentefficacy, but a low-dose weeklyleucovorin-containing regimen has notbeen tested in the United States.The QUASAR (Quick And SimpleAnd Reliable) Group from Birminghamin the United Kingdom hastested the efficacy of low-dose (25mg/m2) vs higher-dose (175 mg/m2)leucovorin with 5-FU, allowing weeklyor daily * 5 administration. Therewas no efficacy improvement for patientsgetting high-dose leucovorin oneither schedule. Thus, most US oncologistscontinue to use the RoswellPark regimen even though there arerandomized trial data to suggest thatusing weekly 5-FU with low-dose leucovorinas adjuvant therapy for resectedcolon cancer is a safe and effectivestrategy.The Role of Radiation Therapyin Colon Cancer
Dr. O'Connell appropriately statesradiation therapy plays a "very limited"role following resection of proximallarge bowel cancers. However,local recurrence even of colonic tumorscan certainly be problematic,particularly if there are a number ofinvolved regional lymph nodes, or ifthe primary tumor is deeply invasive(T4 disease). The North Central CancerTreatment Group performed aphase III randomized trial of 5-FUand levamisole (Ergamisol) with orwithout irradiation in high-risk coloncancers (tumor adherence or invasionof surrounding structures, or T3, N1-2 disease). This trial closed earlydue to poor accrual, and its initialpublication reported that the radiationtherapy did not significantly improveoutcome over the chemotherapyalone. Indeed, review of theactual survival data shows patientson the radiation arm had a slightlyworse outcome. The updated manuscriptfor this trial has been submitted,but it is unlikely its conclusionswill change. Despite the negative result,this study was not really definitive;the question of whether or not toirradiate these patients (a practicewhich is frequently offered, at leastin T4 disease) may remain foreverunanswered.Clinical Trial Design
What is the most expeditious wayto do large-scale, randomized, adjuvantclinical trials in colorectal cancer?In general, standard phase IIItrials, with 5-year survival as theirprimary objective, require long periodsof follow-up. The MOSAIC trial,discussed in detail by Dr. O'Connell,used 3-year disease-free survival asan end point. Certainly several trialswith this potential objective couldbe performed in the time it takes to doone study utilizing 5-year overall survivalas its primary end point. Is3-year disease-free survival a reliablesurrogate for 5-year overall survival?A sophisticated statistical analysisaiming to answer that question, usingpatient data from a number of largetrials, is under way.New Chemotherapeutic Agents
What do we do with new chemotherapeuticagents? In the metastaticsetting, oxaliplatin (Eloxatin) plusinfusional 5-FU and irinotecan, incombination with bolus (Saltz) or infusional5-FU, are all more effectivethan 5-FU/leucovorin alone. However,the addition of oxaliplatin to infusional5-FU (FOLFOX4) improves theoutcome in adjuvant treatment of coloncancer (MOSAIC, discussed aboveand by Dr. O'Connell). But surprisingly,adding irinotecan to bolus5-FU does not improve cure rates.We also know that FOLFOX4 ismore effective than the Saltz regimenin metastatic disease, but regimensusing irinotecan with infusional 5-FUappear equally effective as FOLFOX. Thus, it is possible that usinginfusional 5-FU with irinotecan,or using capecitabine (Xeloda) withthe latter agent, will be better than5-FU/leucovorin alone in the adjuvantsetting. The V307 (infusional5-FU with or without irinotecan) andQUASAR 2 (irinotecan with capecitabine,3- or 6-month duration, vs bolus5-FU plus leucovorin) trialsrespectively will answer those questions,but data from those studies arenot yet available.Radiation in Rectal Cancer
Rectal cancer is slightly simpler.Patients with stage II or III resectedtumors need some type of adjuvanttherapy. While we now know that neoadjuvantchemoradiotherapy is betterthan postoperative treatment, at leastin terms of toxicity, the question remainswhether the irradiation componentis always necessary. Dr.O'Connell's article somewhat downplaysthe National Surgical AdjuvantBreast and Bowel Project's R-02 trial,which compared postoperative adjuvanttherapy with 5-FU-basedchemotherapy, with or without radiation(5,040 cGy), in patients with resectedstage II and III tumors. Theradiation added no disease-free oroverall survival benefit, but it did decreasethe cumulative incidence of localrelapse from a relatively low 13%to an even lower 8%. Thus, it seemsreasonable to treat patients felt to beat low risk of locoregional relapse(T3, N0 disease) with chemotherapyalone. It is also possible that the resultswith chemotherapy alone maybe even better (both locally and distantly)when oxaliplatin and targetedagents make their way into standardtreatment of rectal cancer, as they almostcertainly will.Conclusions
This is an extraordinary time to bea colorectal oncologist. No new drugswere approved in this disease between1962 (5-FU) and 1990/1991 (levamisole/leucovorin). In the past 8 years,however, five new agents were suddenlyregistered. However, Dr.O'Connell is correct in saying that weshould not be satisfied. Median survivalfor advanced neoplasms willlikely break the 2-year barrier soon,and even incremental gains made inmetastatic disease should translate intohuge improvements in cure rates whensimilar regimens are used in adjuvantpatients.
The author is a consultantfor Pfizer. He also is on the speaker’sbureau and receives grant support (pending).
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