Update on Chemotherapy for Advanced Colorectal Cancer

ABSTRACT: Efforts to improve the length and quality of life, as well as toexpand treatment options, for patients with metastatic colorectal cancer haveonly recently become more successful. With maximization of dose and scheduleschemes for fluoropyrimidine therapy, new drugs such as irinotecan (CPT-11,Camptosar) and oxaliplatin have also become part of the standard therapy forpatients. Combination chemotherapy has been established to have superiorresponse rates and progression-free survival and—in some instances, forfluorouracil and irinotecan combinations—improved overall survival compared tofluorouracil alone. There is still much to be learned about the optimalmanagement of patients with colorectal cancer, including the role of second- andthird-line chemotherapy in the overall survival outcome, and the role of salvagetherapy in patients with limited metastatic disease. Most importantly, thedevelopment of a biological marker of prognosis and response should help toselect appropriate chemotherapy programs for patients on a rational andindividual basis, not only in the setting of metastatic disease, but also in theadjuvant population. [ONCOLOGY 15(Suppl 5):11-15, 2001]

Introduction

During the past decade, morechanges in the management ofcolorectal cancer have come about than in the previous half-century of clinicalresearch. Such changes include the establishment of adjuvant treatment forpatients with high-risk stage II and III colorectal cancer, in addition to newapproaches to managing advanced disease. Previously, there was much nihilism inthe management of these patients. This translated into low expectations ofbenefit from systemic chemotherapy or multimodality approaches, which couldpossibly extend the life of a patient with metastatic disease and also possiblycure some patients.

The past decade of clinical research in colorectal cancer hasalso sparked discussion about establishing appropriate end points of clinicalbenefit from chemotherapy. The gold standard for regulatory approval in theUnited States is an overall survival advantage with treatment. Previously, onlythe addition of leucovorin to fluorouracil (5-FU) was approved on this basis. Inaddition to overall survival, many investigators think that progression-freesurvival—if properly measured—could provide a surrogate of treatment effectin clinical trials and also a measure of clinical benefit for patients.

This has not been a universally accepted end point, however, andis not currently used for approval of oncologic drugs in the United States.Although clinical investigators have depended on response rates to establishinterest in a treatment program, this measure is associated with widevariability and thus may not be dependable for establishing patient benefit,particularly in retrospective analyses. Furthermore, measures of quality of lifehave generally fallen short of establishing clinical benefit of treatment. It isin the setting of this controversy that new treatments are being assessed, atleast one of which has achieved the gold standard for approval in the UnitedStates, namely the addition of irinotecan (CPT-11, Camptosar) to fluorouracil(5-FU) and leucovorin for first-line therapy of patients with metastaticcolorectal cancer.

Fluoropyrimidine Therapy

Until recently, various methodologies of systemic 5-FUadministration have represented not only the standard of practice but also thestandard of care in clinical trials for patients with metastatic disease. Thedevelopment of optimal treatment programs has been both arduous and long.Ansfield and colleagues reported a phase III trial comparing four different 5-FUregimens in 1977.[1] Results of this early trial suggested that loading course(ie, repetitive daily dosing) 5-FU, with moderate toxicity, was superior to aweekly intravenous (IV) schedule, a nontoxic IV schedule, and an oral schedule.In the latter part of the 20th century, countless patients participated inclinical trials comparing various doses and schedules of 5-FU, with and withoutnew drugs.

Perhaps the most significant change in 5-FU use for metastaticcolon cancer was the development of biochemically modulated regimens withleucovorin. Leucovorin stabilizes the ternary complex with fluorodeoxyuridinemonophosphate (FdUMP) and the enzyme thymidylate synthase. The combination of5-FU and leucovorin has been compared with bolus 5-FU alone. A meta-analysis ofthe randomized trials demonstrated a significantly improved response rate with5-FU and leucovorin but no significant improvement in overall survival.[2]

A standard regimen for the treatment of metastatic colorectalcancer has been the Mayo Clinic regimen, in which 5-FU and leucovorin areadministered for 5 consecutive days every 4 weeks for two cycles, followed bythe same regimen every 5 weeks. Results from the first two trials conducted atthe Mayo Clinic and the North Central Cancer Treatment Group (NCCTG) showedresponse rates of 43% and 35%, and median survival times of 12.7 and 9.3 months,respectively.[3,4] With further study, response rates with the Mayo Clinicregimen have ranged from 11% to 19%, and median survival times from 9.2 to 13.1months.[5-7]

Continuous-Infusion vs Bolus 5-FU

Both the efficacy and toxicity of 5-FU depend—to some degree—onthe drug dose and schedule and whether leucovorin is administered concurrently.Early in the use of 5-FU, it was observed that the toxicity profile ofcontinuously infused 5-FU was different from that of bolus regimens, eg,decreased myelosuppression and mucositis but increased dermatologic toxicities,including hand-foot syndrome. An early clinical trial by Seifert et al comparingcontinuously infused 5-FU with bolus injection demonstrated this toxicitydifference and also suggested an improved clinical benefit with infusional 5-FUin terms of response and survival rates.[8]

A subsequent meta-analysis of six randomized trials ofcontinuously infused 5-FU was published in 1998.[9] Results were similar tothose obtained with the addition of leucovorin to 5-FU, with an improvement inresponse rate from 14% to 22% (P = .0002), but only a marginal improvement inoverall survival from 11.3 to 12.1 months (P = .04). The incidence ofhematologic toxicity significantly decreased and hand-foot syndrome increasedwith infusional 5-FU.

Many infusional 5-FU regimens are currently in use. One of thefirst regimens developed is a true continuous-infusion program, in which 5-FU at300 mg/m² is administered for more than 4 weeks or until significant toxicityoccurs.[10] Alternative regimens have also been developed, including a high-dose24-hour regimen known as the AIO regimen or Andolan regimen, with 5-FU dosesranging from 2,000 to 2,600 mg/m².[11] This regimen has also been combined withleucovorin.

Results of a large trial comparing the 24-hour infusionalregimen, with and without leucovorin, to the Mayo Clinic regimen were recentlyreported.[12] The findings suggested that the infusional approach improvedresponse rate and time to treatment failure, with an increase in toxicity whenleucovorin was added, but with no significant improvement in survival.

Another commonly used regimen combines bolus and infusionaladministration, as devised by de Gramont and colleagues.[5] Bolus 5-FU andleucovorin are administered on the first and second days of a 2-week cycle, with22-hour 5-FU infusions after each bolus dose. This regimen has been compareddirectly with a Mayo Clinic-type regimen in which bolus therapy wasadministered every 4 weeks.[5] A significantly better response rate (32.6% vs14.4%) and improvement in progression-free survival resulted from the infusionapproach; however, overall survival was similar with the two regimens (14.3 vs13.1 months, P = .067).

Infusional approaches, therefore, have not consistently improvedoverall survival but have been associated with higher response rates, longertime to tumor progression, and a toxicity profile more suitable than that ofbolus regimens for combination with myelosuppressive drugs. An open question,which will be addressed in another paper in these proceedings, is whether oralfluoropyrimidines will offer the clinical benefit of infusional 5-FU while alsoimproving patient acceptance.

Based on an overview of either biochemically modulatedfluorouracil with leucovorin or methotrexate or continuous-infusion 5-FU, thereis a consistent trend toward improved response rate with newer regimens usingother than bolus 5-FU alone.[2,9] However, the impact on overall survival fromthese changes has been modest, with an overall survival hazard ratio of 0.90(0.84, 0.97) compared with bolus 5-FU alone. These data strongly suggest thatfurther studies of fluoropyrimidine therapy alone are unlikely to show theclinical benefit desired for optimal management of metastatic disease.

Irinotecan

Irinotecan is a topoisomerase I inhibitor that has a mechanismof action different from that of fluoropyrimidines. In previously treatedcolorectal cancer patients, irinotecan at 125 mg/m² weekly or 350mg/m² every 3weeks resulted in response rates of 15.0% and 12.1%, respectively.[13] Thissingle-agent activity is comparable to that observed in patients treated withfluoropyrimidines. In early phase II trials, the toxicity of single-agentirinotecan included manageable myelosuppression and diarrhea. Although diarrheamay be dose-limiting, in the clinic it is usually quite manageable withaggressive loperamide use.

Single-Agent Activity

Based on the early phase II data and on the anticipated resultsof second-line trials of irinotecan in 5-FU-refractory patients, irinotecanwas approved in the United States in 1996 for the treatment of colorectalcancer. Approval was initially limited to 5-FU-refractory disease, but resultsof two further landmark studies led to its approval as for second-line therapyin 1998.

In the first of these trials, patients who had failed bolus 5-FUtherapy were randomly assigned to receive irinotecan plus best supportive careor best supportive care alone.[14] The study end point was improvement inoverall survival, which was achieved. Median survival was 9.2 months in theirinotecan-treated group and 6.5 months inthe best supportive care alone group (P = .00001). Quality-of-life measures suggested that this improvement insurvival was achieved without increasing toxicities significantly.

In the second trial, patients who had failed bolus 5-FU wererandomly assigned to receive irinotecan or one of three infusional 5-FUregimens.[15] Median survival was 10.8 months in irinotecan-treated patientscompared with 8.5 months in fluorouracil-treated patients (P = .035). Based onthe known modest activity of infusional 5-FU in patients who have failed bolustherapy, it was not surprising that the overall survival advantage of irinotecanwas somewhat less than in the previous study. Nevertheless, both achieved theclinical trial objective for patients with advanced disease, which wasimprovement in overall survival. Since 1998, irinotecan has been the standardsecond-line therapy for 5-FU refractory patients with advanced colorectal cancerin the United States and much of the world.

Combination Chemotherapy

Given irinotecan’s single-agent activity and its differentmechanism of action compared to 5-FU, combinations of these agents, typicallyalso with leucovorin, were assessed in phase I and II trials. Of severalregimens that were developed, one used bolus 5-FU and leucovorin for 4 weeks outof 6, with irinotecan also administered on the same days.[16] In anotherregimen, infusional 5-FU was administered with biweekly irinotecantreatment.[17] Using these regimens, two phase III prospective randomizedcontrolled trials evaluated the combination of 5-FU, leucovorin, and irinotecanvs 5-FU and leucovorin alone. The first of these pivotal trials compared bolus5-FU, leucovorin, and irinotecan with bolus 5-FU and leucovorin alone.[18] Athird arm of irinotecan alone was also included.

More than 200 patients were entered into each study arm. Theprimary end point was progression-free survival. Results showed that thecombination was superior in terms of response rates, time to tumor progression,and overall survival rates.[18] Response rates were 39%, 21% , and 18% withcombination treatment, 5-FU/leucovorin, or irinotecan, respectively; this washighly significant in favor of the combination. Time to tumor progression (7.0vs 4.3 months; P = .004) and median survival (14.8 vs 12.6 months; P = .042)were also significantly improved with the combination, compared with5-FU/leucovorin alone. Once again, the available data suggest that theseimprovements were achieved without a substantial decrement in overall quality oflife or increased toxicity.[19]

The second pivotal trial of combination chemotherapy withirinotecan compared two different regimens of infusional 5-FU and leucovorin(either the AIO or the de Gramont regimen).[20] Irinotecan was administeredweekly or biweekly according to the 5-FU schedule. This trial also demonstratedimproved response rate, time to tumor progression, and median survival forpatients receiving the irinotecan combination. Median survival, the mostimportant end point, was 17.4 months with the combination vs 14.1 months withfluorouracil and leucovorin (P = .032).

A combined survival analysis of these two trials was recentlypresented at the American Society of Clinical Oncology (ASCO) meeting.[21]Combined survival for the irinotecan/5-FU/leucovorin regimen was 15.9 months,and for the nonirinotecan regimen, 13.3 months (P = .003; survival hazard ratio,0.79). Notably, a significant proportion of patients in both trials who wereassigned to 5-FU and leucovorin alone subsequently received second-lineirinotecan. Despite this crossover, a survival advantage was maintained,suggesting that sequential chemotherapy for advanced colorectal cancer may notbe as effective as combination first-line treatments.

Analyses have also been undertaken to determine which patientsbenefit most from combination chemotherapy.[22] Preliminary results suggest thatall patients benefit, but that those with normal performance status and lactatedehydrogenase levels have the greatest improvement in overall survival comparedwith that achieved with 5-FU and leucovorin. Preliminary results of acost-effectiveness analysis done in the United Kingdom also suggested thatcombination chemotherapy was more cost-effective than 5-FU and leucovorin.[23]

Taken together, these data suggest that combination chemotherapyrepresents a new standard of care for patients with advanced colorectal cancer.In the United States, the combination used is 5-FU, leucovorin, and irinotecan,as approved by the U.S. Food and Drug Administration (FDA) Oncology DrugsAdvisory Committee (ODAC) in March 2000.[19]

Oxaliplatin

Oxaliplatin is another nonfluoropyrimidine therapy that isavailable in many countries. Oxaliplatin is a platinum derivative whose mainmechanism of action is the formation of DNA adducts. The carrier ligands forthis compound are bulkier and more cytotoxic than those of cisplatin (Platinol)or carboplatin (Paraplatin), and oxaliplatin activity in tumor cell linessuggests a broad spectrum of activity, including in colorectal cancer.[24] As asingle agent, oxaliplatin has demonstrated response rates similar to those of5-FU or irinotecan, in both previously treated or untreated patients.[25] Theprimary unique toxicity of oxaliplatin appears to be neurotoxicity.

Because oxaliplatin and 5-FU appear to have synergistic activityin tumor cell lines, many trials of oxaliplatin have been in combinations with5-FU and leucovorin. Furthermore, many of the studies were conducted in Europe,so the regimens typically included infusional, rather than bolus, 5-FU withleucovorin. Results of a comparative trial of the de Gramont 5-FU and leucovorinregimen vs the same regimen with biweekly oxaliplatin added were recentlyreported.[26] The overall objective response rate was significantly higher withoxaliplatin added (49% vs 21.9%; P < .001). As with the irinotecan-containingcombination, progression-free survival also significantly improved with thecombination regimen; however, overall survival was not significantly different(15.9 vs 14.7 months; P = .13).

Although a significant survival advantage was obtained whenthese data were adjusted for performance status, organ involvement, and baselinealkaline phosphatase level, the unadjusted survival did not show a clear benefitfor the combination. For this reason, the combination was not approved forfirst-line therapy in the United States when first presented to the ODAC inMarch 2000.[19] Results of a second supportive trial, which used chronomodulateddrug therapy, also demonstrated a higher response rate for the combination ofoxaliplatin, 5-FU, and leucovorin, but no significant difference in overallsurvival.[27]

There are many possible, post hoc explanations for the lack ofsignificant survival advantage in these trials, including use of crossovertherapy, aggressive surgical salvage therapy, and an infusional fluorouracilcontrol arm that may have been superior to bolus therapy. Clearly, additionaloxaliplatin trials are needed, particularly in the United States. A currenttrial design will recruit patients who have failed first-line 5-FU, leucovorin,and irinotecan and randomly assign them to receive infusional 5-FU andleucovorin alone, oxaliplatin alone, or infusional 5-FU and leucovorin withoxaliplatin.

Based on current US regulatory standards, the primary study goalwould be to establish a survival advantage for second-lineoxaliplatin-containing regimens, similar to the end point that led to thewidespread use of irinotecan as second-line therapy in the United States. Thepreviously described combination chemotherapy trials demonstrated response ratesranging from 34% to 51%, progression-free survivals from 6.7 to 9.3 months, andoverall survivals from 14.0 to 19.4 months. These represent significantincremental improvements over traditional 5-FU approaches in the management ofpatients with metastatic colorectal cancer.

Future Directions

Based on results of these combination trials, 5-FU plusleucovorin has largely been abandoned as the control arm for clinical trials inthe United States and abroad. For example, the NCCTG trial N9741, originallydesigned as a six-arm trial with the Mayo Clinic 5-FU and leucovorin regimen asthe standard, was recently modified to compare 5-FU, leucovorin, and irinotecan(weekly) vs the de Gramont regimen of 5-FU, leucovorin, oxaliplatin (biweekly),vs oxaliplatin plus irinotecan (every 3 weeks). Thus, three differentcombination approaches will be directly compared. Whether any combination issuperior for large patient groups is still uncertain, although a regimen’sbenefits and toxicities may differ in various patient populations based onsensitivity to each drug in a combination. Preliminary results have beenreported of a French trial in which patients were randomly assigned to receivethe de Gramont 5-FU and leucovorin regimen with either oxaliplatin oririnotecan, with a planned crossover approach.[28] The response rates have beenequivalent for the two regimens, although longer follow-up will be required toassess survival differences.

Triple combinations of fluoropyrimidines, irinotecan, andoxaliplatin are being tested in phase I and II trials to ascertain whether suchapproaches may be preferable in advance disease patients or in the adjuvantsetting. Although available data suggest that first-line combination therapy issuperior to single-agent treatment, this has not been optimally defined. Inaddition, the optimal treatment duration for patients with metastatic colorectalcancer is still not clear. Typically, chemotherapy is continued in respondingpatients; this was relatively easy with fluoropyrimidines, which are notassociated with cumulative toxicity or secondary malignancies. However,cumulative neurotoxicity, myelosuppression, and other late toxicities may limitthe total dose of newer agents such as oxaliplatin or irinotecan for patients inthe advanced disease and adjuvant settings.

Conclusion

Although overall survival remains the gold standard forassessing therapeutic efficacy, the role of salvage surgery in patients withmetastatic colorectal cancer remains to be defined, both in terms of itsincreased use in patients receiving combination chemotherapy and its effect onmedian survival in the clinical trial setting. In this regard, colorectal canceris relatively unique in that patients with pulmonary and hepatic metastases maybe treated with curative, ablative approaches in combination with systemictherapy. The increased efficacy of combination chemotherapy also raises the barfor median survival, so that very large trials would be required to detectimproved outcomes when testing new agents.

Furthermore, patients with metastatic colorectal cancer are nota homogeneous group in terms of prognosis or sensitivity to chemotherapy.Markers of prognosis, such as thymidylate synthase, allelic loss on chromosome18, and microsatellite instability, may become useful in the advanced diseaseand adjuvant settings.[29] In addition, several markers of drug resistance andsensitivity that remain to be prospectively validated in large-scale trials havebeen identified. These include thymidylate synthase levels, dihydropyridinedehydrogenase (DPD) levels, and genetic polymorphisms that may predictresistance or increased toxicity to irinotecan or oxaliplatin.

When fluoropyrimidine therapy was the only available modality oftreatment, the identification of sensitive or resistant patients would simplylead to either a treatment or no-treatment approach. With two new agentsavailable for patients with colorectal cancer, however, the ability to selectpatients for more- or less-intensive therapy, based on tumor sensitivity orresistance, will be a major step forward in the management of this disease.

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