Future Directions in Adjuvant Therapy for Stage III Colon Carcinoma

ABSTRACT: The current recommendation for adjuvant chemotherapy forpatients with newly diagnosed stage III colon cancer involves 6 months offluorouracil (5-FU) plus low- or high-dose leucovorin. In clinical trialsperformed throughout the world, several drugs have demonstrated either improvedtoxicity profiles or antitumor activity for patients with advanced colorectalcarcinoma. Uracil and tegafur (UFT) and capecitabine (Xeloda) are two examplesof new oral chemotherapy compounds with acceptable side-effect profiles in earlyadjuvant or advanced disease trials. Irinotecan (CPT-11, Camptosar) andoxaliplatin, when administered intravenously in combination with a 5-FU regimen,have both demonstrated significant antitumor effects for patients withadvanced-stage disease. Other immunotherapies, including monoclonal antibodiesand cancer vaccines, are being evaluated to help stimulate immune responses inpatients with resected colon cancer. These agents are just a few examples of thenew compounds being tested in the next generation of clinical trials forresected stage III colon cancer. Future and ongoing investigations will look tointegrate these new therapies as we attempt to move beyond the era of 5-FU andleucovorin. [ONCOLOGY 15(Suppl 5):31-36, 2001]

Introduction

Colorectal cancer is the secondleading cause of cancer-relateddeath in the United States. It is the most common cause of cancer-related deathin nonsmokers.[1] The estimated number of new colon cancers diagnosed in 2000was 93,800, and that of new rectal cancers was 36,400.[2] Most patientspresenting with this disease can undergo complete gross resection with thepossibility of negative microscopic margins. Any residual cancer is likelymicroscopic in nature. Adjuvant therapy generally refers to the administrationof chemotherapy and/or radiation therapy following surgery of curative intent.The goal of postoperative chemotherapy is to eradicate the invisiblemicrometastases that are responsible for postoperative relapses.

Despite many clinical trials from the 1950s to the 1980s, therewas no convincing evidence that effective adjuvant therapy existed for patientswith resected colon cancer. A meta-analysis published in 1988 showed anonsignificant survival benefit in patients who received adjuvant treatment withfluorouracil (5-FU) that ranged from a 2.3% to 5.7% difference in 5-year overallsurvival for treated patients over surgical controls.[3]

A small study by the North Central Cancer Treatment Group(NCCTG) published in 1989 reported on the possible benefits of levamisole(Ergamisol) in combination with 5-FU for patients with surgically treated stageII and III colon cancer.[4] Subsequent trials were performed to confirm andbuild upon this experience. With the introduction of many new active agents forthe treatment of advanced colorectal cancer, current and future adjuvant trialswill be testing a variety of new regimens. This article will briefly reviewclinical trials of treatments for colorectal cancer that were reported in thepast decade and then focus on ongoing and future studies.

Past Trials of Adjuvant Therapy

The first Intergroup trial to confirm the efficacy of 5-FU andlevamisole set a new standard for treatment of patients with resectednode-positive colon cancer (Table 1).[5] The trial enrolled patients over 3.5years through October 1987. The benefits of 5-FU plus levamisole in stage IIIdisease translated into an absolute reduction in risk of recurrence of 15% witha relative-risk reduction of 41% (P < .0001). The death rate was reduced by33% (P = .0007). No benefit was noted for the group receiving levamisole alone.Final results after a median follow-up of 6.5 years showed no loss of protectionfrom recurrence over time.[6] Based on the initial results, the National CancerInstitute (NCI) issued a clinical update in October 1989 that stated "thetherapeutic option of postsurgical observation (‘no treatment’ controlgroups) is no longer justifiable for NCI-sponsored adjuvant studies for Dukes’C patients." A subsequent National Institutes of Health (NIH) consensusconference in 1990 confirmed this recommendation but concluded that optimaladjuvant therapy "has not yet been devised" and encouraged continuedefforts to discover more active regimens.[7]

The next generation of trials all included 5-FU and levamisoleadministered for 12 months as the control arm. An NCCTG trial addressed theimportant issue of whether 6 or 12 months of adjuvant therapy were required forpatients with resected colon carcinoma.[8] After a median follow-up of 5.1years, results showed a significant duration-by-regimen interaction.Specifically, the standard 5-FU plus levamisole was inferior to 5-FU/levamisoleplus leucovorin when treatment was given for 6 months (P < .01). The authorsconcluded that 5-FU plus levamisole for 6 months should not be used in clinicalpractice. The three-drug regimen for 6 months was as effective as 12 months ofstandard 5-FU and levamisole.

The largest study of adjuvant therapy for colon cancer that hasbeen conducted in the United States is Intergroup-0089. Of 3,759 patientsenrolled, 80% had stage III colon cancer. The trial initially had asurgery-alone control arm that was discontinued in 1989 and replaced by standard5-FU plus levamisole for 12 months. At the same time, a three-drug regimen of5-FU, levamisole, and leucovorin for 6 months was added. The other two originalstudy arms prescribed 5-FU with leucovorin either in the high-dose weeklyleucovorin regimen developed at Roswell Park Cancer Institute or the regimen oflow-dose leucovorin daily for 5 days in a row each month developed at the MayoClinic.

Mature results of Intergroup-0089 showed that 5-yeardisease-free and overall survival rates were not significantly different for thevarious treatment strategies and schedules, except for the comparison between5-FU and levamisole vs 5-FU, leucovorin, and levamisole.[9] Toxicity datarevealed important differences among the various treatments. Regimens containing5-FU plus low-dose leucovorin (with or without levamisole) had significantlyhigher incidences of stomatitis than the 5-FU/levamisole or 5-FU/high-doseleucovorin regimens (Table 2).[10] Conversely, diarrhea was more common with5-FU and high-dose leucovorin than with 5-FU plus levamisole or 5-FU pluslow-dose leucovorin.

In the National Surgical Adjuvant Breast and Bowel Project(NSABP) C-04 trial, more than 2,100 patients with stage II and III colon cancerwere randomly assigned to receive one of three different 5-FU regimens (Table1).[11] The results indicated that 5-FU and high-dose leucovorin given for 8months conferred a small disease-free survival advantage (P = .04) and aprolongation in overall survival of borderline significance (P = .07) ascompared with 5-FU and levamisole for 12 months. The addition of levamisole tothe 5-FU and leucovorin regimen provided no additional benefit.

Based on results from these studies, clinicians treatingpatients with stage III colon cancer who are not enrolled in a clinical trialmay choose from a variety of regimens with apparently equivalent efficacy andoverall treatment durations of 6 to 12 months. Because Intergroup-0089 has shownthat either of the 5-FU plus leucovorin regimens given for approximately 6months is equivalent to 5-FU and levamisole given for 12 months, there is littlereason for clinicians to use 5-FU and levamisole outside of a clinical trialsetting.

Current and Future Trials of Adjuvant Therapy

Researchers assessing current and future directions for adjuvanttreatment of resected colon cancer are using two possible approaches: Someinvestigators seek to improve on the toxicity profile of current standardregimens by incorporating new orally administered fluorinated pyrimidinecompounds into adjuvant therapy trials. Others will investigate new chemotherapyor immunotherapy agents that have demonstrated activity in colorectal carcinomapatients.

UFT

A series of new orally administered fluorinated pyrimidinecompounds are of particular interest in colon cancer. UFT, which was developedin the 1970s, is a combination of uracil and tegafur in a 4:1 molarconcentration. Tegafur is a 5-FU prodrug, and uracil competes with 5-FU as asubstrate for dihydropyrimidine dehydrogenase, an enzyme responsible for thecatabolism of 5-FU. In phase II studies of UFT administered orally with thebiochemical modulator leucovorin (calcium folinate) to metastatic colon cancerpatients, response rates ranged from 25% to 43%.[12,13] In a phase III trial ofmore than 800 patients with advanced disease, UFT and oral leucovorin hadsimilar response rates and survival to a standard intravenous (IV) regimen.[14]Use of UFT was associated with a significant decrease in grade 4 stomatitis andhematologic toxicity. The toxicity profiles observed in these studies wereconsidered acceptable for treatment in the adjuvant setting.

The NSABP C-06 study is comparing the relative efficacies of5-FU and high-dose leucovorin to UFT plus oral leucovorin. In this phase IIItrial, patients with resected stage II and III colon carcinoma were stratifiedby number of positive lymph nodes before random assignment to one of theregimens. The accrual goal of more than 1,450 patients has been satisfied andthe study is currently closed with analysis pending. Preliminary toxicityassessment involving more than 470 evaluable patients indicates that bothregimens are well tolerated and have similar toxicity profiles (Table3).[15]The toxicity profile is favorable in that the oral regimen is not associatedwith any significant increase in hematologic or nonhematologic toxicity. Thisstudy is important because an oral treatment with efficacy equal to that of IVapproaches would be preferred by many patients and physicians in the adjuvantsetting.

Capecitabine

Capecitabine (Xeloda) is a prodrug of 5-FU that is currentlyapproved in the United States as third-line therapy for advanced breastcancer.[16] Capecitabine is converted to 5-FU in a series of four enzymaticactivation steps. In the first activation step, capecitabine is converted to5-deoxy-5-fluorocytidine by carboxylesterase in the liver while the finalactivation step occurs in tumor tissue and in normal cells by the enzymethymidine phosphorylase. Capecitabine is thought to be selectively activated to5-FU in tumor cells because of increased amounts of thymidine phosphorylase intumor tissue relative to normal tissue. This preferential activation in thetumor cell may increase its therapeutic index, resulting in higher cytotoxicityin colon cancer cells than in normal tissue. Ongoing trials are assessing itsefficacy in patients with advanced colon cancer.[17] Capecitabine would be anexcellent agent to test as adjuvant treatment of patients with resectedcolorectal carcinoma.

Raltitrexed (Tomudex) is a quinazoline analog that beganclinical development in the early 1990s. The drug is a direct, specificinhibitor of thymidylate synthetase that undergoes intracellularpolyglutamination.[18] This increases the drug’s potency and allows forevery-3-week dosing. Raltitrexed has demonstrated less toxicity (stomatitis,diarrhea, and leukopenia) as compared with 5-FU and high-dose leucovorin inpatients with advanced colorectal cancer.[19] Although response and mediansurvival rates were comparable, time to progression was statistically shorter inthe raltitrexed group.

Despite these results, the Pan-European Trials in Adjuvant ColonCancer (PTACC) planned to enroll more than 2,700 patients with resectednode-positive colon cancer in a randomized trial comparing raltitrexed and5-FU/low-dose leucovorin. The trial opened in February 1998 and accrued morethan 360 patients in the first 6 months. Unfortunately, an early safety analysisdemonstrated excessive toxicity in the raltitrexed arm, primarily related tocases of lethal toxicity in patients with compromised renal function, andaccrual was suspended (personal communication, D. Cunningham, study chair, June2000). Combination regimens that include raltitrexed may offer new avenues ofresearch for future trials of adjuvant therapy.[20]

Irinotecan

Irinotecan (CPT-11, Camptosar) is a potent inhibitor oftopoisomerase I with demonstrated single-agent activity in advanced colorectalcancer patients who have previously received 5-FU.[21] In two studies, thecombination of irinotecan with 5-FU and leucovorin resulted in a statisticallysignificant survival advantage over standard 5-FU and leucovorin regimens (Table4).[22,23] Toxicity was manageable in one study, with slightly more grade 3diarrhea and vomiting and less mucositis, grade 4 neutropenia, and neutropenicfevers in the irinotecan combination arm.[22]

The Cancer and Leukemia Group B (CALGB) is leading anNCI-sponsored phase III trial of irinotecan, 5-FU, and leucovorin vs 5-FU andhigh-dose leucovorin in resected node-positive patients. The accrual goal is1,260 patients over 3 years. Patients are stratified according to lymph nodeinvolvement (1-3 vs ³ 4), histology, and preoperative serum carcinoembryonicantigen levels. The schedules both involve weekly chemotherapy administration ofsimilar duration (30 vs 32 weeks, respectively).

Two European trials will also evaluate irinotecan in combinationwith5-FU in the adjuvant setting. A multicenter trial, with a planned enrollment of1,800 patients with stage II and III disease, will administer one of two5-FU/leucovorin regimens commonly used in Europe (the infusional 5-FU de Gramontregimen[24] and the high-dose 5-FU German AIO [German Cancer Society]regimen).[24,25] Investigators may choose to use either of these 5-FU regimens,and patients will be randomly assigned to receive additional irinotecan or nofurther therapy.

A smaller French study will evaluate irinotecan in high-riskstage III patients (more than four positive nodes or any positive nodes withobstruction and/or perforation). A total of 400 patients will be randomlyassigned to the de Gramont regimen with or without irinotecan. The primary endpoint is event-free survival at 3 years; secondary objectives are overallsurvival, toxicity, and quality of life. Despite the use of three differentstandard regimens, nearly 3,500 patients will be included in these randomizedstudies evaluating the role of irinotecan in resected colon cancer.

Oxaliplatin

Oxaliplatin is a diaminocyclohexane (DACH) platinum derivativethat has demonstrated activity in advanced colorectal carcinoma. Levi andcolleagues first reported results combining oxaliplatin, 5-FU, and leucovorin ina chronomodulated fashion and observed a 55% response rate in 42 patients withmetastatic colorectal carcinoma.[26] These impressive phase II results led tosubsequent phase III trials in Europe comparing 5-FU plus leucovorin with orwithout oxaliplatin. In one trial, more than 200 patients received thecombination regimen in a chronomodulated fashion (Table5).[27] In the second,larger trial, 5-FU and leucovorin were administered by bolus and shortcontinuous infusion (de Gramont schedule) for 2 days every 2 weeks with orwithout oxaliplatin.[28]

In both of these trials, response rates and medianprogression-free survivals (the primary end points in each trial, respectively)were statistically significantly different in favor of the oxaliplatin arm.However, median overall survival was not significantly different. Severalexplanations for these findings have been proposed, including (1) use ofoxaliplatin or irinotecan in secondary salvage chemotherapy regimens, (2) use ofaggressive salvage surgery in select patients enrolled in these trials, and (3)use of too small a sample to detect a survival difference.

The clinical data on oxaliplatin in advanced disease have ledinvestigators to assess oxaliplatin in the adjuvant setting. The NSABP C-07study was initiated to compare weekly 5-FU and high-dose leucovorin with andwithout oxaliplatin in stage II and III colon cancer. Each study arm willconsist of three 8-week cycles of 5-FU and high-dose leucovorin with oxaliplatin(85 mg/m²) given on days 1, 15, and 19 of each cycle. The projected accrual isapproximately 2,500 patients over 3 years.

In Europe, approximately 1,500 of a planned accrual of 2,000patients with stages II and III disease have been enrolled in a multicenterinternational study of oxaliplatin/5-FU and leucovorin as adjuvant therapy forcolon cancer (MOSAIC). The trial is comparing the de Gramont regimen of 5-FU andleucovorin to the same schedule with the addition of oxaliplatin (FOLFOX-4).Results of this trial will be eagerly awaited by the oncology community in thecoming years.

Monoclonal Antibody 17-1A

Use of adjuvant immunotherapy has been an intriguing conceptthat has been tested in many colon cancer trials. Interferon-alpha combined with5-FU and leucovorin was tested in NSABP C-05; the regimen only increasedtoxicity without improving outcomes for patients treated with immunotherapy.[29]Riethmuller and colleagues reported 7-year results of a study of monoclonalantibody therapy in patients with resected Dukes’ C colorectal cancer.[30]Monoclonal antibody 17-1A recognizes a 34-kd glycoprotein on the cell membraneof epithelial cells. The trial included 189 patients, 70 of whom had rectalcancer.

Patients were randomly assigned to an observation arm or toreceive monoclonal antibody treatment. After 7 years of follow-up, overallmortality was reduced by 32% (P ≤ .01) and recurrence rate decreased by 23%(P< .04). The benefits observed in this small trial were of the same order ofmagnitude as in the initial 5-FU and levamisole study,[5] with the therapeuticeffect maintained after long-term follow-up.

Based on these results, a large international study wasinitiated. As of early 1999, more than 2,700 patients were enrolled and thetrial was closed to accrual. Patients were randomly assigned to one of threetreatment arms: 5-FU and low-dose leucovorin (six cycles), monoclonal antibody17-1A (five infusions), or the combination 5-FU/leucovorin and monoclonalantibody 17-1A. This trial and a study being performed in North America ofmonoclonal antibody 17-1A vs no treatment in stage II patients will helpdetermine whether monoclonal antibody 17-1A is effective adjuvant therapy andwhether chemotherapy alters or enhances the immune effects of monoclonalantibody 17-1A.

Carcinoembryonic Antigen Vaccine

Vaccines offer an innovative approach to cancer therapy. Foonand colleagues have demonstrated clinical and immune responses in patientsreceiving an anti-idiotype antibody (termed CeaVac) that is an internal image ofcarcinoembryonic antigen (CEA).[31] Patients with CEA-positive resected orincompletely resected stage II-IV disease were treated with subcutaneousinjections of CeaVac. Of 32 patients, 14 received concurrent 5-FU-basedchemotherapy. All patients generated high-titer IgG (immunoglobulin G) andT-cell proliferative immune responses against CEA. The use of 5-FU did notchange the quantitative or qualitative effect of the immune response.

Several of these patients fared "remarkably well"according to the authors, even though patients were allowed to enter the trialup to 1 year after surgical resection. In an ideal world, adjuvant therapy wouldbegin immediately after surgery. Thus, a cooperative group in the United Statesis considering conducting a large-scale clinical trial of CeaVac as adjuvanttherapy for resected colon cancer, in which patientswould be randomly assigned to receive5-FU and leucovorin with or withoutCeaVac. Results of this trial may address whether specific immunization againstthe tumor-associated antigen in humans will result in beneficialimmunotherapeutic antitumor effects.

Summary

In summary, adjuvant therapy for colon cancer is now widelyaccepted as a standard of care for patients with node-positive disease. The mostcommonly used regimens involve approximately 6 months of 5-FU and low- orhigh-dose leucovorin. New chemotherapy agents and immunotherapy agents offer thepotential for less toxicity and/or improved overall survival for patients withstage III disease. In the coming years, thousands of patients with resectedcolon cancer will be enrolled in randomized clinical trials evaluating these newagents. Many of these trials will incorporate a translational component, whichwill help focus future innovative clinical research. With the multitude oftreatment opportunities available to patients with colon cancer, the oncologycommunity can hopefully move beyond5-FU and leucovorin during the next decade.

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