• ENDPOINTS IN CLINICAL TRIALS OF ADJUVANT TREATMENT
• FLUOROPYRIMIDINE MONOTHERAPY
• Bolus 5-Fluorouracil regimens
• Continuous infusion 5FU
• Oral fluoropyrimidines
• COMBINATION CHEMOTHERAPY
• BIOLOGIC THERAPIES AS ADJUVANT TREATMENT
• ADJUVANT TREATMENT FOR RESECTED STAGE II COLON CANCER
• Rectal cancer
• Timing and duration of treatment
• Molecular markers in stage II and III colorectal cancer
• CONCLUSIONS
• REFERENCES

Worldwide, over a million new cases of colorectal cancer are diagnosed each year, with this disease causing approximately half that number of deaths annually [1]. In developed countries, colorectal cancer is one of the top three most common new cancer diagnoses and causes of cancer-related mortality [2,3]. The staging of colorectal cancer is based on the depth of invasion of the bowel wall and the spread of disease to regional lymph nodes and beyond (Figure 1). Approximately 70% of newly diagnosed patients will have disease that is localized and suitable for resection. The five-year survival of these patients depends on the stage of the tumors at resection (Table 1) [4].

	Figure 1. Anatomic staging, stage distribution, and prognosis of colorectal cancer. (Modified with permission from Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th Edition. New York, NY: McGraw-Hill Companies; 2008)
	TABLE 1. Five-year survival of patients with resected colon cancer by stage group (Adapted from O'Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 2004;96:1420-1425)

Clearly not all patients are cured of their cancer despite having all known disease removed at the time of primary surgery. Relapse in these patients is likely due to micrometastatic disease, which is below the threshold for detection by the currently available staging technologies. Adjuvant treatment, therefore, has been explored as a means of improving patient outcomes by eradicating micrometastases.
The role of adjuvant chemotherapy in patients with stage III resected colon cancer is now well established. Following the results of the Multicentre International Study of Oxaliplatin/Infused 5-Fluorouracil (5FU)/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial, the oxaliplatin-based folinic acid (leucovorin), fluorouracil (5FU), and oxaliplatin (Eloxatin; FOLFOX) regimen may be an alternative to fluoropyrimidine monotherapy for some of these state III patients [5].
The benefit of adjuvant chemotherapy has been harder to demonstrate in other subgroups of patients, notably those with stage II colon cancer and those with rectal primaries. This review will summarize the development of adjuvant chemotherapy in colorectal cancer and focus on discussing particular topical issues related to its use. A discussion of the use of radiotherapy given either pre- or postoperatively in patients with rectal cancer is beyond the scope of this article. The addition of radiotherapy to adjuvant postoperative chemotherapy in resected colon cancer has not been found to be beneficial and will not be discussed further [6].

ENDPOINTS IN CLINICAL TRIALS OF ADJUVANT TREATMENT

There is a trend toward using primary endpoints such as disease- or relapse-free survival as a surrogate for overall survival in trials of adjuvant treatment. This allows the primary efficacy measure of the trial to be evaluated earlier than if overall survival was used. However, there is not as yet a surrogate endpoint for survival with a universally accepted standard definition, so that in evaluating the results of these trials attention should be given to considering the definitions for disease- and relapse-free survival used by a particular trial. Variance seems to lie in whether either second primary cancers (including noncolorectal primaries) or second primary colorectal cancers are included as significant events [7]. At least in studies in which adjuvant treatment consisted of 5FU with either leucovorin or levamisole, 3-year disease-free survival was shown to correlate with 5-year survival [8]. (Disease-free survival is defined as the time from randomization to the first event of either recurrent disease or death, excluding the occurrence of second primary tumors as events.) It should be noted, however, that the 18 randomized controlled trials that were included in this analysis of the pooled individual data of 20,898 patients were conducted when there were fewer treatment options available to patients upon relapse and patients were less frequently considered for resection of metastases compared to today. Furthermore, disease-free survival as defined in this analysis is similar to relapse-free survival used by other clinicians. Nevertheless, the results of this analysis support the use of disease-free survival as a surrogate endpoint for overall survival in clinical trials.

FLUOROPYRIMIDINE MONOTHERAPY

Bolus 5-Fluorouracil regimens

The majority of 5FU-based regimens evaluated as adjuvant treatment deliver the drug by bolus administration. Various trials, including those that established the benefit of this agent, also used either leucovorin or levamisole to modulate the activity of 5FU. By forming a stable ternary complex with thymidylate synthase (TS), leucovorin (or folinic acid) and 5FU in combination leads to prolonged inhibition of the enzyme, which is the main target of 5FU [9]. Levamisole, in comparison, is an antihelminthic with immunomodulatory properties that may also potentiate the cytotoxic effects of 5FU in a dose-dependent manner [10].
The first randomized trial to demonstrate a survival benefit in favor of adjuvant chemotherapy compared to surgery alone was the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-01 study, in which chemotherapy consisted of semustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea] or methyl-CCNU], vincristine, and 5FU (MOF regimen) [11,12]. However, this regimen has since fallen out of use following reports of an association between semustine and the development of acute leukemia or preleukemia [13]. In addition, the improvement in 5-year survival and disease-free survival initially observed was not maintained with further follow-up at 10 years.
Adjuvant chemotherapy based on 5FU was then recommended as treatment for stage III colon cancer by the 1990 National Institutes of Health (NIH) Consensus Conference following the reporting of a trial that showed an improvement in survival and reduction in recurrence with the use of bolus 5FU with levamisole compared to surgery alone [14,15]. This guidance has also been amended to include the recommendation of 5FU with leucovorin for the same indication.
Subsequent randomized trials on both sides of the Atlantic have evaluated the addition to bolus 5FU with high- or low-dose leucovorin, high- or low-dose levamisole, both leucovorin and levamisole, or interferon (Table 2) [16-28]. The following conclusions can be made from the results of these trials:

• 5FU/low-dose leucovorin (20 mg/m²) improves overall and disease-free survival compared to surgery alone.
• The efficacy of 5FU/high-dose leucovorin (200-500 mg/m²) is not better than 5FU/low-dose leucovorin.
• Six months of 5FU/leucovorin is as effective as 12 months of the same therapy.
• There is no evidence that either of the two most commonly used bolus 5FU/leucovorin regimens (Mayo Clinic: 425 mg/m² + leucovorin 20 mg/m² days 1 to 5 every 4 weeks for 6 months; Roswell Park: 5FU 500 mg/m² + leucovorin 500 mg/m2 weekly for 6 weeks every 8 weeks for 3 to 4 cycles) is better than the other.
• 5FU/leucovorin is probably better than 5FU/ levamisole, and the latter is no longer used as adjuvant treatment.
• The addition of interferon to adjuvant treatment increases toxicity without additional survival benefit.

TABLE 2. Summary of randomized trials evaluating the addition of high- or low-dose leucovorin and/or levamisole, or interferon to 5FU

Continuous infusion 5FU

Based on observations of advanced colorectal cancer that prolonged infusions of 5FU improved survival compared to bolus 5FU regimens with less hematological toxicity, continuous infusion of 5FU regimens have also been evaluated in the adjuvant setting. However, in none of the trials performed thus far, including the recently reported preliminary results of the Pan-European Trials in Adjuvant Colon Cancer (PETACC)-2 trial, has a statistically significant improvement in overall or disease-free survival been observed in favor of infused 5FU compared to bolus 5FU [29-33].
The Short Adjuvant Fluorouracil and Folinic Acid (SAFFA) trial randomized 801 patients with stage II and III colorectal cancer to the Mayo Clinic regimen 5FU/leucovorin for 6 months or a protracted venous infusion (PVI) 5FU regimen (300 mg/m²/day) for 3 months [30]. This trial reported a trend toward improved relapse-free (time from randomization to relapse or second colon cancer) and overall survival at 5 years that did not reach statistical significance (p = .10 and p = .83, respectively).
Continuous infusion 5FU is better tolerated than bolus administration when used as adjuvant treatment, as in the advanced disease setting. In general, significantly less myelosuppression (particularly neutropenia), diarrhea, and stomatitis have been observed, although hand-foot syndrome may be increased, when compared to treatment with a bolus 5FU. Because of the improved side-effect profile, continuous infusion regimens such as LV5FU2 (leucovorin 200 mg/m2 followed by bolus 5FU 400 mg/m² and then a 22-h infusion of 5FU 600 mg/m²/day for 2 days every 14 days for 24 weeks) was used as the comparator regimen in trials such as MOSAIC and PETACC-3 [5,34]. The main drawback of these regimens is the requirement for in-dwelling intravenous access (eg, Hickman’s lines or ports) and infusion pumps, which may be an inconvenience to patients and are associated with increased cost, as well as risk of line-related complications.

Oral fluoropyrimidines

Oral fluoropyrimidines have been explored as adjuvant treatments on the basis that they might combine the improved tolerability of the continuous infusion 5FU regimens with more convenient administration. In the advanced disease setting at least, capecitabine results in equivalent survival, and may also increase response rate, compared to bolus 5FU/leucovorin [35].
Capecitabine is a fluoropyrimidine carbamate that is metabolized by a series of activation steps to 5FU. Thymidine phosphorylase is the final enzyme in this process and is present at a higher level in tumor tissue compared to normal tissue so that there may be some degree of selectivity of the action of capecitabine, with less systemic toxicity. UFT is a combination of tegafur with uracil, the latter competing with 5FU for degradation resulting in more sustained concentrations of active metabolite in plasma and tumor tissue.
Capecitabine (1250 mg/m² twice daily for days 1 to 14 every 21 days) has been compared to bolus 5FU/leucovorin (Mayo Clinic regimen) in the Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial, which included 1987 patients with stage III colon cancer who were treated for 24 weeks in both treatment arms (Table 3) [36]. This study met its primary endpoint of showing that capecitabine was at least equivalent to bolus 5FU in its effect on disease-free survival (defined as the time from randomization to relapse of colon cancer, second primary colon cancers, and death from any cause). Relapse-free survival in this trial had a similar definition to disease-free survival except that patients without documented relapse, and those who died from causes other than colon cancer or treatment toxicity, were censored. Time to relapse, second primary cancer, or death, however, was longer in the patients treated with capecitabine (hazard ratio 0.86, 95% confidence interval 0.74-0.99, p = .04). With a median follow-up of only 3.8 years at the time of this report, no difference in overall survival had been observed. Capecitabine was associated with a significantly more favorable safety profile (diarrhea, nausea and vomiting, stomatitis, alopecia, and neutropenia) compared to bolus 5FU, although hand-foot syndrome and hyperbilirubinemia were increased with capecitabine. Also, a pharmacoeconomic analysis has shown that the high cost of capecitabine is offset by the higher cost of 5FU administration, so that overall there is a saving of hospital costs with capecitabine.

The final results of the NSABP C-06 trial, which enrolled 1608 patients with stage II and III colon cancer, stated that UFT/leucovorin resulted in equivalent overall and disease-free survival compared to the Roswell Park regimen bolus 5FU/leucovorin with similar toxicity in both arms [37]. However, UFT is not licensed in the United States, whereas capecitabine is licensed in both the United States and Europe, so that the use of the latter in practice is likely to be greater.

COMBINATION CHEMOTHERAPY

Combination chemotherapy based on oxaliplatin and irinotecan is now standard treatment in advanced colorectal cancer following the reporting of trials confirming the benefit of these regimens as both first- and second-line treatment [38-40]. The addition of these agents to 5FU has also been tested as adjuvant treatments, although the results have not always been as expected. Whereas oxaliplatin has been shown to be beneficial by the MOSAIC and NSABP C-07 trials, similar trials with irinotecan have failed to show an advantage [5,34,41-43].
The benefit of oxaliplatin-based chemotherapy as adjuvant treatment was first demonstrated by the European-run MOSAIC trial, which included 2246 patients with stage II (approximately 40%) and III colon cancer (Table 3) [5,42]. These patients were randomized to treatment with 6 months of the LV5FU2 regimen previously described or the same regimen with the addition of oxaliplatin 85 mg/m² given on day 1 of each cycle (FOLFOX4 regimen). At the time of publication, the study had met its primary endpoint of showing an improvement in disease-free survival (same definition as X-ACT) in favor of FOLFOX4 (78.2% at 3 years with FOLFOX4 compared to 70.2% with LV5FU2, p = .002), with an associated hazard ratio for recurrence of 0.77. This suggests nearly a 25% reduction in risk of relapse. In an analysis by stage, however, statistical significance was maintained only in stage III patients. When these results were updated after a median of 6 years of follow up, the benefit to disease-free survival was maintained, but a statistically significant overall survival benefit has been observed only in the patients with stage III disease (73.0 vs 68.6%, p = .029) with an associated hazard ratio for death of 0.80 [42]. However, overall survival may be affected by treatments used upon relapse. Indeed, so far more patients in the LV5FU2 arm received oxaliplatin-based treatment upon disease recurrence than did patients in the FOLFOX4 arm (42.7 vs 15.5%). The NSABP C-07 trial also demonstrated an improvement in disease-free survival in favor of oxaliplatin combination treatment (76.1 vs 71.8% at 3 years, p = .0034) [41]. This trial was based on the Roswell Park bolus 5FU regimen, however. Results of a Roche-sponsored trial comparing oxaliplatin/capecitabine to FOLFOX that completed accrual are expected soon.
Clinicians need to be aware of the risk of peripheral neuropathy associated with oxaliplatin. In MOSAIC, the incidence of paraesthesia was increased with FOLFOX4 compared to LV5FU2 (any grade: 92.0 vs 15.6% respectively, p <.001; grade 3: 12.4 vs 0.2% respectively, p = .001) [5]. Neurotoxicity was both observer-assessed (using a modified scale based on National Cancer Institute grading) and patient-assessed in NSABP C-07; the latter in a subcohort of 395 patients [44]. The incidence of observer-assessed neurotoxicity of grade 1-2 and 3-4 levels was higher at cycle 2 and 12 months after randomization in the oxaliplatin arm. At 12 months, 29.4% of patients in the oxaliplatin arm had grade 1-2 neurotoxicity compared to 4.7% in the control arm, whereas grade 3-4 neurotoxicity was 0.5% compared to 0.2% (p-values not shown). The time to resolution of neurotoxicity was also longer in the oxaliplatin arm (9.0 vs 4.8 months, p <.0001). At 18 months, a clinically significant change in neurotoxicity compared to baseline was reported by 31% of patients treated with oxaliplatin, compared to 18% in the control arm (p = .016). Based on experience with oxaliplatin in the advanced disease setting, restricting treatment to 6 months should limit the development of this complication [45]. However, unlike advanced disease patients, many patients in the adjuvant setting may be long-term survivors and may, therefore, be less willing to accept even low levels of persistent peripheral neuropathy.
On the basis of the results of MOSAIC, oxaliplatin has been licensed for use as adjuvant treatment, but only in stage III colon cancer. It is also recommended for this indication by the United Kingdom National Institute of Clinical Excellence (NICE). Although treatment with FOLFOX4 should be considered for these patients, it may not be suitable for all patients, because the modest improvement in disease-free survival with oxaliplatin, without an improvement in overall survival seen so far, comes at a cost of increased risk of treatment-related morbidity. The patients included in clinical trials tend to be younger and less likely to have comorbid disease and may not reflect the toxicity risk of patients more likely to be seen in practice. For example, the median age of patients in MOSAIC was approximately 60 years, with no patients enrolled who were older than 75 years, whereas colorectal cancer is diagnosed at a median age of 71 [46]. Clinicians should therefore consider the individual patient (age and the presence of comorbidities, such as diabetes or preexisting peripheral neuropathy) and disease factors (good-risk tumors—T3N1 or lower in stage—vs high-risk tumors—T4 or N2 stage, or the presence of extramural venous invasion) when deciding between FOLFOX4 or fluoropyrimidine monotherapy.
In contrast, the three randomized trials in which irinotecan was added to either bolus or continuous infusion 5FU regimens have not shown a benefit [34,43,47]. This could have been in part a result of the design of some of these trials. However, based on these results it is unlikely that further testing of irinotecan as adjuvant treatment will occur, or whether irinotecan-based combination treatment can be recommended as adjuvant chemotherapy in colon cancer.

BIOLOGIC THERAPIES AS ADJUVANT TREATMENT

Several targeted agents have been shown to be beneficial in advanced colorectal cancer and are already licensed. These include the antiepidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab, and the antivascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab [48-51]. Bevacizumab has been shown to improve response rate and survival when added to chemotherapy in the first- and second-line settings, whereas mature results for the anti- EGFR antibodies is limited to the third-line setting. These agents have specific side-effect profiles that are different from the cytotoxic agents, and in general can be used with chemotherapy without the need to lower the doses of chemotherapy. The addition of these agents to chemotherapy in the adjuvant setting is therefore appealing and is the subject of ongoing trials. For example, the addition of bevacizumab to oxaliplatin-based treatment is being evaluated by NSABP C-08, Eastern Cooperative Oncology Group (ECOG) E5202, and the Roche-sponsored Avastin International Phase III Trial (AVANT), whereas PETACC-8 and US Intergroup 0147 are evaluating the addition of cetuximab to FOLFOX chemotherapy.
The concept of biologic therapies as adjuvant treatment is not a new one, with previous attempts focusing on immunotherapy. One of the 3 arms of NSABP C-01 was immunotherapy with bacillus Calmette-Guerin (BCG), which did not appear to prevent tumor relapse [11,12]. The apparent beneficial effect on 10-year overall survival compared to surgery alone (relative risk = 1.27, p = .02) seemed to be due to a smaller number of deaths from comorbidities in the BCG arm, rather than to a decrease in death due to colon cancer recurrence. Edrecolomab is a chimeric monoclonal antibody against a cell-surface glycoprotein known as epithelial-cell adhesion molecule (Ep-CAM). The mechanism of action of this antibody in colorectal cancer is unknown, although it may activate antibody-dependent cell-mediated cytotoxicity. Results from randomized trials with edrecolomab have been conflicting, so that it is unlikely to replace fluoropyrimidine-based adjuvant treatment [52-54].

ADJUVANT TREATMENT FOR RESECTED STAGE II COLON CANCER

It has been more difficult to show conclusively the benefit of adjuvant treatment in stage II colon cancer. These patients already have a good outcome with surgery alone, with a low risk of relapse and a higher likelihood of long-term survivorship compared to stage III patients. Therefore, more patients are required for adequate statistical power if the incremental improvement is small with a given experimental treatment. Although many previous adjuvant trials have included stage II patients alongside patients with stage III tumors, the planned accrual numbers have not been based on the requirement for adequate power to show a statistically significant difference in the stage II subset.
The largest randomized trial of patients with stage II disease was the Quick and Simple and Reliable (QUASAR) uncertain indication trial in which 3239 patients (92% with stage II colorectal cancer) were randomized between observation or 5FU/leucovorin [55]. In this trial, adjuvant chemotherapy was associated with significantly reduced recurrence (risk ratio: 0.78, 95% confidence interval 0.67- 0.91; p = .001) and improved survival (risk ratio: 0.83, 95% confidence interval 0.71-0.97; p = .02) after a median follow up of 4.6 years. The 5-year recurrence for 5FU/leucovorin and observation were 22.2 and 26.2%, and overall survival rates were 80.3 and 77.4%, respectively.
Several meta-analyses have been performed to address the question of the role of adjuvant treatment in stage II colon cancer [56-59]. A meta-analysis by the Cancer Care Ontario Program (CCOP) group included 4187 patients with stage II disease, finding a nonstatistically significant benefit in survival for these patients (risk ratio: 0.87, 95% confidence interval 0.75-1.01; p = .07) [57]. The QUASAR trials, however, were not included in the analysis. Based in part on these results, and in collaboration with CCOP, the American Society of Clinical Oncology (ASCO) issued guidelines recommending against routine adjuvant therapy in patients with stage II colon cancer [60]. Importantly, however, these guidelines recommend that adjuvant chemotherapy should still be considered for patients who are medically fit with stage II disease and considered to be at high risk of recurrence by the presence of at least one of the following features:

• T4 tumors
• Poorly differentiated histology
• Presentation with perforation
• Inadequate sampling of lymph nodes, with less than 13 lymph nodes in the surgical specimen

The last factor was derived from data showing that survivorship was significantly poorer in patients who had lymph node-negative disease with fewer lymph nodes sampled than in those with a greater number of lymph nodes sampled [61]. The average yield of positive lymph nodes did not significantly increase when 13 or more lymph nodes were examined, suggesting this to be the minimum number for adequate staging in these patients.

Rectal cancer

The 1990 NIH Consensus Conference recommended postoperative 5FU-based chemotherapy and chemoradiotherapy in patients with resected stage II and III rectal cancer based on the results of a number of trials including NSABP R-01 and the Gastrointestinal Tumor Study Group (GITSG) protocol 7175 [14,62,63].
More recently, there have been relatively few randomized trials specifically addressing the use of adjuvant chemotherapy in rectal cancer. In the European Organization for Research and Treatment of Cancer (EORTC) trial 22921, a 2x2 randomization was employed to evaluate the addition of chemotherapy to long-course preoperative radiotherapy (45 Gy over 5 weeks), and four cycles of chemotherapy (5FU 350 mg/m² + leucovorin 20 mg/m² days 1 to 5 every 4 weeks), or no chemotherapy after surgery [64]. With a total of 1011 patients enrolled, a small benefit was seen with postoperative chemotherapy to overall (67.2 vs 63.2%, p = .12) and disease-free (58.2 vs 52.2%, p = .13) survival at 5 years, which did not reach statistical significance. In a comparison of the individual study arms, the addition of any chemotherapy significantly reduced local recurrence rates at 5 years compared to the arm that received preoperative radiotherapy only (preoperative radiotherapy only: 17.1%; preoperative chemoradiotherapy only: 8.7%; preoperative radiotherapy + postoperative chemotherapy: 9.6%; preoperative chemoradiotherapy + postoperative chemotherapy: 7.6%; p = .002).
Approximately 30% of the 3239 patients in the QUASAR uncertain indication trial had rectal primary tumors [55]. Although the improvement in 5-year survival with chemotherapy did not reach statistical significance in the rectal subgroup of patients (p = .06), a significant improvement in 5-year recurrence rate was observed in this trial (19.6 vs 26.8%, p = .005).
A 276-patient Japanese trial evaluated UFT adjuvant chemotherapy over 1 year after standardized mesorectal excision surgery with selective lateral pelvic lymph node excision [65]. Adjuvant chemotherapy was found to significantly improve relapse-free and overall survival (78 vs 60%, p = .001 at 3 years; and, 91 vs 81%, p = .005, respectively) compared to surgery alone.
Gunderson et al reported on a pooled analysis of 3791 patients from 5 US randomized trials of rectal adjuvant treatment [66]. The 5-year overall survival of patients in any of the arms receiving chemotherapy (either alone or with radiotherapy) was significantly better than those who received surgery alone or surgery with adjuvant radiotherapy (p <.001).
In patients with operable rectal cancer who are considered to be at risk of both local and systemic failure if treated with surgery alone, a preoperative radiotherapy-based strategy and postoperative adjuvant chemotherapy should be considered. In contrast, patients mainly at risk of systemic relapse of disease may not require preoperative treatment, but should still be considered for postoperative adjuvant chemotherapy.

Timing and duration of treatment

For the safe delivery of treatment, an adequate interval for recovery from the procedure must be allowed after surgery before commencement of adjuvant chemotherapy. Most clinical trials usually specify that treatment should be started within 6 to 8 weeks of surgery, so that in clinical practice, it is also preferable that adjuvant treatment should be commenced within a similar time frame.
There is no evidence from the trials that have been conducted to date that there is any additional benefit from treatment with 5FU/leucovorin adjuvant chemotherapy for longer than 6 months [26,32]. Only one, the Royal Marsden Hospital SAFFA randomized trial, evaluated treatment for a shorter duration than 6 months. Its results suggest that 3 months of PVI 5FU is as good as 6 months of bolus 5FU/leucovorin adjuvant treatment [30]. The issue of whether short durations of treatment may be feasible without loss of efficacy should be explored further. For example, with agents such as oxaliplatin where there is a cumulative risk of peripheral neuropathy, short treatment durations may be one means of limiting the occurrence of this side effect.

Molecular markers in stage II and III colorectal cancer

There is significant ongoing interest in developing better prognostic and predictive tools than the current staging methods used. One area of active research is in the use of molecular factors for this purpose, and whether such markers may help clinicians tailor treatment to an individual patient’s needs. Markers that have been found thus far to have prognostic or predictive significance in patients undergoing adjuvant treatment include TS (either overexpression or genotype), chromosome 18q deletion, microsatellite instability (MSI), p53 mutation, deoxy-ribonucleic acid (DNA) ploidy, and gene expression profiling [67-78]. Although none are yet in clinical use, they are starting to be evaluated for prospectively guiding clinical management in trials. For example, ECOG E5202 is a study in which patients with stage II colon cancer are stratified into high-risk (microsatellite stable [MSS] or low-frequency MSI with chromosome 18q loss of heterozygosity) or low-risk (MSS or low-frequency MSI with retention of 18q alleles, or high-frequency MSI regardless of 18q allele status) groups. Whereas patients in the low-risk group will be managed with observation only, the high-risk patients will be randomized between oxaliplatin/5FU/leucovorin with or without bevacizumab.

CONCLUSIONS

Adjuvant chemotherapy is recommended in patients with stage III colon cancer. Treatment options include oxaliplatin-based/5FU/leucovorin combination chemotherapy (eg, FOLFOX4 regimen), or fluoropyrimidine monotherapy with 5FU/leucovorin or capecitabine, depending on the assessed risk-benefit ratio from combination treatment in each patient. For patients with stage II colon cancer, adjuvant treatment should be considered in patients who have any of the risk factors suggested by the ASCO guidelines previously described [60]. Adjuvant chemotherapy should also be considered for patients with resectable rectal cancer who are at significant risk of systemic failure if treated with locoregional treatments alone. Treatment should commence between 6 to 8 weeks after surgery, provided patients adequately recover from the procedure. Treatment should be administered for 6 months. Ongoing and future clinical trials will determine the role of targeted agents such as bevacizumab and cetuximab as adjuvant treatments.

REFERENCES

1. Parkin DM, Bray F, Ferlay J et al. Global cancer statistics, 2002. CA Cancer J Clin 2005;55(2):74-108. [Medline]

2. Jemal A, Siegel R, Ward E et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56(2):106-130. [Medline]

3. Office for National Statistics. Cancer statistics registrations: Registrations of cancer diagnosed in 2004, England. 2006.

4. O’Connell JB, Maggard MA, Ko CY. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 2004;96(19):1420-1425. [Medline]

5. Andre T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350(23):2343-2351. [Medline]

6. Martenson JA Jr, Willett CG, Sargent DJ, et al. Phase III study of adjuvant chemotherapy and radiation therapy compared with chemotherapy alone in the surgical adjuvant treatment of colon cancer: results of intergroup protocol 0130. J Clin Oncol 2004;22(16):3277-3283. [Medline]

7. Chua YJ, Sargent D, Cunningham D. Definition of disease-free survival: this is my truth-show me yours. Ann Oncol 2005;16(11):1719-1721. [Medline]

8. Sargent DJ, Wieand HS, Haller DG, et al. Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 2005;23(34):8664-8670. [Medline]

9. Pinedo HM, Peters GF. Fluorouracil: biochemistry and pharmacology. J Clin Oncol 1988;6(10):1653-1664. [Medline]

10. Kovach JS, Svingen PA, Schaid DJ. Levamisole potentiation of fluorouracil antiproliferative activity mimicked by orthovanadate, an inhibitor of tyrosine phosphatase. J Natl Cancer Inst 1992;84(7):515-519. [Medline]

11. Wolmark N, Fisher B, Rockette H, et al. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst 1988;80(1):30-36. [Medline]

12. Smith RE, Colangelo L, Wieand HS, Begovic M, Wolmark N. Randomized trial of adjuvant therapy in colon carcinoma: 10-year results of NSABP protocol C-01. J Natl Cancer Inst 2004;96(15):1128-1132. [Medline]

13. Boice JD Jr, Greene MH, Killen JY Jr, et al. Leukemia and preleukemia after adjuvant treatment of gastrointestinal cancer with semustine (methyl-CCNU). N Engl J Med 1983;309(18):1079-1084. [Medline]

14. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990;264(11):1444-1450. [Medline]

15. Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322(6):352-358. [Medline]

16. O’Connell MJ, Mailliard JA, Kahn MJ, et al. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 1997;15(1):246-250. [Medline]

17. O’Connell MJ, Laurie JA, Kahn M, et al. Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 1998;16(1):295-300. [Medline]

18. Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. QUASAR Collaborative Group. Lancet 2000;355(9215):1588-1596. [Medline]

19. Porschen R, Bermann A, Loffler T, et al. Fluorouracil plus leucovorin as effective adjuvant chemotherapy in curatively resected stage III colon cancer: results of the trial adjCCA-01. J Clin Oncol 2001;19(6):1787-1794. [Medline]

20. Arkenau HT, Bermann A, Rettig K, Strohmeyer G, Porschen R. 5- Fluorouracil plus leucovorin is an effective adjuvant chemotherapy in curatively resected stage III colon cancer: long-term follow-up results of the adjCCA-01 trial. Ann Oncol 2003;14(3):395-399. [Medline]

21. Taal BG, Van Tinteren H, Zoetmulder FA. Adjuvant 5FU plus levamisole in colonic or rectal cancer: improved survival in stage II and III. Br J Cancer 2001;85(10):1437-1443. [Medline]

22. Di Costanzo F, Sobrero A, Gasperoni S, et al. Adjuvant chemotherapy in the treatment of colon cancer: randomized multicenter trial of the Italian National Intergroup of Adjuvant Chemotherapy in Colon Cancer (INTACC). Ann Oncol 2003;14(9):1365-1372. [Medline]

23. Link KH, Kornmann M, Staib L, Redenbacher M, Kron M, Beger HG. Increase of survival benefit in advanced resectable colon cancer by extent of adjuvant treatment: results of a randomized trial comparing modulation of 5-FU + levamisole with folinic acid or with interferonalpha. Ann Surg 2005;242(2):178-187. [Medline]

24. Schippinger W, Jagoditsch M, Sorre C, et al. A prospective randomised trial to study the role of levamisole and interferon alfa in an adjuvant therapy with 5-FU for stage III colon cancer. Br J Cancer 2005;92(9):1655-1662. [Medline]
25. Sobrero A, Frassineti G, Falcone A, et al. Adjuvant sequential methotrexate—5-fluorouracil vs 5-fluorouracil plus leucovorin in radically resected stage III and high-risk stage II colon cancer. Br J Cancer 2005;92(1):24-29. [Medline]

26. Haller DG, Catalano PJ, Macdonald JS, et al. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol 2005;23(34):8671-8678. [Medline]

27. De Placido S, Lopez M, Carlomagno C, et al. Modulation of 5-fluorouracil as adjuvant systemic chemotherapy in colorectal cancer: the IGCS-COL multicentre, randomised, phase III study. Br J Cancer 2005;93(8):896-904. [Medline]

28. O’Connell MJ, Sargent DJ, Windschitl HE, et al. Randomized clinical trial of high-dose levamisole combined with 5-fluorouracil and leucovorin as surgical adjuvant therapy for high-risk colon cancer. Clin Colorectal Cancer 2006;6(2):133-139. [Medline]

29. Carrato A, Köhne C, Bedenne L, et al. Folinic acid modulated bolus 5-FU or infusional 5-FU for adjuvant treatment of patients of UICC stage III colon cancer: Preliminary analysis of the PETACC-2-study. J Clin Oncol 2006;24(18S suppl). Abstract 3563.

30. Chau I, Norman AR, Cunningham D, et al. A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer. Ann Oncol 2005;16(4):549-557. [Medline]

31. Poplin EA, Benedetti JK, Estes NC, et al. Phase III Southwest Oncology Group 9415/Intergroup 0153 randomized trial of fluorouracil, leucovorin, and levamisole versus fluorouracil continuous infusion and levamisole for adjuvant treatment of stage III and high-risk stage II colon cancer. J Clin Oncol 2005;23(9):1819-1825. [Medline]

32. Andre T, Colin P, Louvet C, et al. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol 2003;21(15):2896-2903. [Medline]

33. Andre T, Quinaux E, Louvet C, et al. Updated results at 6 year of the GERCOR C96.1 phase III study comparing LV5FU2 to monthly 5FU-leucovorin (mFufol) as adjuvant treatment for Dukes B2 and C colon cancer patients. J Clin Oncol 2005;23(16S suppl). Abstract 3522.

34. Van Cutsem E, Labianca R, Hossfeld D, et al. Randomized phase III trial comparing infused irintecan/5-fluorouracil (5-FU)/folinic acid (IF) versus 5-FU/DA (F) in stage III colon cancer patients (pts). J Clin Oncol 2005;23(3s). Abstract LBA8.

35. Van Cutsem E, Hoff PM, Harper P, et al. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer 2004;90(6):1190-1197. [Medline]

36. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005;352(26):2696-2704. [Medline]

37. Lembersky BC, Wieand HS, Petrelli NJ, et al. Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol 2006;24(13):2059-2064. [Medline]

38. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18(16):2938-2947. [Medline]

39. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000;343(13):905-914. [Medline]

40. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22(2):229-237. [Medline]

41. Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C- 07. J Clin Oncol 2007;25(16):2198-2204. [Medline]

42. de Gramont A, Boni C, Navarro M, et al. Oxaliplatin/5FU/LV in adjuvant colon cancer: Updated efficacy results of the MOSAIC trial, including survival, with a median follow-up of six years. 2007 ASCO Meeting Proceedings. J Clin Oncol 2007;25(18 suppl):4007. Abstracts 2007.

43. Ychou M, Raoul JL, Douillard JY, et al. A phase III randomized trial of LV5FU2+CPT-11 vs. LV5FU2 alone in adjuvant high risk colon cancer (FNCLCC Accord02/FFCD9802). J Clin Oncol 2005;23(246s). Abstract 3502.

44. Land SR, Kopec J, Cecchini R, et al. Patient-reported neurotoxicity with FULV versus FLOX in patients with stage II or III carcinoma of the colon: Results of NSABP Protocol C-07. J Clin Oncol 2006;24(162 suppl). Abstract 3564.

45. Green E, Sargent DJ, Goldberg RM, Grothey A. Detailed analysis of oxaliplatin-associated neurotoxicity in Intergroup trial N9741. Ann Oncol 15(suppl 3):70,2004. Abstract 264O.

46. Ries LAG, Harkins D, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2003, National Cancer Institute. Bethesda, MD. Available at: http://seer.cancer.gov/csr/1975_2003/. [based on November 2005 SEER data submission, posted to the SEER web site, 2006.]

47. Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan plus fluorouracil/ leucovorin (IFL) versus fluorouracil/leucovorin alone (FL) in stage III colon cancer (intergroup trial CALGB C89803). 2004 ASCO Annual Meeting Proceedings. J Clin Oncol 2004;22(14S suppl). Abstract 3500.

48. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351(4):337-345. [Medline]

49. Peeters M, Van Cutsem E, Siena S, et al. A phase 3, multicenter, randomized controlled trial (RCT) of panitumumab plus best supportive care (BSC) vs BSC alone in patients (pts) with metastatic colorectal cancer (mCRC). Proceedings of the 97th American Association for Cancer Research Annual Meeting, April 1, 2006; Washington, DC 2006. Abstract CP-1.

50. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350(23):2335-2342. [Medline]

51. Giantonio BJ, Levy D, O’Dwyer PJ, et al. Bevacizumab (anti-VEGF) plus IFL (irinotecan, fluorouracil, leucovorin) as front-line therapy for advanced colorectal cancer (advCRC): Updated results from the Eastern Cooperative Oncology Group (ECOG) Study E2200. 2004 Gastrointestinal Cancers Symposium 2004. Abstract 289.

52. Riethmuller G, Schneider-Gadicke E, Schlimok G, et al. Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes’ C colorectal carcinoma. German Cancer Aid 17-1A Study Group. Lancet 1994;343(8907):1177-1183. [Medline]

53. Punt CJ, Nagy A, Douillard JY, et al. Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study. Lancet 2002;360(9334):671-677. [Medline]

54. Fields AL, Keller AM, Schwartzberg L, et al. Edrecolomab (17-1A antibody) (EDR) in combination with 5-fluorouracil (FU) based chemotherapy in the adjuvant treatment of stage III colon cancer: results of a randomised North American phase III study. Program and abstracts of the American Society of Clinical Oncology 38th Annual Meeting; May 18-21, 2002; Orlando, Florida. Abstract 508.

55. Gray RG, Barnwell J, Hills R, McConkey C, Williams N, Kerr D, for the QUASAR Collaborative Group. A randomized study of adjuvant chemotherapy (CT) vs observation including 3238 colorectal cancer patients. Proc Am Soc Clin Oncol 2004;23(14S suppl):246. Abstract 3501.

56. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. J Clin Oncol 1999;17(5):1356-1363. [Medline]

57. Figueredo A, Charette ML, Maroun J, Brouwers MC, Zuraw L. Adjuvant therapy for stage II colon cancer: a systematic review from the Cancer Care Ontario Program in evidence-based care’s gastrointestinal cancer disease site group. J Clin Oncol 2004;22(16):3395-3407. [Medline]

58. Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol 2004;22(10):1797-1806. [Medline]

59. Mamounas E, Wieand S, Wolmark N, et al. Comparative efficacy of adjuvant chemotherapy in patients with Dukes’ B versus Dukes’ C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol 1999;17(5):1349-1355. [Medline]

60. Benson AB 3rd, Schrag D, Somerfield MR, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004;22(16):3408-3419. [Medline] 

61. Swanson RS, Compton CC, Stewart AK, et al. The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 2003;10(1):65-71. [Medline]

62. Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst 1988;80(1):21-29. [Medline]

63. Prolongation of the disease-free interval in surgically treated rectal carcinoma. Gastrointestinal Tumor Study Group. N Engl J Med 1985;312(23):1465-1472. [Medline]

64. Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006;355(11):1114-1423. [Medline]

65. Akasu T, Moriya Y, Ohashi Y, Yoshida S, Shirao K, Kodaira S. Adjuvant chemotherapy with uracil-tegafur for pathological stage III rectal cancer after mesorectal excision with selective lateral pelvic lymphadenectomy: a multicenter randomized controlled trial. Jpn J Clin Oncol 2006;36(4):237-244. [Medline]

66. Gunderson LL, Sargent DJ, Tepper JE, et al. Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: a pooled analysis. J Clin Oncol 2004;22(10):1785-1796. [Medline]

67. Dotor E, Cuatrecases M, Martinez-Iniesta M, et al. Tumor thymidylate synthase 1494del6 genotype as a prognostic factor in colorectal cancer patients receiving fluorouracil-based adjuvant treatment. J Clin Oncol 2006;24(10):1603-1611. [Medline]

68. Popat S, Matakidou A, Houlston RS. Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J Clin Oncol 2004;22(3):529-536. [Medline]

69. Iacopetta B, Grieu F, Joseph D, et al. A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil. Br J Cancer 2001;85(6):827-830. [Medline]

70. Jen J, Kim H, Piantadosi S, et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 1994;331(4):213- 221. [Medline]

71. Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatelliteuncorrected instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003;349(3):247-257. [Medline]

72. Carethers JM, Smith EJ, Behling CA, et al. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology 2004;126(2):394-401. [Medline]

73. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005;23(3):609-618. [Medline]

74. Westra JL, Schaapveld M, Hollema H, et al. Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients. J Clin Oncol 2005;23(24):5635-5643. [Medline]

75. Barratt PL, Seymour MT, Stenning SP, et al. DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: a molecular study. Lancet 2002;360(9343):1381-1391. [Medline]

76. Eschrich S, Yang I, Bloom G, et al. Molecular staging for survival prediction of colorectal cancer patients. J Clin Oncol 2005;23(15): 3526-3535. [Medline]

77. Shibata D, Reale MA, Lavin P, et al. The DCC protein and prognosis in colorectal cancer. N Engl J Med 1996;335(23):1727-1732. [Medline]

78. Wang Y, Jatkoe T, Zhang Y, et al. Gene expression profiles and molecular markers to predict recurrence of Dukes’ B colon cancer. J Clin Oncol 2004;22(9):1564-1571. [Medline]

79. Wolmark N, Bryant J, Smith R, et al. Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst 1998;90(23):1810-1816. [Medline]

80. Wolmark N, Rockette H, Mamounas E, et al. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes’ B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol 1999; 17(11):3553-3559. [Medline]