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10.1245/ASO.2006.08.015
Annals of Surgical Oncology 13:1021-1034 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Surgical Adjuvant Therapy for Colorectal Cancer: Current Approaches and Future Directions

Dulabh K. Monga, MD and Michael J. O’Connell, MD

Department of Human Oncology, Allegheny Cancer Center, Allegheny General Hospital, 320 East North Avenue, 5th Floor, Pittsburgh, Pennsylvania 15212

Correspondence: Address correspondence and reprint requests to: Dulabh K. Monga, MD; E-mail: dmonga{at}wphas.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 HIGH-RISK STAGE II AND...
 STAGE II CONTROVERSY
 CURRENT TREATMENT...
 CURRENT CLINICAL TRIALS
 RECTAL CANCER
 ADJUVANT THERAPY AFTER COMPLETE...
 SUMMARY
 REFERENCES
 
Colon cancer is the fourth most common cancer worldwide. The role of systemic adjuvant chemotherapy in colorectal cancer patients with lymph node involvement has been established in a large number of clinical trials. However, its role in stage II colorectal cancer is less well established. 5-Fluorouracil has been the mainstay of therapy for the last four decades. With the development of novel chemotherapy and biological agents, we have entered into a new era for the treatment of colorectal cancer. The combination of adjuvant 5-fluorouracil, leucovorin, and oxaliplatin has been shown to significantly improve disease-free survival and is now considered the standard of care for completely resected colon cancer in healthy patients. For rectal cancer patients with locally advanced tumors, neoadjuvant chemoradiation followed by adjuvant chemotherapy after surgery is the mainstay of treatment. The availability of oral chemotherapy agents has helped with the ease of administration and avoidance of indwelling catheters. A number of national clinical trials are under way to determine the role of targeted agents in combination with chemotherapy. The goal is to develop a regimen that would improve survival without excessive toxicity while maintaining quality of life. Patients should be encouraged to participate in clinical trials whenever feasible. Despite the advances, many patients will develop recurrent disease. It is of utmost importance to develop molecular markers that could predict which patients are at high risk for disease recurrence. Clinical trials are under way to address this issue. Thus, it will be advantageous to be able to tailor therapy individually, according to the risk of recurrence.

Key Words: 5-FU • Oxaliplatin • Capecitabine • Stage II • Stage III • Chemoradiation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
HIGH-RISK STAGE II AND...
 STAGE II CONTROVERSY
 CURRENT TREATMENT...
 CURRENT CLINICAL TRIALS
 RECTAL CANCER
 ADJUVANT THERAPY AFTER COMPLETE...
 SUMMARY
 REFERENCES
 
Colon cancer is the second leading cause of cancer mortality in the United States. The American Cancer Society estimates that in the year 2006, approximately 148,610 people will be diagnosed with colorectal cancer, of which 55,170 will die of this disease.1

Surgical stage remains the most accurate predictor of survival. Pathologic prognostic factors of primary tumor invasion, regional lymph node involvement, and the presence or absence of metastasis predict the risk of relapse of this disease. Table 1Go shows the 5-year survival rates according to stage after surgical resection for cure. It is important to note that as many as 50% to 60% of patients who undergo definitive surgery have residual microscopic disease that may manifest either locally or at distant sites after surgery.2,3


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  		TABLE 1. Surgical stage and survival in colon cancer
 
Adjuvant therapy is systemic treatment administered with the intent of reducing the risk of recurrences and increasing the proportion of patients cured. The risk of recurrence after resection can be predicted by pathologic staging. The benefit of adjuvant therapy in patients with lymph node involvement (stage III/ Dukes’ C) has been well established in large prospective randomized trials over the last two decades. The role in stage II or Dukes’ B is less well established, although there is a growing consensus that stage II patients also benefit from adjuvant therapy on the basis of pooled analyses of large randomized adjuvant therapy trials6,7 and a recent randomized trial8 that documented a survival benefit for stage II patients treated with adjuvant chemotherapy.

The liver is the most common site of metastatic disease. Approximately 15% of patients have liver involvement at the time of diagnosis. The 5-year survival for patients with one to three metastatic lesions who have a resection of colorectal liver metastasis is ≥30%.9,10 Patients with completely resected metastatic disease may benefit from adjuvant therapy.

Rectal cancer differs from colon cancer in that there is an increased risk of local recurrence. Therefore, the optimal adjuvant therapy for patients with rectal cancer is combined systemic chemotherapy and radiotherapy.11


   HIGH-RISK STAGE II AND STAGE III COLON CANCER
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 ABSTRACT
 INTRODUCTION
 HIGH-RISK STAGE II AND...
STAGE II CONTROVERSY
 CURRENT TREATMENT...
 CURRENT CLINICAL TRIALS
 RECTAL CANCER
 ADJUVANT THERAPY AFTER COMPLETE...
 SUMMARY
 REFERENCES
 
5-Fluorouracil (5-FU) has been the mainstay of therapy for colorectal cancer for the last several decades. Adjuvant 5-FU and levamisole was tested in a North Central Cancer Treatment Group (NCCTG) randomized trial versus observation alone. This trial demonstrated an improvement in survival for stage III patients.12 This was confirmed by an intergroup trial that demonstrated a 40% decrease in the relative risk of recurrence and a 33% decrease in the relative risk of mortality in patients with stage III colon cancer13–15 and led to approval of the combination by the Food and Drug Administration (FDA) in 1990 as the new standard of care.

Subsequently, 5-FU and leucovorin (LV) demonstrated a significant survival advantage over surgery alone16 or surgery followed by chemotherapy with semustine, vincristine, and 5-FU.17 The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-03 was the first trial to demonstrate the value of 5-FU and LV (Roswell Park Schedule) in the adjuvant setting. 5-FU/LV increased the disease-free survival (DFS) and reduced the mortality risk when compared with a 5-FU/semustine/vincristine regimen when administered for 1 year.17 The 10-year follow-up results presented at the American Society of Clinical Oncology (ASCO) 2005 meeting18 continue to confirm the highly significant improvement in DFS and overall survival (OS) for patients with stage II and III colon cancer. These results translate into a relative risk reduction of 24% in DFS and 22% in OS and an absolute advantage in each of these parameters of approximately 10% at 10 years.

The NCCTG trial demonstrated a significant survival benefit with only six monthly cycles of 5-FU and low-dose LV.16

The International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) group performed a meta-analysis of three trials comparing 5-FU/LV and observation alone. Long-term follow-up demonstrated a survival benefit for 5-FU/LV for patients with stage III cancer with a 22% relative reduction in mortality, although the difference was not significant among patients with stage II disease.19

Subsequently, different 5-FU–based regimens including levamisole, LV, or both were compared in large randomized trials. These trials demonstrated that a 6-month 5-FU/LV–containing regimen was equivalent to a 12-month 5-FU/levamisole regimen. Also, 5-FU/levamisole for 6 months was an inferior regimen.20 The INT-0089 trial was another pivotal trial that confirmed that 6 months of adjuvant 5-FU/ LV was as effective as 12 months of 5-FU/levamisole.21 It also demonstrated that the addition of levamisole to the 5-FU/LV combination was not beneficial, thus confirming an earlier NSABP clinical trial (NSABP C-04).22 On the basis of these studies, 6 months of 5-FU/LV became the standard of care.

More recently, the positive results of the international MOSAIC (Multi-center International Study of Oxaliplatin/5-FU/Leucovorin in the Adjuvant Treatment of Colon Cancer) trial were reported.23 This study led to US FDA approval of oxaliplatin plus 5-FU/LV (FOLFOX) for patients with stage III colon cancer in November 2004. The FOLFOX regimen demonstrated superiority in terms of 3-year DFS compared with an infusional 5-FU/LV (LV5FU2) regimen. A total of 1123 patients were randomized to each arm. The primary end point was DFS. At 3 years, DFS in the 5-FU, LV, and oxaliplatin arm was 77.8%, compared with 72.9% in the 5-FU/LV arm. There was a 23% risk reduction in the FOLFOX arm. The incidence of grade 3 neuropathy was 12.4% during treatment in the oxaliplatin arm, and this decreased to 1.1% at the 1-year follow-up. A 4-year update was presented at ASCO in 2005.24 The 4-year DFS was 76.4% in patients receiving FOL-FOX versus 69.8% in the LV5FU2 arm, thus translating to a 24% reduction in the relative risk of relapse in the FOLFOX group. Overall, 84.3% and 82.7% of patients are still alive in the FOLFOX4 and the LV5FU2 arms, respectively, and further follow-up will be required to determine the magnitude of the survival benefit. It is important to note that at 4 years, only 3.4% of patients had persistent localized paresthesias of moderate intensity (2.7%) or paresthesias that might interfere with functional activities (.7%); this indicates that the neurotoxicity from oxaliplatin is reversible in the vast majority of patients.

NSABP C-07 was a phase III trial that compared 5-FU/LV (Roswell Park bolus schedule) with the same regimen but with the addition of oxaliplatin (FLOX) in stage II and III carcinoma of the colon.25 At 34 months’ follow-up, results demonstrated that the adjuvant bolus FLOX regimen was superior to bolus 5-FU/LV, with a similar benefit in risk reduction, as demonstrated with FOLFOX in the MOSAIC trial. The 3-year DFS was 76.5% in the FLOX arm versus 71.6% in the 5-FU/LV arm (P < .004), thus translating into a 21% risk reduction. The frequency of severe neuropathy (8%) was lower than that seen with FOLFOX in the MOSAIC trial, probably because of a lower cumulative dose of oxaliplatin, although the incidence of diarrhea was somewhat higher. An additional advantage of the FLOX regimen is the ease of administration without the need for central venous catheters and infusion pumps.

With irinotecan showing promising activity in the metastatic setting, it was sought to be tested in the adjuvant setting. Intergroup Cancer and Leukemia Group B 89803 randomized stage III patients to 5-FU/LV or irinotecan, 5-FU, and LV (IFL).26 This trial demonstrated greater toxicity and an increased risk of death with weekly bolus IFL. There was no associated clinical benefit compared with weekly bolus 5-FU/LV. The Pan-Adjuvant Trials in Adjuvant Colon Cancer (PETACC) III trial27 failed to demonstrate a significant benefit from adding irinotecan to an infusional schedule of 5-FU and LV, and the Foundation Francoise de Cancérologie Digestive Adjuvant Trial (ACCORD) trial28 clearly ruled out any significant benefit for the IFL regimen in patients with high-risk stage III disease. These three trials failed to provide any justification for the use of irinotecan-based regimens in the adjuvant setting.

Oral chemotherapeutic agents are advantageous because of their ease of administration, patient convenience, and lack of the need for central venous catheters. Capecitabine and UFT (tegafur plus uracil) are oral chemotherapy agents with activity against colorectal cancer. The role of capecitabine, which is a tumor-activated oral fluoropyrimidine, was evaluated in the Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) study.29 The 4.3-year follow-up continues to confirm that capecitabine is at least equivalent to 5-FU/LV in terms of DFS.30 Furthermore, the safety profile for capecitabine was better compared with the Mayo Clinic regimen of 5-FU and LV. There was decreased gastrointestinal toxicity, grade 3 or 4 neutropenia, fever, and sepsis. This advantage was maintained in older patients. Hand-foot syndrome was more common with capecitabine but was manageable. Hand-foot syndrome is a palmar-plantar erythrodysesthesia that can manifest as erythema, tenderness, blistering, or desquamation on the palms or plantar aspects of feet. The X-ACT study was conducted in Europe, where patients tolerate higher doses of capecitabine than do patients in the United States, perhaps because of differences in dietary folate content. Oncologists in the United States need to carefully monitor patients receiving capecitabine in the recommended adjuvant therapy doses (1250 mg/m2 twice daily) for signs of hand-foot syndrome or diarrhea. The FDA approved capecitabine in May 2005 for adjuvant treatment of stage III colon cancer in patients who would not tolerate an oxaliplatin-based regimen.

NSABP C-06 demonstrated the equivalence of oral UFT and LV to 5-FU/LV in resected stage II and III colon cancer.31 Quality-of-life studies demonstrated improved patient convenience for the oral regimen. Nevertheless, UFT is not approved by the FDA in the United States at this time, but it is routinely used in other countries.


   STAGE II CONTROVERSY
TOP
 ABSTRACT
 INTRODUCTION
 HIGH-RISK STAGE II AND...
 STAGE II CONTROVERSY
CURRENT TREATMENT...
 CURRENT CLINICAL TRIALS
 RECTAL CANCER
 ADJUVANT THERAPY AFTER COMPLETE...
 SUMMARY
 REFERENCES
 
Early clinical trials were not adequately powered to demonstrate a statistically significant advantage for chemotherapy in stage II colon cancer. The relatively good prognosis with surgery alone in these patients makes it difficult to demonstrate a survival benefit without enrolling thousands of patients in adjuvant chemotherapy trials. The IMPACT investigators and the NSABP performed pooled retrospective analyses in an attempt to answer this question.

The IMPACT investigators pooled data on 5 prospective trials of 5-FU/LV versus observation consisting of 1016 stage II patients.32 A 2% absolute improvement in OS favoring the treatment arm was demonstrated, and this came close to, but did not achieve, statistical significance.

The NSABP compared the inferior arms of the C-01, C-02, C-03, and C-04 with the superior arms of these trials.7 The four trials included Dukes’ B and C patients. Two trials compared surgery-alone therapy to surgery plus adjuvant therapy, and two compared two different chemotherapy regimens. Forty-one percent of the patients included in these four trials had resected Dukes’ B tumors. Combined analysis of the data from all four trials demonstrated a mortality reduction of 30% for Dukes’ B patients versus 18% for Dukes’ C patients. The mortality reduction in Dukes’ B patients occurred irrespective of the presence or absence of adverse prognostic factors. The investigators concluded that stage II patients receive a reduction in the risk of relapse or death from adjuvant chemotherapy similar to stage III patients and should be presented with this treatment option.

Recently a pooled analysis of seven randomized trials, which included the five IMPACT B2 trials, compared adjuvant 5-FU/LV or 5-FU/levamisole with surgery alone in stage II and stage III colon cancer.6 The goal of the study was to estimate the effects of treatment in different subsets of patients. There was a significant improvement in 5-year DFS in the node-negative patients (72% vs. 76%; P = .0490). The difference in 5-year OS (80% vs. 81%; P = .1127) did not reach statistical significance. A significant stage x treatment interaction was present. Adjuvant chemotherapy seemed to benefit stage III patients to a greater extent than stage II patients. A difference in the degree of benefit was observed, with reductions in the risk of recurrence and death of 17% and 15%, respectively, for node-negative disease as compared with 40% and 35%, respectively, for node-positive disease. The study confirmed that nodal status, histological grade, and depth of tumor invasion into the bowel wall were the only prognostic factors independently significant for both DFS and OS.

The CCOPEBC (Cancer Care Ontario Program in Evidence-Based Care’s gastrointestinal cancer disease site group) recently performed a systematic review of data from clinical trials comparing adjuvant therapy with observation in patients with resected stage II colon or colorectal cancer.33 In 1997, the CCOPEBC published an evidence-based practice guideline on the use of adjuvant chemotherapy in stage II colon cancer after complete resection.34 This trial was updated and also included literature published since 1997. Analysis was based on 37 randomized controlled trials and 11 meta-analyses including 20,317 patients. Meta-analysis of stage II patients (n = 4187) was performed. The relative risk reduction in mortality across the trials was 13% (hazards ratio, .87; 95% confidence interval, .75–1.01; P = .07).

In 2004, ASCO recommended guidelines for adjuvant chemotherapy in stage II patients. ASCO, in conjunction with the Cancer Care Ontario Practice Guideline Initiative, performed a literature-based meta-analysis through May 2003.35 Thirty-seven randomized controlled trials and 11 meta-analyses of adjuvant chemotherapy or immunotherapy were identified. There was no evidence of a significant survival benefit for stage II patients. An analysis of a subset of 12 trials from the 37 pooled trials was also performed. The 12 trials required the inclusion of a surgery-alone control arm and at least one 5-FU–based arm. This also did not show any significant survival benefit. On the basis of these results, the authors recommended against the routine use of adjuvant chemotherapy for stage II patients. However, it was suggested that it could be considered for patients with high-risk prognostic features on an individualized basis.

Subsequently, the QUASAR (Quick and Simple and Reliable) Collaborative Group from the United Kingdom conducted the QUASAR trial, which was completed and presented at ASCO 2004. This clinical trial compared adjuvant 5-FU–based chemotherapy with observation in patients with resected colon or rectal cancer.8 A total of 3238 patients were enrolled, of whom 91% had stage II disease. At 4.6 years, there was a significant improvement in the 5-year survival rate (80.3% vs. 77.4%; P = .02) and the 5-year recurrence rate (22.2% vs. 26.2%; P = .001) in the adjuvant chemotherapy group. It is important to note that when stage II patients were analyzed separately, there was a significant reduction in the number of deaths with adjuvant chemotherapy (224 vs. 262; P = .04). This is the first study to demonstrate a statistically significant advantage of chemotherapy in a large population of stage II patients <70 years of age. The authors concluded that chemotherapy produces a small survival benefit (1%–5%) for Dukes’ B patients; this is sufficient to outweigh the inconvenience and cost for high-risk and younger patients.


   CURRENT TREATMENT RECOMMENDATIONS
TOP
 ABSTRACT
 INTRODUCTION
 HIGH-RISK STAGE II AND...
 STAGE II CONTROVERSY
 CURRENT TREATMENT...
CURRENT CLINICAL TRIALS
 RECTAL CANCER
 ADJUVANT THERAPY AFTER COMPLETE...
 SUMMARY
 REFERENCES
 
As discussed previously, there are now several options for the adjuvant treatment of colon cancer (Table 2Go). Various treatment options need to be discussed with patients. The decision of whether to treat and what regimen to use is based on an assessment of prognosis based on clinical factors such as pathologic stage and tumor grade, patient comorbidities, and the risk-benefit ratio of different chemotherapy regimens. For an otherwise healthy patient with a high-risk colon cancer, adjuvant FOLFOX or the FLOX regimen would provide the most effective therapy. An oxaliplatin-based regimen would not be appropriate for patients with underlying diabetes complicated by peripheral neuropathy. For patients with multiple comorbidities and suboptimal performance status or for patients at lower risk of tumor relapse, an oral drug such as capecitabine or intravenous 5-FU and LV may be administered with careful monitoring of side effects. With the expansion in the armamentarium of drugs for colon cancer and the demonstrable benefits in DFS and OS, it is imperative that surgeons refer their patients with resected stage II and III colon cancer to a medical oncologist for a discussion regarding the various treatment options in the adjuvant setting. This should include discussion of various clinical trials whenever they are available.


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  		TABLE 2. Current options for adjuvant treatment in colorectal cancer
 

   CURRENT CLINICAL TRIALS
TOP
 ABSTRACT
 INTRODUCTION
 HIGH-RISK STAGE II AND...
 STAGE II CONTROVERSY
 CURRENT TREATMENT...
 CURRENT CLINICAL TRIALS
RECTAL CANCER
 ADJUVANT THERAPY AFTER COMPLETE...
 SUMMARY
 REFERENCES
 
The development of targeted agents has led to a new era in the treatment of colon cancer. Bevacizumab is an antiangiogenic monoclonal antibody to vascular endothelial growth factor. In combination with IFL in the first-line metastatic setting, bevacizumab has been shown to significantly improve OS.36 A total of 813 patients with previously untreated metastatic colorectal cancer were randomized to IFL plus bevacizumab (402 patients) or IFL plus placebo (411 patients). The primary end point was OS. The median duration of survival in the IFL plus bevacizumab group was 20.3 months, versus 15.6 months in the group given IFL plus placebo. The statistically significant improvement in survival led to the recent approval of bevacizumab by the FDA in the first-line metastatic setting in combination with intravenous 5-FU–based regimens.

Cetuximab is another monoclonal antibody directed against the ligand-binding site of the epidermal growth factor receptor. It has been approved by the FDA in patients with metastatic colon cancer in combination with irinotecan in patients who are irinotecan refractory.26,37 The efficacy of cetuximab in combination with irinotecan was compared with that of cetuximab alone in metastatic colon cancer refractory to irinotecan alone. The response rate in the combination therapy group was 22.9% vs. 10.9% in the monotherapy group, which was statistically significant (P = .007). The median time to progression was greater in the combination-therapy group (4.1 vs. 1.5 months; P < .001). The median survival was 8.6 months in the combination-therapy group and 6.9 months in the monotherapy group (P = .48). The impressive response rates of the combination therapy in irinotecan-refractory tumors suggest that cetuximab may overcome irinotecan resistance.

The development of targeted therapies with activity in the metastatic setting has led to the development of a number of promising national clinical trials using FOLFOX as a chemotherapy platform, with the addition of a monoclonal antibody in the adjuvant setting (Fig. 1A and BGo). A number of studies have been conducted to identify prognostic markers that would aid in therapeutic decision making in patients with early stage cancer. The Eastern Cooperative Oncology Group 5202 intergroup trial is stratifying stage II patients into high-risk and low-risk groups based on microsatellite instability and 18q deletion in the resected colon tumor. High-risk patients will receive FOLFOX with or without bevacizumab, whereas low-risk patients will be followed up on an observation basis (Fig. 1CGo).


Figure 1
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  		FIG. 1. (A) National Surgical Adjuvant Breast and Bowel Project C-08 schema: randomized phase III trial. (B) Intergroup study North Central Cancer Treatment Group 0147 schema: randomized phase III trial. (C) E5202 Intergroup trial schema: randomized phase III trial. MSS, microsatellite stability; MSI, microsatellite instability; LOH, loss of heterozygosity.

 

   RECTAL CANCER
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 ABSTRACT
 INTRODUCTION
 HIGH-RISK STAGE II AND...
 STAGE II CONTROVERSY
 CURRENT TREATMENT...
 CURRENT CLINICAL TRIALS
 RECTAL CANCER
ADJUVANT THERAPY AFTER COMPLETE...
 SUMMARY
 REFERENCES
 
A total of 34,000 new cases of rectal cancer are diagnosed each year. The successful treatment of patients with rectal cancer requires a multidisciplinary approach. This includes an optimal surgical approach and, frequently, adjuvant chemoradiotherapy. This approach maximizes the number of patients cured, reduces the risk of symptomatic pelvic recurrences, and maintains quality of life. The incidence of local recurrence and distant failure is related to the degree of transmural invasion and the number of lymph nodes involved.38–40 Distant failure is the most common cause of death, but most patients with locoregional and pelvic recurrences experience severe sacral or deep pelvic pain. Therefore, decreasing locoregional failure is an important end point in the treatment of rectal cancer. This serves as the basis for prescribing adjuvant chemoradiotherapy as a standard for American Joint Committee on Cancer stage II and III disease.

The major advantage of postoperative therapy in rectal cancer is the ability to base treatment on the operative findings and pathologic staging. The role of postoperative adjuvant 5-FU–based chemoradiotherapy was defined in early studies such as the Gastrointestinal Tumor Study Group41 and the NCCTG.14 These studies demonstrated an improvement in local control, DFS, and OS with combined-modality therapy after surgical resection. On the basis of these results, postoperative chemoradiation became the standard of care for T3, T4, and/or N1 or N2 rectal cancer.13

The NSABP R-01 study was a 3-arm study conducted in 555 patients with Dukes’ B and C rectal cancer.38 After curative surgical resection, patients were randomized to receive no further treatment, postoperative adjuvant chemotherapy, or postoperative radiotherapy. The chemotherapy group demonstrated an improvement in DFS and in OS. The observed advantage was restricted to men. Postoperative radiotherapy reduced the incidence of locoregional recurrence but had no effect on DFS and OS.

The NSABP R-02 study was a follow-up study designed to evaluate the effect of radiation on the OS in the postoperative adjuvant setting.42 Patients were randomly assigned to receive either postoperative adjuvant chemotherapy alone or chemotherapy with postoperative radiotherapy. At a median follow-up of 7 years, there was no survival advantage with postoperative radiation. However, the local recurrence rate was significantly lower in the combined-modality group at 5 years. Locoregional relapse was reduced from 13% to 8% at the 5-year follow-up (P = .02). This study demonstrated that the addition of postoperative radiation to chemotherapy in Dukes’ B and C rectal cancer did not alter the incidence of distant disease, although there was a reduction in local relapse when compared with chemotherapy alone. Results from both R-01 and R-02 studies laid the backbone for future studies by demonstrating the importance of combined-modality treatment in rectal cancer with chemotherapy for controlling distant disease and radiotherapy for decreasing the incidence of locoregional recurrence, which is associated with significant morbidity and reductions in quality of life.

Subsequently, several trials were conducted to evaluate the safest and most effective way of administering chemoradiotherapy. Protracted venous infusions of 5-FU concurrently with postoperative radiation to the pelvis demonstrated an improvement in relapse-free interval and decreased death rates when compared with patients who received a bolus 5-FU and semustine regimen.43 This has been widely adopted as the standard in the United States.

Intergroup 0114 demonstrated that there was no advantage to adding levamisole or LV to bolus 5-FU when combined with irradiation as postoperative adjuvant therapy.44 All patients had a curative surgical resection and were treated with two cycles of chemotherapy followed by chemoradiotherapy and two additional cycles of chemotherapy. Chemotherapy regimens were bolus 5-FU; 5-FU and LV; 5-FU and levamisole; and 5-FU, LV, and levamisole. The median follow-up was 7.4 years. There was no difference in OS and DFS by drug regimen. The local recurrence rate was 14% (9% in low-risk [T1/2N+] and 18% in high-risk [T3N+ and T4N+] patients). The 7-year OS rates were 70% for the low-risk and 45 % for the high-risk groups.

The follow-up Intergroup 0144 study evaluated longer periods of continuous-infusion 5-FU and demonstrated similar 3-year relapse-free survival (68%–69%; P = .45) and OS (81%–83%; P = .21) rates.45 Grade 3 and 4 hematological toxicity was 50% with bolus 5-FU, compared with 4% for the continuous-infusion 5-FU arm. Because of the more favorable hematological toxicity profile, many oncologists favor continuous-infusion 5-FU.

There has been a growing interest over the last decade in the role of preoperative therapy in patients with American Joint Committee on Cancer stage II and III rectal cancer. Adjuvant preoperative therapy, which is usually concurrent chemoradiotherapy, has certain advantages over postoperative adjuvant therapy. The major benefits are downstaging of the tumor, increasing resectability, and sphincter preservation, thus allowing for a curative surgical resection with adequate margins.46 This also allows tumors to be resected with limited longitudinal surgical margins, hence increasing the level to which sphincter-sparing procedures can be performed in the distal rectum.47 Preoperative therapy is also associated with a significant reduction in tumor spillage and the potential for dissemination of tumor cells during surgery, thus leading to an increased risk of distant metastatic disease. Before surgery, the tumor bed blood supply is well preserved. This enhances oxygenation, thereby improving the effects of radiation.48,49 There is a reduced risk of chemoradiation-induced morbidity because the small bowel is less likely to be fixed in the treatment field if chemo-radiation therapy is given before surgery. After surgery, adhesions develop, thus causing the small bowel to be fixed in the pelvis and thereby increasing treatment-related toxicity.

The Swedish multicenter trial48,49 compared pre-operative versus postoperative radiation in rectal and rectosigmoid carcinoma. The local recurrence rate was lower after preoperative radiation than after postoperative radiation. In a follow-up trial, the Swedish group conducted a study evaluating preoperative radiotherapy 25 Gy in 5 days versus surgery alone. This was the first trial to demonstrate a 5-year survival benefit of in the preoperative radiation plus surgery group compared with the surgery-alone group.50

The Dutch Colorectal Cancer Group randomized patients with resectable rectal cancer to preoperative radiation before total mesorectal excision versus total mesorectal excision alone.51 This study again demonstrated a significant reduction in the risk of local recurrence at 2 years, and this reduction continues at 5 years in the preoperative radiation group.52 The rate of local recurrence at 2 years was 5.3% in the surgery-only group, 2.4% in the radiotherapy and surgery group, and 8.2% in the surgery-alone group (P < .001).

There have been several phase II studies of pre-operative chemoradiation with 5-FU–based chemotherapy. The pathologic complete response rates range from 20% to 26%, compared with only 6% to 12% with radiation alone.53–56 The advantage of combined chemoradiation administered before surgery is increased sphincter preservation with coloanal anastomosis instead of abdominoperineal resection. This can be achieved in 60% to 80% patients.57–59

The direct comparison of preoperative versus postoperative chemoradiation for clinically resectable cancers was attempted in three randomized controlled trials.60,61 The two trials conducted in the United States (Intergroup 0147 and NSABP R-03) underwent early closure secondary to poor accrual. The 1-year follow-up analysis of the R-03 trial demonstrated that more patients underwent sphincter preservation without evidence of disease in the pre-operative group compared with the postoperative group. The 5-year follow-up results of the 267 enrolled patients revealed prolonged OS and DFS in the preoperative group; this difference did not reach statistical significance.

The recently published German study, CAO/ARO/ AIO-94,61 randomized 799 patients to similar 5-FU–based preoperative and postoperative regimens of chemoradiation. The standard total mesorectal excision technique of surgical resection was used. One month after surgery, four cycles of 5-FU were administered. There was no difference in OS at a median follow-up of 4 years. However, rates of pelvic recurrence (6% before vs. 13% after surgery; P = .006) favored the preoperative arm. It is important to note that the sphincter-preservation rate was 39% in the preoperative group in patients deemed to have an abdominoperineal resection by the surgeon before randomization, compared with 19% in the postoperative group (P = .004). In addition, tumor down-staging, grade 3 and 4 toxicity, and treatment compliance were in favor of the preoperative arm. Given the compelling results of the German rectal trial, preoperative chemoradiation should now be considered the standard of care for patients with stage II or III rectal cancer.

With the development of several active systemic agents, such as irinotecan, oxaliplatin, capecitabine, bevacizumab, and cetuximab, trials are under way in combination with radiotherapy. The NSABP R-04 is a phase III study comparing capecitabine or the standard continuous-infusion 5-FU with or without oxaliplatin concurrently with radiation (Fig. 2Go). Eastern Cooperative Oncology Group 5204 is an intergroup randomized phase III postoperative study for patients with stage II or III rectal cancer who will receive either postoperative 5-FU, LV, and oxaliplatin or a similar regimen with bevacizumab for 6 months. Patients who have completed R-04 would be eligible for this study.


Figure 2
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  		FIG. 2. National Surgical Adjuvant Breast and Bowel Project R-04 schema: phase III randomized trial. RT, radiotherapy.

 
The national goal is to find an optimal combination of novel agents (chemotherapeutic as well as biological) that, in combination with radiotherapy, will have tolerable toxicity profiles, improve preoperative response rates, and maximize the efficacy of postoperative systemic control. This will require a combined national effort of the various cooperative groups.


   ADJUVANT THERAPY AFTER COMPLETE RESECTION OF LIVER METASTASIS
TOP
 ABSTRACT
 INTRODUCTION
 HIGH-RISK STAGE II AND...
 STAGE II CONTROVERSY
 CURRENT TREATMENT...
 CURRENT CLINICAL TRIALS
 RECTAL CANCER
 ADJUVANT THERAPY AFTER COMPLETE...
SUMMARY
 REFERENCES
 
The liver is the most common site for distant metastatic disease in colorectal carcinoma.62 The gastrointestinal tract is drained by the portal vein, and this explains the high rate of liver metastasis from these sites. A total of 15% of patients with colorectal cancer will present with liver metastasis, and approximately 50% of patients will develop liver metastasis.62 The liver has a dual blood supply from both the hepatic artery (25%) and the portal vein (75%). However, the areas of liver metastasis derive most of their blood supply from the hepatic artery (80%).63

Hepatic resection of liver metastasis is now accepted as the gold standard whenever feasible. Five-year survival rates after hepatic metastasectomy in patients with liver-only disease are in the range of 25% to 44%.9,64–66 Despite this cure rate, the rate of recurrence is as high as 50% in the liver. To optimize surgical outcome, a small number of studies have been conducted to evaluate the role of adjuvant chemotherapy and regional therapies, including hepatic arterial infusion of chemotherapy.

In one study conducted at Memorial Sloan-Kettering Cancer Center, patients (n = 156) were randomized at the time of resection of liver metastasis to receive either 6 cycles of hepatic arterial infusion with floxuridine plus systemic chemotherapy with 5-FU/LV or 6 weeks of 5-FU/ LV. The study end points were OS, survival without recurrence of hepatic metastasis, and survival without any metastasis at 2 years. The 2-year survival was significantly increased in the combination arm (86% vs. 72%; P = .03). The median survival was 72.2 months in the combined-therapy group and 60% in the monotherapy group. The liver recurrence–free survival at 2 years was in favor of the combination arm67 (90% vs. 60%; P < .001), and the progression-free survival was 57% and 42%, respectively (P = .07). The fact that overall progression–free survival was not increased as much as hepatic progression–free survival in the combined-therapy group indicates that systemic chemotherapy must be used in addition to chemotherapy delivered via hepatic arterial infusion. The rates of adverse effects of moderate severity were similar in both groups, except for an increased frequency of diarrhea and hepatic effects in the combined-therapy group.

In an intergroup study (Eastern Cooperative Group and Southwest Oncology Group), patients were randomized before surgery to either hepatic resection alone or resection followed by 4 cycles of hepatic arterial infusion with floxuridine and 12 cycles of systemic infusion of 5-FU. The 4-year liver recurrence–free survival was in favor of the chemotherapy group (46% and 25%, respectively; P = .04). The median survival was not significantly different between the two groups (47 vs. 34 months; P = .19).68 Given the small number of patients in this study, the definitive role of this approach is yet to be determined.

The NSABP C-09 study is comparing adjuvant capecitabine and oxaliplatin with hepatic arterial infusion with floxuridine plus capecitabine and oxaliplatin in patients who have undergone complete resection of liver metastasis (Fig. 3AGo). This randomized clinical trial should put the value of hepatic arterial chemotherapy into perspective compared with modern systemic combination chemotherapy alone in a multi-institutional setting.


Figure 3
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  		FIG. 3. (A) National Surgical Adjuvant Breast and Bowel Project C-09 schema: randomized phase III trial. (B) North Central Cancer Treatment Group phase II N 014A schema: phase II. HAI FUDR, hepatic arterial infusion with floxuridine. PR, partial response; CR, compete response.

 
Recently, there has been an increasing interest in neoadjuvant therapy for patients with liver metastases in an attempt to increase resectability. This approach would help in determining the biology of disease and, potentially, in tailoring postoperative therapy. Also, patients whose disease progresses rapidly despite chemotherapy would most likely experience recurrence after liver resection and may be saved an unnecessary operation. Retrospective analyses with oxaliplatin-based therapy regimens have demonstrated downstaging of hepatic metastasis, resulting in 15% of cases being converted to resectability and, thus, yielding an enhanced OS.67,69–72 In an international phase II study using FOLFOX4 with cetuximab in the first-line treatment of patients with metastatic colorectal cancer, approximately 20% patients treated with a palliative intent were able to undergo hepatic resection.73

The European Organization for Research and Treatment of Cancer has recently completed accrual on a clinical trial evaluating preoperative and postoperative FOLFOX versus no chemotherapy for resectable liver metastasis. There are currently no data available from this clinical trial.

The NCCTG and NSABP conducted a phase II study in which patients with initially unresectable liver-only metastasis received FOLFOX. Of the 42 eligible patients, 26 patients (62%) had tumor reduction by preoperative imaging, and 17 patients (41%; 65% of responders) underwent surgery (14 complete resections and 1 partial resection) after 6 months of therapy. The median survival was 31.4 months.74 The NCCTG trial N014A will assess the efficacy of FOLFOX and cetuximab (C225) in patients with liver-only metastasis, who are not considered optimally resectable (Fig. 3BGo).


   SUMMARY
TOP
 ABSTRACT
 INTRODUCTION
 HIGH-RISK STAGE II AND...
 STAGE II CONTROVERSY
 CURRENT TREATMENT...
 CURRENT CLINICAL TRIALS
 RECTAL CANCER
 ADJUVANT THERAPY AFTER COMPLETE...
 SUMMARY
REFERENCES
 
In the last decade, there have been rapid advances in the adjuvant therapy of colorectal cancer. Current evidence supports the use of either the FOLFOX or the FLOX regimen as the first choice for patients with surgically resected high-risk stage II and stage III colon cancer. For patients with multiple comorbidities and for those who are less fit, single-agent oral capecitabine or 5-FU/LV can be used. Preoperative chemoradiotherapy is now the standard of care for patients with locally advanced rectal cancer, followed by adjuvant chemotherapy after surgical resection. There are questions that remain over the role of adjuvant hepatic arterial infusion with systemic chemotherapy in patients with liver-only metastatic disease that has been completely resected. The NSABP C-09 trial is in progress and will help to answer this question.

It is imperative for physicians to discuss the various treatment options that are available and their risk-benefit ratio for individual patients. The development of various molecular targeted agents has led to the integration of these agents into various national clinical trials. Patients should be strongly encouraged to participate in these clinical trials. The aim of these trials is to improve the cure rate and demonstrate a favorable toxicity profile so that patients can continue to maintain their quality of life. Physicians may refer to algorithms for adjuvant therapy in colon and rectal cancer to aid in the decision-making process (Fig. 4Go).


Figure 4
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  		FIG. 4. (A) Algorithm for adjuvant treatment of colon cancer. (B) Algorithm for adjuvant treatment of rectal cancer. 5-FU, 5-fluorouracil; LV, leucovorin.

 
Despite the advances that have been made, many patients will die of recurrent or distant metastatic disease. To better tailor therapy to each patient, molecular markers need to be identified that will accurately identify prognosis and predict the response to therapy.

Received for publication August 10, 2005. Accepted for publication January 6, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 HIGH-RISK STAGE II AND...
 STAGE II CONTROVERSY
 CURRENT TREATMENT...
 CURRENT CLINICAL TRIALS
 RECTAL CANCER
 ADJUVANT THERAPY AFTER COMPLETE...
 SUMMARY
 REFERENCES
 

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