Radiation Therapy for Resectable Colon Cancer

Colon cancer is a major public health problem. The primary treatment is resection. For patients with early-stage disease, surgery results in excellent survival rates. In contrast, patients with locally advanced tumors arising in "anatomically immobile" segments of large bowel have a less satisfactory outcome, in part secondary to compromised surgical clearance. Patterns-of-failure analyses suggest that for tumors that invade adjacent organs, exhibit perforation or fistula, or are subtotally resected, local failure rates exceed 30%. Multiple single-institution retrospective studies have shown improved local control and possibly survival with the addition of external irradiation and/or intraoperative radiation. In contrast, a recent Intergroup trial failed to show any benefit by the addition of adjuvant radiation therapy combined with chemotherapy. Interpretation of this trial's results is handicapped by low patient accrual. With the advent of novel and more effective systemic therapies for metastatic colon cancer, current and future clinical research will address the efficacy of these agents in the adjuvant setting. Adjuvant radiation therapy should be considered in patients with colon cancer at high risk for local failure.

Colorectal cancer remains a major worldwide health problem. In the United States alone it is estimated that there will be 145,290 patients diagnosed with colon cancer and 54,200 deaths this year.[1] Worldwide, approximately 1 million new cases per year are diagnosed, with 529,000 deaths.[2]

Most colon cancers arise in the mucosa, and more than 90% are adenocarcinomas. These tumors invade from the mucosa through the bowel wall into surrounding tissues. Lymphatic channel and subsequent lymph node involvement is common. Hematogenous metastases occur primarily in the lung and liver. In contrast to other gastrointestinal malignancies, colon cancer has little propensity to spread longitudinally within the bowel wall.

Clinical Manifestation and Staging

Colon cancer frequently produces minimal or no symptoms, highlighting the importance of screening programs. Many symptoms related to colon cancer are nonspecific, including changes in bowel habits, intermittent abdominal pain, weakness, and nausea and vomiting. Location of a malignancy within the colon influences clinical presentation. Specifically, right-sided colon cancers are frequently exophytic and may be associated with iron deficiency anemia due to occult blood loss. Over recent decades, the incidence of cancer of the right colon has increased and accounts for approximately one-third of large bowel cancers. Many of these are diagnosed at a later stage. Cancer of the left or sigmoid colon is often deeply invasive, annular, and accompanied by obstructive symptoms and rectal bleeding.

For patients with potentially resectable disease, pretreatment evaluation should include colonoscopy to establish pathologic confirmation of adenocarcinoma, to evaluate the extent of tumor, and to detect synchronous primary cancers, which occur in 3% to 5% of patients. Baseline blood counts with liver function tests and carcinoembryonic antigen levels should be obtained. Abdominal and pelvic computed tomography (CT) scan and chest x-ray/chest CT scan allow for evaluation of the extent of locoregional disease as well as the presence or absence of distant metastases. Positron-emission tomography, magnetic resonance imaging, and ultrasound may be useful in evaluating patients with oligometastatic disease who may be appropriate candidates for resection of distant metastases with curative intent. Figure 1 shows a diagnostic algorithm for the management of patients with potentially resectable colon cancer.

Prognostic factors influencing survival in colon cancer patients include depth of tumor invasion into and beyond the bowel wall, the number of involved regional nodes, and the presence or absence of distant metastases. These factors are included in the tumor-node-metastasis (TNM) system of the American Joint Committee on Cancer (AJCC), which can be used as a clinical (preoperative) or postoperative staging system (Tables 1 and 2).[3]

Surgery

Surgery remains the primary treatment for patients with colon cancer. Approximately 75% of patients are candidates for resection at presentation. Surgical technique is based on large bowel anatomy and patterns of disease spread. Adenocarcinomas generally grow by direct extension into the bowel wall and submucosal lymphatics. Resection of sufficient lengths of bowel proximally and distally to the primary cancer avoids cutting across intramural lymphatics. Resection generally includes removal of the mesentery, where the major lymphatic drainage is located. The boundaries for resection of large bowel cancers are relatively uniform and include named blood vessels along with their associated draining lymphatics (Figure 2).

In patients with disease limited to the bowel wall without involved nodes, resection provides excellent cure rates (5-year survival rate of 97% for T1, N0; 85%-90% for T2, N0). When disease extends beyond the colonic wall (T3-4, N0) or involves locoregional lymph nodes (T0-2, N1-2), 5-year survival with surgery falls to approximately 65% to 75%. Adjuvant treatment is often indicated in these patients. For higher-risk patients with extension beyond the colonic wall and nodal involvement (T3-4, N1-2), 5-year survival ranges from 35% to 50% and adjuvant treatment is strongly recommended.

Adjuvant Chemotherapy

Fluorouracil/Leucovorin

For more than a decade, fluorouracil (5-FU)-based chemotherapy has been considered standard adjuvant therapy for stage III colorectal cancer. Three major clinical trials defined the use of 5-FU/leucovorin chemotherapy as the standard of care for these patients. The first of these trials was National Surgical Adjuvant Breast and Bowel Project (NSABP) C-03, which randomized 1,081 patients with resected Dukes B and C colon cancer to either a regimen known as MOF (methyl-lomustine [CCNU, CeeNU], vincristine [Oncovin], 5-FU) or 5-FU/leucovorin.[4] This trial showed a significant increase in 3-year disease-free survival (73% vs 64%) and overall survival (84% vs 77%) for the 5-FU/leucovorin group.

The IMPACT report pooled data from 1,526 patients with resected Dukes B or C colon cancer who were treated on one of three randomized clinical trials from Canada, Italy, and France. Patients were randomized to 5-FU and leucovorin given as a daily bolus on days 1 to 5 of a monthly cycle for 6 months, or observation. The 3-year overall survival rate was superior for the treated group (83% vs 78%), translating to a 22% reduction in mortality.[5] The North Central Cancer Treatment Group (NCCTG) randomized 317 patients with resected high-risk stage II or III disease to bolus 5-FU and leucovorin delivered as the Mayo Clinic regimen (bolus 5-FU, 425 mg/m2, and leucovorin, 20 mg/m2, given on days 1 to 5 of a 28-day cycle) or observation.[6,7] Treated patients showed a statistically significant improvement in overall survival.

Oxaliplatin

Recently, newer chemotherapy agents demonstrating benefit in patients with metastatic disease have been tested in the adjuvant setting. The benefit of oxaliplatin (Eloxatin) in the metastatic setting was shown by Goldberg et al in the Intergroup 9741 study. This trial randomized 795 patients with metastatic colorectal cancer to IFL (irinotecan [Camptosar], 5-FU, leucovorin), FOLFOX4 (a regimen of infusional 5-FU/leucovorin with oxaliplatin chemotherapy), or IROX (irinotecan, oxaliplatin). Compared to patients receiving IFL or IROX, patients receiving FOLFOX experienced an improved median survival (19.5 vs 15 vs 17.4 months; P < .05 for oxaliplatin vs non-oxaliplatin-containing regimens).[8]

In the adjuvant setting, the MOSAIC study demonstrated the benefit of oxaliplatin. This trial randomized 2,246 patients with resected stage II/III colon cancer to FOLFOX4 or the same infusional 5-FU/leucovorin regimen alone.[9] The 3-year disease-free survival in the FOLFOX4 group was significantly improved with the addition of oxaliplatin (78.2% vs 72.9%).

The beneficial role for oxaliplatin in the adjuvant setting was further confirmed with the results of NSABP C-07. This trial randomized 2,407 patients with resected stage II/III colon cancer to bolus 5-FU and leucovorin (5-FU, 500 mg/m2, and leucovorin, 500 mg/m2, given weekly for 6 out of 8 weeks for three cycles) or the same bolus 5-FU/leucovorin regimen plus oxaliplatin at 85 mg/m2 on weeks 1, 3, and 5 of each cycle.[10] The addition to oxaliplatin resulted in a significant improvement in 3-year disease-free survival (76.5% vs 71.6%), similar to the MOSAIC study.

Irinotecan

Irinotecan, a topoisomerase I inhibitor, has also been shown to improve survival when combined with 5-FU and leucovorin in the metastatic setting. Saltz et al reported a randomized trial comparing IFL, 5-FU/leucovorin, and irinotecan alone. Patients receiving IFL had an improved median survival and response rate compared to 5-FU/leucovorin alone (14.8 vs 12.6 months, 39% vs 21%, respectively, P < .05).[11]

As with oxaliplatin, adjuvant trials have been reported using irinotecan in combination with 5-FU and leucovorin. However, these trials have not confirmed benefit. The first reported phase III trial of this combination was CALGB 89803, which randomized 1,264 patients with resected stage III disease to bolus irinotecan, 5-FU, and leucovorin or 5-FU/leucovorin alone.[12] No significant difference in disease-free or overall survival was observed. In addition, patients receiving irinotecan had a significantly higher mortality rate during treatment (2.8% vs 1.0%), prompting premature closure of the trial.

The PETACC 3 study examined the use of irinotecan with an infusional 5-FU/leucovorin regimen. These investigators randomized 3,278 patients with resected stage II or stage III colon cancer to one of two infusional 5-FU/leucovorin regimens with irinotecan.[13] Patients with stage III disease showed no statistically significant improvement in 3-year disease-free survival with the addition of irinotecan. Pooled data including stage II patients showed a significant (although marginal) benefit for disease-free survival (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.76-0.99).

Capecitabine

Capecitabine (Xeloda), an oral fluoropyrimidine, was compared to 5-FU/leucovorin bolus chemotherapy in the Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial. Investigators randomized 1,987 patients with resected Dukes C colon cancer to capecitabine or bolus 5-FU and leucovorin given on days 1 to 5 of a 28-day cycle for 24 weeks.[14] Disease-free and overall survival rates were comparable in the two arms, with a nonsignificant trend toward improved disease-free and overall survival in the capecitabine arm. Despite recent improvements in chemotherapy, patterns-of-recurrence analyses suggest that 5-FU-based therapy has only minimal efficacy in preventing local recurrence in resected stage III disease, and local failure rates may be similar to those in patients undergoing surgery alone.[15,16]

Targeted Therapies

The current focus in adjuvant therapy for colon cancer involves the incorporation of targeted therapies. In 2003, Hurwitz et al first reported the results of a randomized trial comparing IFL with or without bevacizumab (Avastin), a monoclonal antibody directed against vascular endothelial growth factor.[17] Median survival was significantly improved in patients receiving bevacizumab (20.3 vs 15.6 months, P < .001). Additionally, patients receiving bevacizumab demonstrated improved response rates (45% vs 36%, P < .05).

The first of the trials evaluating the addition of bevacizumab in the adjuvant setting is MOSAIC-2, or AVANT, which is being conducted in Europe. This trial is randomizing patients with resected stage II or III colon cancer to FOLFOX4, FOLFOX4 plus bevacizumab, or a regimen of capecitabine, oxaliplatin, and bevacizumab. A similar trial is enrolling patients in the United States through the National Cancer Institute and Roche Pharmaceuticals. Additionally, the NSABP C-08 is currently randomizing patients with resected high-risk stage II or III colon cancer to modified FOLFOX6 (another regimen of infusional 5-FU, leucovorin, oxaliplatin) vs FOLFOX6 plus bevacizumab. Patients randomized to the bevacizumab arm will then receive bevacizumab alone for 6 months after completion of chemotherapy.

Cetuximab (Erbitux), a monoclonal antibody targeting the epidermal growth factor receptor, has also shown benefit in patients with metastatic colorectal cancer. Cunningham et al described 329 patients with irinotecan-refractory colorectal cancer who received cetuximab alone or cetuximab with irinotecan. Response rates and median time to progression were significantly improved in patients receiving combination therapy, although no survival difference was observed.[18]

The NCCTG is currently randomizing patients with resected stage III colon cancer to infusional 5-FU/-leucovorin and oxaliplatin, infusional 5-FU/leucovorin and irinotecan, infusional 5-FU/leucovorin and oxaliplatin followed by infusional 5-FU/leucovorin and irinotecan, or these regimens plus cetuximab. The role of targeted therapies in the adjuvant treatment of colon cancer remains an area of active investigation.

Adjuvant Radiation Therapy

Patterns of Relapse With Surgery Alone

In contrast to chemotherapeutic regimens, there has been little systematic evaluation of adjuvant radiation therapy for patients with resected colon cancer. This is likely due to the documented efficacy of adjuvant chemotherapy as well as the perception by many oncologists that colonic (as opposed to rectal) cancer is much more likely to relapse distantly vs locally.

Increasing TNM stage predicts for local failure in both colon and rectal cancers; however, local failure in colon cancer is dependent on anatomic location. The ascending and descending colon are considered "anatomically immobile" structures. The close proximity of these bowel segments to retroperitoneal tissues often precludes wide surgical resection (Figure 3).[19] These relationships may limit the ability of the surgeon to obtain adequate radial margins at resection, thus increasing the risk of residual disease and subsequent local failure. In contrast, the midsigmoid and midtransverse colon are more "mobile" structures, where obtaining wide margins in the mesentery is often achievable. In the absence of adjacent organ adherence, local failure at these sites is uncommon. Local failure rates in the cecum, hepatic and splenic flexure, as well as proximal and distal sigmoid tumors vary depending on the amount of mesentery present, extent of primary disease, and adequacy of radial margins.

Clinical Trials

• Nonrandomized Series-Until recently, data evaluating adjuvant radiation therapy in the setting of high-risk colon cancer was limited to single-institution retrospective analyses.[20-24] In summary, these studies suggested that failure rates within the operative bed in high-risk patients undergoing resection alone were at least 30%, and that this risk was reduced by the administration of adjuvant radiation therapy. These studies are discussed in detail below.

• University of Minnesota Reoperation Series-Gunderson et al reported a series of 91 patients with colon cancer undergoing resection for locally advanced disease. At 6 to 12 months following the initial surgery, reoperation (the so-called "second look") was carried out in patients without evidence of recurrence. The underlying rationale was to define the location of subclinical failures at a time when additional operative excision and cure might be possible.

Most (87/91) patients had ≥ T3 and/or node-positive disease at initial resection. Approximately half of the patients had disease in segments of colon with a complete or nearly complete mesentery (ie, the "anatomically mobile" transverse colon or "semimobile" cecum) and the remainder, in "immobile" locations (ascending, descending, and hepatic/splenic flexure). At reexploration, a total of 44 (48%) were found to have locoregional failure. In node-positive patients, increasing depth of penetration of the bowel wall predicted for increasing risk of locoregional failure. When assessed by colonic subsite, all patients had a risk of locoregional failure > 40% except those with transverse (38%) and ascending (29%) lesions. The lower risk of locoregional failure in the "anatomically immobile" ascending colon was attributed to a disproportionate percentage of early T-stage lesions.

The authors concluded that (1) locoregional failure in resected colon cancer is common, (2) patterns-of-failure analyses using imaging, as compared to reoperation or autopsy, likely underestimate the incidence of locoregional recurrence, (3) similar to what is seen in rectal cancer, locoregional recurrence is a major cause of failure in advanced colon cancer, and (4) certain high-risk patients may benefit from adjuvant radiation therapy.[20]

• Massachusetts General Hospital-A series from the Massachusetts General Hospital (MGH) evaluated outcomes in high-risk colon cancer patients undergoing resection followed by adjuvant radiation therapy and compared these to a historical series treated by resection alone. Irradiated patients included T4, N0/+; T3, N+ (excluding midsigmoid and midtransverse colon); and selected high-risk T3, N0 patients. A total of 171 patients received postoperative irradiation, with 63 patients receiving concurrent chemotherapy (usually 5-FU, 500 mg/m2/d on days 1-3 during the first and last week of radiation therapy). Radiation therapy was administered through a multifield approach, including treatment of the tumor bed with a 3- to 5-cm margin to 45 Gy. Thereafter, reduced fields were used to bring the total dose to 50.4-54 Gy. Draining nodes were included if patients were deemed to be at high risk for involvement.

The irradiated cohort was compared to 395 patients of similar T and N stage undergoing surgery alone. Table 3 shows 5-year actuarial local control and relapse-free survival in patients receiving adjuvant treatment compared to surgery alone. Local failure rates in T4, N0 and T4, N+ patients treated with radiation therapy were 7% and 28%, respectively, compared to 31% and 53%, respectively, in patients undergoing surgery alone. Similarly, disease-free survival rates were 79% and 53%, respectively, in T4, N0 and T4, N+ patients receiving adjuvant radiation vs 63% and 38%, respectively, in patients undergoing surgery alone.

No significant outcome differences were seen in patients with T3, N0 or T3, N+ disease. However, many of these patients were referred secondary to concerns about adequacy of resection and local control after resection, raising the possibility of selection bias. A nonsignificant trend toward improved local control was seen in patients receiving 5-FU. The authors concluded that patients with T4 tumors, tumors with abscess/fistula formation or margin-positive resection may benefit from postoperative irradiation.[21]

Follow-up analysis from the MGH evaluated 152 patients with T4 disease receiving adjuvant radiation therapy. Of these patients, 28% underwent margin-positive resection. In patients undergoing margin-negative resection, the 10-year actuarial local control in T4, N0 and T4, N+ was 87% and 65%, respectively. In patients with node-negative tumors, the 10-year actuarial relapse-free survival rate was 58%, compared to 33% in patients with node positive tumors. For patients with one involved lymph node, local control and relapse-free survival were similar to that seen in patients without nodal involvement. However, increasing nodal number correlated with decreasing survival.[22]

• Mayo Clinic-Investigators from the Mayo Clinic reported on 103 patients receiving radiation therapy following resection of locally advanced colon cancer. Microscopic (R1) and gross residual (R2) resection were noted in 18 and 35 patients, respectively. Over 90% of patients had T4, N0/N+ disease. Patients received 50.4 Gy of external-beam irradiation given through a multifield technique. Most received concurrent 5-FU-based chemotherapy. Eleven patients received an intraoperative irradiation "boost" of 10 to 20 Gy.

The overall local control rate was 40%. Patients undergoing margin-negative resection had a 5-year local control rate of 90%; patients with microscopic or gross residual disease following resection had local control rates of 46% and 21%, respectively (Figure 4). In patients with R1/R2 resection undergoing intraoperative irradiation, local control was 89%, compared to 18% in patients receiving external irradiation alone (P = .02). Similarly, 5-year survival was improved in patients undergoing margin-negative resection compared to R1 or R2 resection (66% vs 47% vs 23%, respectively). Patients receiving the intraoperative boost experienced improved 5-year survival (76% vs 26%, P = .04).[23]

• University of Florida-Investigators from the University of Florida described 78 patients with locally advanced but completely resected colon cancer receiving adjuvant radiation. The overall local control rate was 88%. These figures are similar to the 90% local control rate reported by the Mayo Clinic investigators in patients undergoing R0 resection. Additionally, these investigators reported on a possible dose-response relationship to local control, with patients receiving greater than or equal to 50 Gy experiencing a 5-year local control rate of 96% vs 76% for patients receiving less than 50 Gy (P = .01).[24]

• Randomized Phase III Trial-Based on the above studies, the Intergroup undertook a randomized phase III trial to assess whether the addition of radiation therapy to adjuvant chemotherapy improved survival and locoregional failure rates in resected high-risk colon cancer patients. Eligibility criteria included patients with T4 tumors undergoing margin-negative resection (excluding peritoneal invasion) or T3, N+ tumors arising in the ascending or descending colon. Patients were randomized to receive weekly 5-FU combined with levamisole (Ergamisol) for 12 months or 5-FU and levamisole for 12 months with concurrent radiation starting 1 month after the first 5-FU administration. Patients received 45 Gy at 1.8 Gy per fraction over 5 weeks with an optional 5.4-Gy boost.

The initial accrual goal of this trial was 700 patients. However, between 1992 and 1996, only 222 patients were entered, with 189 evaluable. Therefore, total accrual was approximately one-third of the initially intended goal, significantly decreasing the study's statistical power to detect differences between the two groups. That said, no difference in overall or disease-free survival was observed. Patients receiving chemotherapy alone experienced a 5-year survival of 62%, compared to 58% in patients randomized to chemoradiation (P > .50). There were 18 local recurrences in each arm. Grade 3/4 hematologic toxicity was higher in patients receiving radiation therapy.[25] Because of the study's decreased statistical power, no definitive conclusions could be made regarding the efficacy (or lack thereof) of postoperative irradiation and chemotherapy.

Adjuvant Hepatic and Whole-Abdominal Irradiation

Patterns-of-failure analyses have demonstrated that, in addition to local failure, development of hepatic metastases is a common mode of failure in patients with stage III colon cancer. Based on such findings, investigators have examined the role of hepatic irradiation following resection in high-risk patients. A prospective trial performed by the Gastrointestinal Tumor Study Group (GITSG) randomized 300 patients with resected T3-4, N0-N+ colon cancer to observation only or adjuvant hepatic irradiation concurrent with bolus 5-FU administered during week 1. Patients received 1.5 Gy daily to the liver, to a total dose of 21 Gy. Patients receiving radiation went on to receive additional 5-FU following completion. Results of this study showed no improvement in overall or disease-free survival with the addition of radiation therapy and 5-FU.[26]

In addition to locoregional and hepatic recurrence, relapse within the peritoneal cavity remains a common mode of failure in patients with locally advanced colon cancer. Based on this tendency, investigators from the Southwest Oncology Group (SWOG) performed a pilot study in 41 patients with resected T3, N+, M0 colon cancer. Patients received continuous-infusion 5-FU (200 mg/m2/d) with concomitant whole-abdominal irradiation. Radiation was given at 1 Gy per fraction daily to a total of 30 Gy, followed by a 16-Gy boost to the tumor bed. Patients then received further 5-FU therapy.

Five-year disease-free and overall survival rates were 58% and 67%, respectively. In patients with more than four involved lymph nodes, 5-year disease-free and overall survivals were 55% and 74%, respectively. Grade 3 and 4 toxicity was seen in 17% and 7% of patients, respectively. Compared to matched-stage patients from prior Intergroup trials treated with 5-FU/levamisole alone, these results appeared favorable. The investigators concluded that a randomized trial evaluating continuous-infusion 5-FU and whole-abdominal irradiation with boost should be carried out.[27]

With the multitude of new and novel agents approved for use in metastatic colorectal cancer, present and future clinical research will be focused on assessing the efficacy of these agents. As previously mentioned, integrating these agents in the adjuvant setting for patients with resected stage II/III disease in the cooperative group trial networks is a high priority.

Recommendations

Because the role of adjuvant radiation therapy in colon cancer remains undefined and unlikely to be further evaluated in a definitive randomized trial, treatment recommendations should be made on a case-by-case basis with the previously discussed data. The risks, benefits, and potential side effects of such an approach should be discussed with patients in the setting of an informed consent. Table 4 presents general treatment recommendations for appropriate patients, reflecting the preferences of the authors of this review.

The use of intraoperative irradiation in addition to external irradiation in patients with uncertain margins at resection (ie, T4 disease) may also be appropriate. In these situations, a potential treatment sequence would consist of preoperative external irradiation with 5-FU-based chemotherapy, followed by resection with intraoperative irradiation where appropriate. This would be followed by adjuvant systemic therapy. A similar approach would be indicated for patients with locally recurrent colorectal cancer or regional nodal relapse. Our current practice is to offer adjuvant tumor bed irradiation in patients with tumors invading adjoining structures (T4 disease), disease complicated by perforation or fistula, or subtotal resection. Patients are generally given continuous-infusion 5-FU (225 mg/m2/d) 5 days per week throughout the course of radiation therapy.

Conclusions

The role of adjuvant radiation in colon cancer remains ill-defined. Surgery remains the primary treatment for cure in these patients; patterns-of-failure data suggest that subsets of patients undergoing resection alone have a risk of local failure greater than or equal to 30% (ie, T4 disease, disease complicated by perforation or fistula, and patients undergoing incomplete excision).

Retrospective series have suggested that the addition of adjuvant radiation therapy with concurrent chemotherapy may decrease the risk of local failure in these patients. However, an Intergroup randomized trial comparing chemotherapy to chemoradiation showed no obvious benefit with the addition of radiation; this trial failed to meet accrual goals, and thus, interpretation is hampered. With the advent of improved systemic therapies, it is unlikely that this question will ever be definitively answered in a randomized setting. Therefore, treatment recommendations on the use of radiation should be made on a case-by-case basis, identifying patients at high risk for local failure.

Disclosures:

Dr. Czito receives research funding from Roche, Sanofi-Aventis, and Genentech. Dr. Bendell is a consultant for Genentech.

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