Etiology and Epidemiology

In 2011 the American Cancer Society estimated that 141,210 patients were diagnosed with colorectal cancer and 49,380 deaths occurred.¹ Although this malignancy may be linked to chemical carcinogens within the bowel lumen, it is not established whether these are ingested, the result of chemical activation of substances in the fecal stream, or a bacterial byproduct.² Environmental and dietary factors have been established as contributing to colorectal cancer. Factors shown to increase the risk of developing this disease include increasing age, race, male sex, family history of colorectal cancer, increasing height, increasing body mass index, processed meat intake, excessive alcohol intake, and low folate consumption. Of these risk factors, only increasing age, male sex, and excessive alcohol use have been found to be associated with rectal cancer.³ The value of consumption of fruits and vegetables in the prevention of colon and rectal cancer remains controversial, although some studies have suggested that these associations have been overstated.⁴ Contemporary prospective and randomized data do not support a high fiber diet in the prevention of colorectal cancer.⁵ Other studies have suggested that nonsteroidal anti-inflammatory drugs may reduce the risk of colorectal cancer. The role of chemopreventive agents (carotenoids, polyamine inhibitors, aspirin and other nonsteroidal anti-inflammatory drugs) in colorectal cancer is under active investigation.

Prevention and Early Detection

Neoplastic polyps, including tubular adenomas, villous adenomas, and tubulovillous adenomas, are precursors of colon cancers. Most colorectal cancers arise from preexisting polyps.⁶ Patients with neoplastic polyps should be considered at high risk for large bowel cancer, and polypectomy may reduce this risk. With the availability of the flexible colonoscope and endoscopic polypectomy, polyps can be removed at a premalignant stage and patients observed closely.

Biologic Characteristics/Molecular Biology

A detailed discussion of the biologic and genetic pathways of development of colorectal cancer is beyond the scope of this chapter. In brief, it has been established that the development of colon cancer is a multifactorial process, involving changes in many genes, including both proto-oncogenes and tumor suppressor genes. Colorectal cancers appear to arise through inactivation of the adenomatous polyposis coli (APC) and tumor protein p53 (TP53) genes as well as mutations in the RAS proto-oncogene.

Microsatellites are mutated short-repeat DNA sequences usually consisting of one to five nucleotides. Microsatellite “instability” is found in a majority of patients with hereditary nonpolyposis colorectal cancer (HNPCC) as well as a minority of patients with sporadic colorectal cancers. It has been shown that this instability occurs in patients with mutations in genes encoding enzymes that repair DNA replication errors. These defects in mismatch repair lead to high-frequency microsatellite instability. Studies have suggested that patients with tumors possessing a high-frequency of microsatellite instability have a more favorable outcome and develop fewer metastases.⁹ Further elucidation of the genetic pathways in the development of colorectal cancer remains an active area of investigation and may ultimately impact therapy for this disease.

Pathology and Pathways of Spread

Tumors of the colon arise in the mucosa and are virtually all (>90%) adenocarcinomas. Other histologic types include squamous cell carcinoma, carcinoid, leiomyosarcoma, and lymphoma. Most grading systems classify adenocarcinoma as well, moderately, or poorly differentiated.

Large bowel tumors invade from mucosa through the bowel wall and beyond, with involvement of lymphatic channels and lymph nodes. Hematogenous spread can occur, primarily to the lung and liver. There is little propensity for colon cancer to spread longitudinally within the bowel wall, in contrast to esophageal or gastric cancers.

Clinical Manifestations, Patient Evaluation, and Staging

Colon cancer often produces minimal or no symptoms, emphasizing the need for screening programs in the general population. Many colon cancer symptoms are nonspecific, including changes in bowel habits, weakness, intermittent abdominal pain, nausea, and vomiting. The persistence of such symptoms as well as any evidence of iron-deficiency anemia should be investigated.

The clinical presentation of colon cancer is determined largely by site of the tumor. Cancers of the right colon are often exophytic and commonly associated with iron-deficiency anemia owing to occult blood loss. During the past 20 years the relative incidence of cancer of the right colon has increased and accounts for one third of cancers of the large bowel. Many of these are diagnosed late.² Cancers of the left colon and sigmoid colon are often deeply invasive, annular, and accompanied by obstruction and rectal bleeding.

For patients undergoing resection, preoperative evaluation should include pathologic confirmation of adenocarcinoma, colonoscopy to evaluate the extent of tumor and rule out synchronous primary tumors (occurring in 3% to 5%), baseline blood cell counts with liver function tests, and carcinoembryonic antigen levels. Patients should undergo chest, abdominal, and pelvic CT to evaluate the extent of locoregional disease as well as the presence or absence of distant metastases. PET, MRI, and ultrasonography may be useful in evaluating patients with oligometastatic disease who may be appropriate candidates for resection of metastatic disease with curative intent. A diagnostic algorithm of the management of patients with potentially resectable colon cancer is shown in Figure 48-1.

Figure 48-1 Diagnostic algorithm of 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 lymph nodes, as well as the presence or absence of distant metastases. The TNM system of the American Joint Committee on Cancer (AJCC) can be used as a clinical (preoperative) or postoperative staging system (Tables 48-1 and 48-2). Additionally, site-specific prognostic factors have been identified and included in the AJCC staging (Table 48-3).

TABLE 48-1 American Joint Committee on Cancer TNM Staging for Colorectal Cancer (2010)

Note: A satellite peritumoral nodule in the pericolorectal adipose tissue of a primary carcinoma without histologic evidence of residual lymph node in the nodule may represent discontinuous spread, venous invasion with extravascular spread (V1/2), or a totally replaced lymph node (N1/2). Replaced nodes should be counted separately as positive nodes in the N category, whereas discontinuous spread or venous invasion should be classified or counted in the site-specific factor category of Tumor Deposit (TD).

* Direct invasion in stage T4 includes invasion of other organs or segments of the colorectum by way of the serosa, as confirmed by microscopic examination (e.g., invasion of the sigmoid by a carcinoma of the cecum). For cancers in a retroperitoneal or subperitoneal location, direct invasion involves other organs or structures by virtue of extension beyond the muscularis propria (e.g., a tumor on the posterior wall of the descending colon invading the left kidney or lateral abdominal wall or a mid or distal rectal cancer with invasion of the prostate with invasion of the prostate, seminal vesicles, cervix or vagina).

† Tumor grossly adherent to other organs or structures is classified as cT4b. However, if no tumor is present in the adhesion microscopically, the classification should be pT1 to pT4a depending on the anatomic depth of wall invasion. The V and L classifications should be used to identify the presence or absence of vascular or lymphatic invasion where the pN site-specific factor should be used for perineural invasion.

From Edge SB, Byrd DR, Compton CC, et al, editors: Colon and rectum. In American joint committee on cancer staging manual, ed 7, New York, 2010, Springer.

TABLE 48-3 Site-Specific Prognostic Factors for Colorectal Cancer

From Edge SB, Byrd DR, Compton CC, et al, editors: Colon and rectum. In American joint committee on cancer staging manual, ed 7, New York, 2010, Springer.

Primary Therapy

Surgery

Surgery remains the primary treatment of colonic tumors. Resection with curative intent is possible in approximately 75% of patients.² Surgical resection of primary colon cancer is based on the anatomy and mechanisms by which this disease spreads. Adenocarcinomas of the colon may grow by direct extension into the lymphatics of the submucosa and bowel wall. To avoid cutting across tumor in intramural lymphatics, sufficient lengths of bowel must be resected proximal and distal to the primary cancer. Colon cancer often extends through the serosa into mesenteric lymphatics that run along the blood vessels draining into the portal watershed at the root of the mesentery. Resection includes removal of the major lymphatic drainage system in the mesentery. Because anatomic resections designed to include named blood vessels also include the draining lymphatics, the boundaries for resecting large bowel cancer are relatively uniform (Fig. 48-2). Right hemicolectomy, transverse colectomy, left hemicolectomy, and sigmoid resection are performed by adherence to surgical oncologic principles without major sacrifice of large bowel function.

Figure 48-2 Extent of surgical resection at various colonic sites. The darkened circle represents primary disease site (anastomoses are shown in the insets).

From Shrock TR: Large intestine. In Way LW, editor: Current surgical diagnosis and treatment, ed 7, Los Altos CA, 1985, Lange Medical Publishers.

Resection results in excellent cure rates for lesions limited to the bowel wall with negative nodes (estimated 5-year survival, 97% for T1N0; 85% to 90% for T2N0 disease). With a single high-risk feature of extension beyond the colonic wall (T3 to T4, N0) or involved nodes (T0 to T2, N+), 5-year survival with surgery falls to 65% to 75% and adjuvant treatment is often indicated. When both high-risk features are present (T3 to T4, N+), 5-year survival with surgery alone drops to approximately 50% (T3N+) and 35% (T4N+) and adjuvant treatment is usually advised. Recent Surveillance, Epidemiology and End Results (SEER) analyses have allowed further refinement of survival outcomes based on the TNM stage (Table 48-4).

TABLE 48-4 Surveillance, Epidemiology and End Results (SEER) Survival Outcomes Based on 2010 AJCC TNM Staging

Adjuvant Irradiation With or Without Chemotherapy

Rationale: Patterns of Relapse, Surgery Alone

Because of the documented efficacy of adjuvant chemotherapy as well as the perception by many oncologists that colon (as opposed to rectal) cancer is much more likely to relapse distantly than locally, there has been little evaluation of the efficacy of postoperative irradiation with chemotherapy. The potential indications for adjuvant radiation therapy in colon cancer are based on analyses of patterns of failure after resection^18,19 (Table 48-5). Advanced stage predicts for local failure in both colon and rectal cancer; however, local failure in colon cancer also depends on anatomic origin. The ascending and descending colon are considered “anatomically immobile,” and their close proximity to the retroperitoneal tissues often limits wide surgical resection (Fig. 48-3). Limitations in achieving satisfactory circumferential margins increase the risk of residual disease and consequently local failure. In contrast, the midsigmoid and midtransverse colon are relatively “mobile” with a wide mesentery, thus permitting the surgeon to obtain wide margins regardless of extent of disease invasion into the mesentery. Unless there is adjacent organ adherence/invasion by tumor, local failure at these sites is uncommon. Local failure rates for cecal, hepatic/splenic flexure, and proximal/distal sigmoid tumors are variable depending on the amount of mesentery present, tumor extension, and the adequacy of radial margins. When colon cancers adhere to or invade adjacent structures, local failure rates exceed 30% after surgery alone.

TABLE 48-5 Five-Year Actuarial Local Control and Relapse-Free Survival after Surgery plus Postoperative Radiotherapy versus Surgery Alone, according to Stage: Massachusetts General Hospital Series

Figure 48-3 Idealized depiction of peritoneal relationships in the colon and rectum. The transverse and sigmoid colon are intraperitoneal, with a complete peritoneal covering (serosa) and mesentery. The ascending and descending colon are retroperitoneal, lack a true mesentery, and usually do not have a peritoneal covering posteriorly or laterally. The upper rectum begins above the peritoneal reflection and has peritoneum anteriorly and laterally. The lower half to two thirds of the rectum is below the peritoneal reflection (infraperitoneal).

Reproduced with permission from Gunderson LL, O’Connell MJ: Postoperative chemotherapy/irradiation adjuvant strategy. In Cohen AF, Winawer SJ, Friedman MA, Gunderson LL, editors: Cancer of the Colon, rectum, and anus, New York, 1995, McGraw-Hill, pp 631-645.

In summary, local failure occurs in patients with colonic tumors where there are anatomic constraints on radial resection margins, including tumors adherent to or invading adjacent structures.

Adjuvant Irradiation: Single-Institution Analyses

Until recently, data evaluating the use of adjuvant radiation therapy in high-risk colon cancer patients was limited to single-institution retrospective analyses.^20–23 To summarize, these studies have suggested that operative bed failures in high-risk patients undergoing resection alone are at least 30% and that the risk of local failure is reduced by the administration of adjuvant radiation therapy.

Massachusetts General Hospital

A report from the Massachusetts General Hospital evaluated outcomes in high-risk patients undergoing resection followed by adjuvant radiation therapy and compared these to a similar cohort of patients treated over the same period undergoing surgery only. Irradiated patients included those with stage T4N0/N+, T3N+ disease (excluding the midsigmoid and midtransverse colon) and patients with stage T3N0 disease with margins of less than 1 cm. A total of 171 patients received postoperative radiation therapy, with 63 patients receiving concurrent chemotherapy, usually with bolus 5-FU (500 mg/m²/d) for 3 consecutive days during the first and last weeks of radiation therapy. Radiation treatment was administered through parallel opposed or other multiple-field techniques to treat the tumor bed with a 3- to 5-cm margin to a total dose of 45 Gy, followed by reduced fields to a total dose of 50.4 to 54 Gy. Draining nodes were included if they were thought to be at high risk for involvement. This cohort was compared with 395 patients with stage T3 to T4,N0/N+ tumors undergoing surgery alone during the same time period.

Table 48-5 shows 5-year actuarial local control and relapse-free survival (RFS) in the adjuvant group compared with patients undergoing surgery alone. Local control rates in patients with stage T4N0 and T4N+ disease treated with radiation therapy were 93% and 72%, respectively, versus 69% and 47%, respectively, in patients undergoing surgery alone. Similarly, RFS were 79% and 53%, respectively, in patients with stage T4N0/T4N+ disease undergoing adjuvant radiation versus 63% and 38%, respectively, undergoing surgery alone. No significant outcome differences were observed in patients with stage T3N0 and T3N+ lesions; however, there may be an element of selection bias in the radiation group given most patients were referred because of concerns of adequacy of local control after surgery alone. There was a trend toward improved local control in patients receiving 5-FU (Table 48-6). The rate of acute enteritis in patients receiving irradiation and 5-FU was 16% versus 4% in patients undergoing irradiation only. This rate of enteritis is similar to data from studies of concurrent 5-FU and radiation therapy in rectal cancer. Late bowel complication rates were not increased by concomitant 5-FU administration. The conclusion was that patients with stage T4 tumors or tumors with abscess/fistula formation or margin-positive resection may benefit from postoperative radiation therapy.²⁰

TABLE 48-6 Five-Year Actuarial Local Control and Relapse-Free Survival of Adjuvantly Irradiated Patients Based on Administration of 5-Fluorouracil (5-FU): Massachusetts General Hospital Series

In an updated analysis from this institution, 152 patients with stage T4 tumors received adjuvant irradiation. On pathologic examination, 42 patients had tumors with positive margins. For patients with negative margins the 10-year actuarial local control in T4N0 and T4N+ disease was 78% and 48%, respectively. In patients with node-negative tumors, the 10-year actuarial local control and relapse-free survival rates were 87% and 58%, respectively, compared with 65% and 33%, respectively, in patients with node-positive tumors. For patients with one involved lymph node, local control and relapse-free survival rates were similar to those without nodal involvement; however, with increasing numbers of nodes involved, survival steadily decreased.²³ The authors’ current policy is to consider adjuvant tumor bed irradiation in patients with tumors (1) invading adjoining structures, (2) when complicated by perforation or fistula, and (3) when incomplete excision is performed. Patients are generally given continuous 5-FU (225 mg/m²/24 h) or capecitabine (825 mg/m² bid) 5 days per week throughout the course of radiation therapy.

Mayo Clinic

A report from the Mayo Clinic described a series of 103 patients receiving radiation therapy after surgery for locally advanced colon cancer. Microscopic and gross residual disease was present in 18 and 35 patients, respectively. Over 90% of patients had stage T4, N0 to N+ disease. A median dose of 50.4 Gy was delivered through multiple-field techniques and most patients received concurrent 5-FU–based chemotherapy. Eleven patients received an intraoperative “boost” of 10 to 20 Gy. The 5-year actuarial overall local control rate was 40%. Patients with margin negative tumors had a 5-year local control rate of 90%, compared with 46% for patients with microscopic residual tumor and 21% with gross residual tumor (Fig. 48-4). In patients with residual disease, local control rates in patients undergoing intraoperative boost irradiation were 89% compared with 18% in patients undergoing external irradiation alone (Fig. 48-5). Similarly, 5-year survival rates were improved in patients undergoing margin negative resection (66%) compared with those with microscopic residual (47%) or gross residual (23%) disease (Fig. 48-6). Additionally, patients undergoing intraoperative boost demonstrated improved survival (76% vs. 26%) (Fig. 48-7).

Figure 48-4 Local control by extent of residual disease after maximal resection in a Mayo Clinic series of 103 colon cancer patients treated with external beam irradiation (EBRT) ± chemotherapy (concomitant ± maintenance) ± intraoperative electron irradiation (IOERT).

Figure 48-5 Local control by administration of IOERT after maximal resection in a Mayo Clinic series of 103 colon cancer patients with residual disease treated with external beam irradiation (EBRT) ± chemotherapy (concomitant ± maintenance).

Figure 48-6 Survival results by amount of residual disease after maximal resection in a Mayo Clinic series of 103 patients with resected colon cancer treated with external beam irradiation (EBRT) ± chemotherapy (concomitant ± maintenance) ± intraoperative electron irradiation (IOERT).

Figure 48-7 Survival results by intraoperative electron beam irradiation (IOERT) administration after maximal resection in a Mayo Clinic series of 103 patients with resected colon cancer treated with external beam irradiation (EBRT) ± chemotherapy (concomitant ± maintenance).

University of Florida Medical Center

A report from the University of Florida Medical Center of patients with locally advanced but completely resected colon cancers receiving adjuvant radiation therapy reported a local control rate of 88%, similar to the 90% reported at the Mayo Clinic in patients who had completely resected tumors.²¹ In addition, there appeared to be a dose-response relationship to local control. The 5-year rate of local control was 96% for patients receiving 50 to 55 Gy versus 76% for patients receiving less than 50 Gy (p = .0095).

Phase III Intergroup Trial

To assess whether the addition of radiation therapy to adjuvant chemotherapy would result in superior survival and locoregional failure rates in resected, high-risk colon cancer patients, the U.S. Intergroup initiated a randomized prospective trial in 1992 in which patients with resected colon cancer were randomized to postoperative irradiation with 5-FU and levamisole or 5-FU and levamisole alone. Eligibility criteria included margin-negative tumors with adherence to or invasion of surrounding structures (i.e., stage T4N0 or N+ disease, excluding peritoneal invasion) or tumors arising in the ascending or descending colon with metastatic regional nodes (T3N+). Patients were randomized to receive (1) weekly 5-FU combined with levamisole for 12 months or (2) 5-FU and levamisole for 12 months with combined radiation therapy and chemotherapy beginning 1 month after the first dose of 5-FU. The recommended total radiation dose was 45 Gy in 25 fractions over 5 weeks with an optional 5.4-Gy boost.

The initial trial accrual goal was 700 patients; however, the study was closed in 1996 owing to poor accrual (222 patients; 189 evaluable). Therefore total accrual was less than one third of initial goals and thus decreased statistical power to detect any differences between the groups. Nonetheless, no difference in OS or DFS was seen between the two groups. The 5-year OS rate of patients receiving chemotherapy only was 62% versus 58% for patients randomized to chemoirradiation (p >.50). Local recurrence rates were identical in both study arms (18 patients each). Grade 3/4 hematologic toxicity was higher in patients receiving radiation therapy. Interpretation of study results was handicapped by decreased statistical power, high ineligibility rates, and lack of surgical clips and/or preoperative imaging to assist the definition of appropriate EBRT fields in a high percentage of patients. No definitive conclusions can be made regarding the efficacy of routine postoperative irradiation with 5-FU and levamisole based on this study; however, this study provides no data supporting its routine use.²⁴

Adjuvant Hepatic and Whole Abdomen Irradiation

In addition to local failure, patterns of failure analyses have shown that hepatic metastases are common in patients with locally advanced colon carcinoma. As a result, investigators have examined the efficacy of hepatic irradiation after resection in high-risk patients. The only randomized, prospective trial evaluating adjuvant hepatic irradiation was performed by the Gastrointestinal Tumor Study Group.²⁵ Three hundred patients with resected, margin-negative Dukes B2/C colon cancer were randomized to observation only or adjuvant hepatic irradiation with concurrent 5-FU given in bolus fashion on week 1. Radiation was administered to the liver at 150 cGy per fraction to a total dose of 2100 cGy. After hepatic irradiation, patients received further 5-FU. The combination of 5-FU and hepatic irradiation did not improve OS or DFS.

Relapse within the peritoneal cavity is also commonly observed in patients undergoing resection of locally advanced colon cancer. Investigators have reported outcomes and toxicities after adjuvant whole abdominal irradiation in high-risk patients. The Southwest Oncology Group (SWOG) reported the results of a pilot study evaluating 41 patients with resected T3, N1 to N2, M0 colon cancer treated with continuous infusion of 5-FU (200 mg/m²/24 hr) with concomitant whole abdominal irradiation. Patients received 30 Gy given at 1 Gy per fraction followed by a 16-Gy boost to the tumor bed at 1.6 Gy per fraction. Further 5-FU therapy was administered after completion of radiation therapy. Five-year DFS and OS estimates were 58% and 67%, respectively. Patients with tumors exhibiting more than four lymph nodes involved experienced 5-year DFS and OS of 55% and 74%, respectively. Grade 3 and 4 toxicity was observed in 17% and 7% of patients, respectively. When compared with similarly staged patients from previous Intergroup trials treated with 5-FU/levamasole only, these survival results appeared favorable. The authors recommended that continuous infusion 5-FU and whole-abdominal irradiation with tumor bed boost should be studied in a randomized trial.²⁶

Estes and associates²⁷ reported a pattern of failure analysis in patients with T3N+ colon cancer treated with 5-FU/levamisole chemotherapy only (Intergroup), combined chemotherapy/whole-abdominal irradiation (SWOG), and patients undergoing surgery only (from the previously described study from the Massachusetts General Hospital). Their analysis showed 5-FU/levamisole reduced the rates of lung metastases but was less effective at preventing local and peritoneal recurrence. In contrast, patients receiving whole-abdominal irradiation with continuous 5-FU experienced a 12% tumor bed relapse rate, 22% hepatic relapse rate, and 15% peritoneal relapse rate, all of which were superior to the results of patients who did not receive irradiation. However, the use of whole-abdominal irradiation should be considered investigational.

Locally Advanced Disease and Palliation

As previously described, the Mayo Clinic analyzed the results of 103 patients with advanced colonic carcinoma (microscopic or gross residual tumor [n = 53]; margin-negative tumors [n = 50]) treated by EBRT alone or in conjunction with intraoperative electron radiation therapy (IOERT).²² For patients with either microscopic or gross residual disease, local failure occurred in 11% of patients receiving IOERT plus EBRT versus 82% of patients receiving EBRT only (p = .02) (see Fig. 48-5). The 5-year actuarial survival rate was 66% for patients with no residual disease, 47% for patients with microscopic residual disease, and 23% for patients with gross residual disease (p = .0009) (see Fig. 48-6). The 5-year survival rate in patients with residual disease was 76% for patients receiving IOERT and 26% for patients receiving EBRT alone (p = .04) (see Fig. 48-7).

For patients with metastatic disease, 5-FU–based chemotherapy is usually administered. Prospective randomized trials have shown that use of multiple agents improves survival in patients with metastatic colorectal cancer. Saltz and colleagues²⁸ reported the results of a three-arm randomized trial comparing (1) irinotecan, 5-FU, and leucovorin, (2) 5-FU/leucovorin, or (3) irinotecan alone. Patients receiving irinotecan, 5-FU, and leucovorin had an improved survival (median survival 14.8 vs. 12.6 months, p = .04) and response rate (39% vs. 21%, p <.001) compared with 5-FU and leucovorin alone. The incidence of grade 3 or higher diarrhea was significantly higher with the three-drug regimen. Hurwitz and associates²⁹ reported a randomized trial comparing irinotecan, 5-FU, and leucovorin with or without bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor. Median survival was significantly improved in the bevacizumab arm of the study (20.3 vs. 15.6 months, p <.001). Additionally, response rates were improved with bevacizumab (45% vs. 35%, p = .004). Cunningham and colleagues³⁰ randomized 329 patients with metastatic colorectal cancer refractory to irinotecan-based chemotherapy regimens to receive cetuximab (a monoclonal antibody directed against the epidermal growth factor receptor [EGFR]) or cetuximab with irinotecan. Response rates in patients receiving combination therapy were significantly higher (23% vs. 11%, p = .007) as was median time to progression (4.1 vs. 1.5 months, p <.001). No difference in survival was observed.

A study by Goldberg and associates³¹ randomized 795 patients with previously untreated, metastatic colorectal cancer to receive (1) irinotecan, 5-FU, and leucovorin, (2) oxaliplatin, 5-FU, and leucovorin, or (3) irinotecan and oxaliplatin. Patients receiving oxaliplatin, 5-FU, and leucovorin had an improved median survival compared with those receiving irinotecan, 5-FU, and leucovorin or irinotecan and oxaliplatin (19.5 vs. 15 vs. 17.4 months; p <.05 for oxiliplatin-containing regimens vs. irinotecan-only regimen). Response rates in patients receiving 5-FU, leucovorin, and oxaliplatin were significantly higher than those receiving irinotecan, 5-FU, and leucovorin or irinotecan with oxaliplatin (45% vs. 31% vs. 35%, p <.05).

Another trial randomized patients with metastatic disease to receive irinotecan, 5-fluorouracil and leucovorin, with or without the EGFR inhibitor cetuximab.³² A significant improvement in progression-free (PFS) but not OS was seen in patients receiving cetuximab, with the benefit of cetuximab limited to patients with KRAS wild-type tumors. Results of a randomized trial comparing the combination of 5-FU, leucovorin, and oxaliplatin, with or without the anti-EGFR antibody panitumumab again showed an improvement in PFS (9.6 vs. 8 months, p = .02) in patients receiving panitumumab. KRAS wild-type tumors were again found to respond better to EGFR-based therapy.³³ In contrast, a randomized study evaluating the combination of capecitabine, oxaliplatin, and bevacizumab, with or without cetuximab, demonstrated a significantly shorter PFS and inferior quality of life in patients receiving cetuximab, with KRAS mutational status again predicting response in patients receiving cetuximab.³⁴ A similarly designed randomized trial evaluated the combination of chemotherapy plus bevacizumab, with or without panitumumab, in metastatic colorectal cancer patients; there was increased toxicity and decreased PFS in patients receiving panitumumab.³⁵ These trial results suggest that dual antibody therapy may not be appropriate for the first-line treatment of metastatic colorectal cancer. Varying combinations of these drugs as well as other novel agents remain the focus of ongoing investigation in both metastatic and nonmetastatic settings.

Palliative irradiation, sometimes in combination with 5-FU–based chemotherapy, is considered for patients with specific symptoms referable to metastatic disease—brain, bone, and other sites. The combination of radiation therapy and newer agents (capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab) remains a topic of investigation.

Irradiation Techniques

Treatment field design in colon cancer is based on patterns of failure data. As is true in the treatment of rectal carcinoma, great care must be taken in the design of postoperative treatment of adenocarcinoma of the colon. Field arrangement will vary depending on the site of the primary disease as well as areas judged to be at high risk for local recurrence.³⁶ Patient positioning (supine, prone, decubitus) should be considered in planning. Small bowel is often a dose-limiting structure in this therapy, and it is often advantageous to position patients in the right or left decubitus position for at least a portion of their treatment, allowing displacement of the small bowel away from the treatment field. Immobilization devices may improve reproducibility. A small-bowel series defines small bowel volume within the treatment field. It may be useful to compare films in both the decubitus and supine positions to determine the actual amount of small bowel displacement. CT-based planning facilitates definition of the tumor bed, determining beam orientation, as well as estimating the volume of small bowel included within the treatment fields. As in other abdominal malignancies, a portion of one kidney may be irradiated. Unilateral renal irradiation results in minimal long-term clinical sequelae, assuming baseline function in the contralateral kidney is normal.³⁷

The total radiation dose used in the adjuvant treatment of colon carcinoma depends on the volume of suspected residual disease and tolerance constraints of surrounding normal tissue. Generally, an initial dose of 45 Gy in 25 fractions of 1.8 Gy per fraction is delivered through larger fields to the primary tumor and at-risk tissues. Reduced fields may be treated to 50 Gy if only a small portion of small bowel is included. For patients with stage T4 tumors, the general goal is to treat the tumor bed to a total dose of 54 to 60 Gy. Any treatment beyond 50 Gy generally mandates exclusion of all small bowel from the field. Spinal cord dose should be limited to 45 Gy. In addition, at least two thirds of one functional kidney should receive no more than 18 to 20 Gy and at least two thirds of the total liver volume should not receive more than 30 Gy. In a Mayo Clinic analysis, small bowel obstruction rates were lower when more than two treatment fields were used, and attempts should be made to implement multiple-field techniques, which is aided by CT-based planning.³⁸ Three-dimensional treatment planning as well as the use of intensity-modulated radiation techniques may facilitate small bowel as well as other normal organ sparing.

Generally, the primary tumor site should be covered with a 4- to 5-cm margin proximally and distally with a 3- to 4-cm margin medially and laterally to cover areas of potential residual disease. The nodal basins in the mesentery beyond surgical margins are usually not treated because satisfactory margin clearance is obtained in these sites. An exception to this may be tumors of the right colon where both small bowel and right colon are supplied by ileocolic vessels, limiting the extent of resection. In some instances, treatment of the para-aortic nodes may be indicated, particularly with extensive retroperitoneal involvement by tumor. Treatment of proximal mesenteric nodes may be appropriate if nodes adjacent to the surgical or resection margin are involved. Figures 48-8 and 48-9 show examples of locally advanced ascending and sigmoid carcinomas with their respective treatment fields, including isodose distributions. In many situations it may be appropriate to exclude treatment of para-aortic nodal basins, based on operative and pathologic findings.

Figure 48-8 Male patient, 60 years old, with T4 ascending colon cancer adherent to the right pericolic gutter just above the level of the iliac crest, after R1 resection. He was treated with concurrent chemoradiotherapy using a three-field approach while in left lateral decubitus position, followed by boost to a total dose of 5400 cGy. A, Preoperative axial CT scan demonstrates a large ascending colon tumor invading pericolic tissues. B, Digitally reconstructed radiograph shows beam’s eye view of anterior beam (clinical tumor volume in green; kidneys [superiorly] in yellow; small bowel in purple); note small bowel displacement because of patient’s decubitus position. C, Relative isodose distributions of primary fields using a three-field technique.

Figure 48-9 Female patient, 54 years old, with nearly obstructing sigmoid lesion at 35 cm from the anal verge. During left hemicolectomy, a perforated sigmoid cancer was found eroding into the proximal rectum with possible vaginal cuff involvement. She was treated with concurrent chemoradiotherapy using a three-field approach, in prone position with false tabletop, to a total dose of 4500 cGy. A, Axial CT slice shows sigmoid tumor (yellow arrows) invading adjacent rectum. B, Digitally reconstructed radiograph shows beam’s eye view of posterior beam (reconstructed gross tumor volume in red). C, Digitally reconstructed radiograph shows beam’s eye view of lateral beam. D, Relative isodose distributions of primary fields.

Because of improved survival seen in patients with rectal cancer treatment with concurrent radiation therapy and 5-FU chemotherapy as well as survival benefit seen in node-positive colon cancer receiving 5-FU based chemotherapy, adjuvant irradiation in patients with resected high-risk colon cancer should be administered concurrently with fluoropyrimidine-based chemotherapy.

Treatment Algorithm, Conclusions, and Future Possibilities

Subsets of patients with colon cancer have local recurrence rates similar to patients with rectal cancer if only surgery is performed. Because of encouraging pilot study results with postoperative irradiation with or without 5-FU for patients with resected high-risk colon cancers, and the positive results of 5-FU and levamisole in high-risk adjuvant colon cancer, an Intergroup randomized trial was undertaken, randomizing patients to 5-FU and levamisole or 5-FU and levamisole with tumor bed irradiation in patients at high risk for local recurrence after surgical resection. There was no benefit in survival in patients receiving adjuvant radiation therapy; however, interpretation of these results is handicapped by inadequate accrual and significant flaws that were previously discussed.

The value of adjuvant postoperative irradiation combined with systemic therapy for patients at high-risk for local relapse is unlikely ever to be further addressed in a definitive randomized trial. Treatment recommendations should be made on a case-by-case basis with existing data in the setting of an informed consent. A potential treatment algorithm for these patients is shown in Table 48-7 and reflects the personal preference of the authors.

TABLE 48-7 Treatment Algorithm: Approach to Therapy for Colon Cancer

The use of intraoperative irradiation as a supplement to EBRT in certain stage T4 tumors (i.e., those with uncertain margins) may also be appropriate. For patients with tumors adherent to or invading adjacent structures, the preferred treatment sequence would be preoperative EBRT plus 5-FU–based chemotherapy followed by resection with or without IOERT and postoperative systemic therapy, based on excellent results in preliminary IOERT reports from both U.S. and European institutions.^22,38,39 A similar approach would be reasonable for patients with locally recurrent cancers or with regional nodal relapse.^40–44