Cancer of the Colon

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40 Cancer of the Colon

Bruce D. Minsky, MD, Mark L. Welton, MD, MHCM, FACS, FASCRS, Carlos E. Pineda, MD, Alan P. Venook, MD

Epidemiology, Etiology, Genetics, and Cytogenetic Abnormalities

Epidemiology

In 2007, there will be an estimated 112,340 new cases of colon cancer in the United States, with 55,290 occurring in men and 57,050 occurring in women. Approximately 52,180 deaths are expected.¹ The median age at diagnosis is 62 years. Patients under 40 years have a less favorable prognosis. However, it is unclear if this is independent of stage.

It has been postulated that colorectal cancer is caused or promoted by environmental factors and especially by dietary factors that affect the enteric milieu.² A number of studies reveal an association of human colorectal cancer with certain diets (such as those rich in animal fats and meat and poor in fiber) and certain high-risk populations.³

In general, the traditional Western diet (high fat, low fiber, high phosphate, and low calcium) is associated with an increased risk of colorectal cancer. However, there have not been any clear studies demonstrating whether dietary factors increase the risk in patients with an underlying genetic susceptibility. There are a variety of risk factors for colorectal cancer (Table 40-1). Approximately 75% of colorectal cancers are sporadic.

Table 40-1 Clinical Risk Factors for Colorectal Cancer

General

Age older than 40

Genetic syndromes

Peutz-Jeghers

Familial adenomatous polyposis

Gardner’s

Turcot’s

Oldfield’s

Familial

Family history

Lynch I: Familial colorectal cancer syndrome

Lynch II: Hereditary adenocarcinomatosis syndrome

Other diseases

Prior colorectal cancer

Malignant colorectal polyps

Inflammatory bowel disease

Only recently has the genetic basis of colorectal cancer and its precursors begun to be understood.⁴^,⁵ The data suggest that the development of colorectal cancer is a multistep process that involves a successive activation or deletion of genes and their protein products.⁶ This process is mediated by regulatory genes. Advances in molecular biology techniques have allowed characterization of the genetic changes thought to be responsible for this multistep process.⁷

Numerous molecular markers examined to date, such as microsatellite instability (MSI),⁸ 18q,⁹ TP53,¹⁰ and others such as proliferation, apoptosis, defective DNA mismatch repair, and p53 overexpression.¹¹ However, they are not currently incorporated in the staging system and T and N classification remain the most predictive factors. But this is rapidly changing, and US intergroup trials now prospectively collect tissue. The phase III ECOG 5202 trial for patients with high-risk stage II colon cancer assigns treatment based on MSI/18q status. In the near future, more-individualized therapeutic recommendations based on genetic markers may be possible.¹²

Anatomy

The large bowel is divided into the colon and rectum.¹³^,¹⁴ The cecum, transverse colon, and sigmoid loop are mobile structures that lie free in the peritoneal cavity and are completely covered with serosa (visceral peritoneum). The dorsal or posterior aspect of the ascending and descending colon, and both flexures are frequently without serosa. Tumor spread from these segments may involve the retroperitoneal soft tissues, kidney, ureter, and pancreas. Although the rectum is frequently considered to be extraperitoneal, the anterior surface of the proximal third of the rectum is covered with serosa and is therefore intraperitoneal. Anatomically, the transition from sigmoid colon to rectum is marked by the fusion of the tenia of the sigmoid colon to the circumferential longitudinal muscle of the rectum at the level of the sacral promontory. This occurs approximately 12 to 15 cm from the dentate line. Patterns of recurrence of proximal rectal cancer may depend upon whether the location of the tumor is anterior or posterior.

The overall rationale of the use of adjuvant radiation therapy in colon cancer is based on the patterns of failure following potentially curative surgery. The primary determinant of failure patterns in colorectal cancer is the location of the tumor in reference to the posterior peritoneal reflection. In contrast to tumors located at or below the posterior peritoneal reflection (rectosigmoid and rectum), most tumors located above the peritoneal reflection (cecum-sigmoid), have a higher incidence of failure within the abdominal cavity.¹⁵^–¹⁸ This is because colon tumors have easier access to a free peritoneal surface.

Representative series examining the patterns of failure after potentially curative surgery are seen in Table 40-2. There is much variation as to what defines failure, the method by which failure is determined, the staging system used, and whether patients with metastatic disease are excluded from analysis. Failure patterns will be lowest in series which use clinical and/or radiographic evidence of first failure,¹⁵ whereas they will be highest in series which use reoperation and/or autopsy evidence of cumulative failure.¹⁸

Table 40-2 Failure Patterns Following Potentially Curative Surgery for Colon Cancer (All Stages)

Treatment recommendations are based on stage and the location of tumor in reference to the posterior peritoneal reflection. If the tumor is completely above the posterior reflection it is treated as a colon cancer. If any portion is at or below the reflection, it is treated as a rectal cancer. However, if a sigmoid or cecal cancer is adherent to a pelvic structure (cT4), the local recurrence rate is similar to a rectal cancer, and it is treated as such with preoperative combined chemotherapy and radiation.

Pathology

Gross Appearance

Tumor configuration may be divided into fungating (exophytic), ulcerating, stenosing, or constricting (annular, circumferential). Although there are data to suggest that ulcerative tumors have a worse prognosis compared with exophytic tumors, it is unclear whether this independent of stage.

Histologic Subtypes

The most common histologic type of large bowel cancer is adenocarcinoma, which accounts for 90% to 95% of all large bowel tumors.¹³ It is the only histologic type further classified by grade. A number of histologic types of large bowel cancer have been identified. The World Health Organization has developed a classification of both benign and malignant tumors. Colloid or mucinous adenocarcinoma represent approximately 17% of large bowel tumors.¹⁹ These adenocarcinomas are defined by large amounts of extracellular mucin retained within the tumor. A separate classification is the rare signet-ring cell carcinoma (2% to 4% of mucinous carcinomas), which contains abundant intracellular mucin, pushing the nucleus to one side. Some signet-ring tumors form a linitis plastica–type appearance, tend to present at later stages, and, thus, have a poor prognosis.²⁰^,²¹

Other rare variants of epithelial tumors include squamous cell carcinomas, adenosquamous carcinoma (adenoacanthoma), undifferentiated carcinomas, small cell,²² and neuroendocrine cancers.²³ Gastrointestinal stromal tumors should be treated as sarcomas.²⁴ Sarcomas account for 0.1 to 0.3% of all malignancies of the colorectum.²⁵ The most common type is leiomyosarcoma. It may arise from the smooth muscle of the muscularis propria, muscularis mucosa, or blood vessels.²⁶ Primary colorectal malignant lymphomas are usually diffuse large B-cell lymphomas.²⁷ Squamous cell cancers of the rectum should be treated as an anal cancer with fluorouracil (5-FU)/mitomycin-C and radiation, reserving surgery for salvage.²⁸

Grade

Broders classified adenocarcinomas by their degree of differentiation. He designated four grades based on the percentage of differentiated tumor cells. Well-differentiated in Broders’ system meant well-formed glands resembling an adenoma. Broders included the mucinous carcinomas in his system. Dukes considered mucinous carcinomas separately.²⁹ There is no uniform agreement on the grading criteria, but most investigators agree on the use of a three-grade system similar to that described in other adenocarcinomas.

Other Clinicopathologic Factors

The influence of clinical and pathologic factors on the patterns of failure and survival following surgery colorectal cancer has been the subject of numerous investigations. By univariate analysis, a number of factors have been reported to be of prognostic importance. Many of these factors are interrelated and merely reflections of the same overall characteristic of the cancer. Using a multivariate (proportional hazards) analysis, a variety of independent factors for survival have been reported. However, the majority of investigators agree that the most important independent pathologic factor for survival and/or recurrence following surgery is stage (depth of penetration through the bowel wall and the presence and number of positive lymph nodes).³⁰^,³¹ Prognosis is related to the number of tumors rather than the volume of tumor present in the nodes.³² The presence of lymphatic vessel (L) or venous (V) invasion is now indicated as an additional descriptor in the TNM staging system.

Selected adverse clinical factors include: age <40 years, blood transfusions, long duration of symptoms, obstruction or perforation, ulceration, and various primary tumor locations. Selected adverse pathologic/molecular factors include: perineural invasion, high grade, colloid, signet ring cell, blood vessel invasion, lymphatic vessel invasion, aneuploidy, elevated carcinoembryonic antigen (CEA) levels, collagen, local immune response, cell surface antigen 19-9, and various growth factors, receptors, oncogenes, and blood group antigens.¹³ Except for CEA, none of these tumor markers have independently been shown to be helpful in prospective follow-up following treatment.³³

In summary, it is difficult to draw firm conclusions from the data, and treatment recommendations based solely on the presence or absence of the above pathologic features should be made with caution. Prospective trials are needed in order to determine whether these pathologic factors should be used to select patients for adjuvant therapy.

Clinical Presentation

Symptoms of colon cancer include intermittent abdominal pain, nausea, vomiting, unintentional weight loss, or a change in bowel habits. Bleeding may be acute and most commonly appears as red blood mixed with stool. Dark blood is most commonly associated with a more proximal source (right colon) and black tarry stools reflect small bowel or stomach as a source. However, any lower gastrointestinal hemorrhage, even in the presence of known pathology (i.e., diverticuli, hemorrhoidal disease) requires a full colonoscopic evaluation. Tumors of the left colon tend to present earlier and with more obstructive symptoms than the right colon, given the reduced diameter of the bowel distally. Patients who present with complete bowel obstruction or perforation have a less favorable prognosis.

Routes of Spread

After the initial mucosal growth, there are several directions in which colorectal cancer may progress.

Bowel Wall

The tumor penetrates through the bowel wall and extracolonic tissues, then directly invades adjacent organs or structures. An additional pattern of local spread is perineural invasion, which may extend as far as 10 cm from the primary tumor.

Lymph Nodes

The risk of lymph node metastases increases with increasing tumor grade. In addition, there is a clear relationship between lymphatic vessel invasion and the incidence and number of lymph node metastases in colorectal cancer.³⁴^,³⁵ At least 12 to 14 lymph nodes must be examined for an accurate classification of nodal status.³⁶^,³⁷ Although they may be confused with lymph nodes, pericolonic tumor deposits are a harbinger of intra-abdominal metastasis in colon cancer.³⁸ In the sixth edition of the American Joint Commission on Cancer (AJCC) TNM Staging System, smooth metastatic nodules in the pericolic or perirectal fat are considered lymph node metastasis, whereas irregularly contoured metastatic nodules in the fat are considered vascular invasion.³⁹

In colon cancer, the normal lymphatic flow is through the lymphatic channels along the major arteries, with three echelons of lymph nodes: pericolic, intermediate, and principal lymph nodes (Table 40-3).¹³ If tumors lie between two major vascular pedicles, lymphatic flow may drain in either or both directions. If the central lymph nodes are blocked by tumor, lymphatic flow can become retrograde along the marginal arcades both proximally and distally.

Table 40-3 Regional Lymph Nodes in Colon Cancer

Site	Regional Nodes
Cecum	Anterior and posterior cecal, ileocolic, right colic
Ascending colon	Ileocolic, right and middle colic
Hepatic flexure	Middle and right colic
Transverse colon	Middle colic
Splenic flexure	Middle and left colic, inferior mesenteric
Descending colon	Left colic, inferior mesenteric, sigmoid
Sigmoid loop	Inferior mesenteric, superior rectal (hemorrhoidal), sigmoid, sigmoid mesenteric

In rectal cancer, the disease metastasizes to the perirectal nodes at the level of the primary tumor, immediately above it and up to 5 cm distal to the primary tumor.⁴⁰^,⁴¹ Then, the chain accompanying the superior hemorrhoidal vessels is involved. Discontinuous or skip metastases are rare. The pericolic lymph nodes along the mesenteric border of the pelvis usually are not involved by these rectal tumors unless there is very extensive tumor with lymphatic blockage.

Distant Metastasis

The liver is the primary site of hematogenous metastases, followed by the lung. In approximately 40% of autopsy studies the liver is the only site involved.⁴² Involvement of other distant sites in the absence of liver or lung involvement is rare.

Diagnostic and Staging Studies

The work-up for colon carcinoma is seen in Table 40-4. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning shows promise, but remains investigational.⁴³^,⁴⁴ The staging of colorectal carcinoma has been complicated by the fact that it has evolved over a century and various authors have developed systems that use the same terms to represent different stages. Because of these discrepancies in coding for the same stages, the comparison of clinical studies reported in the literature is often impossible.

Table 40-4 Workup for Colon Cancer

The first practical staging system was Dukes’ classification. This classified colorectal tumors from A to C, with stage A indicating penetration into but not through the bowel wall, stage B representing penetration through the bowel wall, and stage C representing involvement of lymph nodes regardless of the extent of bowel wall penetration. It has since been modified by many authors, including Dukes, to reflect finer levels of penetration and nodal metastases, and has been extended to include the colon as well as the rectum.

The Astler-Coller staging system allowed separation of wall penetration and nodal status. The Gunderson-Sosin modification of the Astler-Coller staging system subdivided T₃ tumors into those with microscopic (B_2m or C_2m) or gross (B_2m+g or C_2m+g) penetration of tumor through the bowel wall.⁴⁵^,¹⁸ It also defined tumors adherent to or invading an adjacent organ or structure as B₃ if the nodes were negative and C₃ if the nodes were positive. Several studies have analyzed both local failure and survival using the modified Astler-Coller staging system^15,^16,^18,⁴⁵^–⁴⁷ Most have confirmed the predictive capability of this staging system.

In 1988, the AJCC ⁴⁸ and the Union Internationale Contre le Cancer (UICC)⁴⁹ proposed a joint TNM staging system. This was based on the fifth edition of the AJCC TNM staging system. The sixth edition of the AJCC TNM staging system is shown in Table 40-5,³⁹ with four major changes from the fifth edition. These include: (1) a revised description of the anatomy of the colon and rectum which better delineates the data regarding the boundaries between the colon, rectum, and anus. Adenocarcinomas of the veriform appendix are classified with the TNM system, but should be recorded separately. (2) Smooth metastatic nodules in the pericolic or perirectal fat are considered nodal metastasis. By contrast, irregularly contoured metastatic nodules in the peritumoral fat are considered vascular invasion and are coded as a subcategory of the T stage as V1 (microscopic vascular invasion) if microscopically visible or V2 (macroscopic vascular invasion) is grossly visible. (3) stage group II is subdivided into IIA (T3 disease) and IIB (T3 disease) and (4) stage group III is subdivided into IIIA (T1-2N1M0 disease), IIIB (T3-4N1M0 disease), and IIIB (TanyN2M0 disease). There are also additional descriptors which, although they do not affect the stage grouping, do indicate cases needing separate analysis. The AJCC TNM staging system should be used routinely for staging and treatment purposes. Although CEA has prognostic importance, it was not added to the staging system.⁵⁰

Table 40-5 Classification of Colorectal Cancer

An elevated CEA level at the time of presentation has an adverse impact on survival independent of tumor stage.⁵¹ If the pretreatment CEA is >100 and the abdominal/pelvic CT does not reveal evidence of metastatic disease, a liver MRI should be performed to exclude liver metastasis. Preoperative CEA is recommended however there is insufficient evidence at this time for the routine use of molecular markers.⁵²

The role of the pathologist is critical to proper staging. At least 12 pelvic nodes must be examined to obtain an accurate N classification.³⁶

Clinical staging is designated as cTNM and is based on physical examination, radiologic imaging, endoscopy, biopsy, and laboratory findings before initiation of therapy. Pathologic staging is designated as pTNM and depends on data acquired clinically in addition to surgical and pathologic findings. Recurrent tumors are designated with the r prefix. If there is uncertainty regarding the appropriate T, N, or M classification, the lower (less advanced) category should be used.

Standard Therapeutic Approaches

Surgery

Surgery is the standard treatment for both colon and rectal cancer. The successful management of this disease is dependent on a thorough preoperative evaluation, careful surgical technique,⁵³ and the experience of the surgeon.⁵⁴^,⁵⁵ Surgical resection can be performed either open or laproscopically. An 872-patient randomized trial reported by Nelson et al. comparing open versus laparoscopic techniques in colon cancer revealed no significant differences in recurrence or survival.⁵⁶ Laparoscopic colectomies for cancer can result in less postoperative pain and shorter lengths of stay.⁵⁷ However, the improvement is modest at best, and thus has not replaced open surgery. It is important that surgery, whether done open or through minimally invasive techniques, be performed using an oncologic resection (high ligation of the blood supply and minimal tumor handling).

When patients present with bowel obstruction, self-expanding stents should be considered as a bridge to surgery, because emergent procedures are associated with higher rates of stoma creation and higher morbidity rates.⁵⁸ Patients who undergo emergency surgery usually present with more advanced disease and thus have lower resectability rates than those undergoing elective resection.⁵⁹ Patients with metastatic disease may require palliative resection to avoid and/or alleviate obstructive symptoms. Depending on the size and location of metastases in the liver and lung, these may be amenable for resection during the same procedure when the colon is resected.

Patients with locally advanced tumors and those with recurrent disease must be thoroughly evaluated to ascertain the benefit of performing a more radical procedure. Those with suspected or confirmed invasion into peritoneal, retroperitoneal, and/or pelvic structures, who will likely have close or positive margins, may benefit from intraoperative radiotherapy (IORT).

Patients who present with metastatic disease may be treated with neoadjuvant chemotherapy (colon primary) and chemoradiation (rectal primary) if the primary is relatively asymptomatic. There is no standard and treatment is recommended on a case-by-case basis. Multidisciplinary management is essential. Liver lesions that respond may be resected at the time of primary resection in select patients.

Chemotherapy

The standard adjuvant therapy for node positive (T1-4N1-2M0) resectable colon cancer is 12 cycles (6 months) of postoperative FOLFOX chemotherapy.⁶⁰ Capecitabine is an option for patients unable to tolerate FOLFOX.⁶¹ The role of adjuvant therapy in a patient with high risk T3N0M0 disease remains controversial.⁶¹^,⁶² For patients with metastatic disease the standard initial therapy is a combination of a fluropyrimidine and either oxaliplatin or irinotecan. Depending upon comorbidities and the goals of therapy, bevacizumab or cetuximab may also play roles. The concept of “lines” of therapy has been superseded by a continuum-of-care strategy which may soon be driven by biomarkers. The National Comprehensive Cancer Network (NCCN) offers general guidelines for therapy.⁶³

Radiation Therapy

Local/Regional Radiation Therapy

Radiation therapy is an effective but local modality. Its use in the adjuvant setting should be limited to those clinical presentations where (1) the risk of local failure is sufficiently high to justify its use, and (2) an adequate dose can be delivered to the site at the highest risk for failure. In patients with T3-4N0M0 or T1-4N1-2M0 rectal cancer, radiation therapy is reasonable, because the risk of local failure, depending on the stage, is 10% to 67% and an adequate dose to control microscopic disease (≥45 Gy) can be delivered safely to the pelvis.

In contrast to rectal cancer, the role of adjuvant radiation therapy in colon cancer is less well defined. As discussed above, this is due to differences in the natural history of colon cancer compared with rectal cancer. All stages combined, the most common failure site in colon cancer is abdominal rather than local. Furthermore, when local failure occurs outside the pelvis, it usually does not produce the same degree of debilitating symptoms as those seen in rectal cancer.

Although the overall incidence of local failure is relatively low in colon cancer, data suggest that, depending upon the anatomic location and selected pathologic features, there are subsets of patients in whom the incidence of local failure is increased. However, there is not uniform agreement as to how to define these subsets. Gunderson et al ¹⁸ divided the colon into two regions. Anatomically immobile (or mainly retroperitoneal) included the ascending colon, hepatic flexure, splenic flexure, and descending colon. Anatomically mobile (or mainly intraperitoneal) included the cecum and transverse colon. The highest incidence of local failure occurred in the cecum (30%), whereas the other intraperitoneal site, the transverse colon, had one of the lowest rates of local failure (13%).

By contrast, Minsky et al.¹⁵ reported a general trend of increased local failure with more distal colon sites. Patients with cecal cancer had a significantly lower incidence of local failure (3%) compared to those with cancer of the transverse (15%) or descending colon (25%). These data do not support the notion that bowel mobility is predictive of local failure.

Willett et al.¹⁶^,¹⁷ divided the colon into two groups. Group 1 included the cecum, ascending, midsigmoid, transverse, and descending colon. Group 2 included the high and low sigmoid colon, the splenic flexure, and the hepatic flexure. In T1-2N0M0 disease, there was a higher incidence of local failure in Group 1 tumors (16% to 24%) compared with Group 2 tumors (0% to 11%).

In summary, from series to series, there is no consistency as to which anatomic site(s) have the highest local failure rates. This inconsistency may reflect the differences in methods used to determine failure rather than the true natural history of the disease.

In addition to stage and site, pathologic features may be helpful in predicting those patients with a higher risk of local or distant failure. Although there are some pathologic features which, by multivariate analysis, have a significant impact on local failure and/or survival the primary decision for adjuvant therapy should be based primarily on stage. Molecular markers may be helpful and are under active investigation.

Whole Abdominal Radiation Therapy

The rationale of whole abdominal radiation therapy is based on the high incidence of abdominal failure in colon cancer. With this technique, the whole abdomen receives 30 Gy and, in selected series, is followed by a cone-down to the primary tumor bed. The results will be discussed in Outcomes.

Techniques of Radiation Therapy

Introduction

The design and delivery of radiation therapy for colon cancer requires a knowledge of the natural history of the disease, patterns of failure, anatomy, identification of surrounding structures, and radiobiologic principles. Furthermore, the use of proper equipment, implementation of methods to decrease treatment-related toxicity, and a close collaboration with the physics and technology staff is essential.

The biologic mechanisms of acute and delayed toxicity as well as dietary interventions have been previously published.⁶⁴^,⁶⁵ This review will be limited to the technical aspects of the design of local/regional radiation therapy fields for colon cancer. It will include idealized treatment fields for a variety of common clinical presentations. These techniques are modified from Gunderson, Martenson, and Willett.

General Treatment Techniques

For nonsigmoid primaries, patients should be initially be placed in the lateral decubitus position. Immobilization devices are recommended to help stabilize the patient. The lateral decubitus position may help exclude small bowel from the treatment field. In the majority of cases, parallel opposed fields are recommended. Wedges or compensation devices should be used as needed.

In most cases where the majority of the pelvis is being treated, (i.e., cecal and low sigmoid primaries), treatment in the prone position and a three-field technique (if possible) should be used to help exclude the small bowel and maximize homogeneity within the treatment volume. These techniques are outlined in the chapter on rectal cancer.

Definition of the Treatment Field

The tumor bed is defined as the involved segment of large intestine and when present, the adjacent organ or structure to which it was adherent or invading. If the tumor was adherent to an organ that was only partially resected (i.e., bladder, stomach), all or a majority of that organ should be treated to 45 Gy providing this does not exceed tolerance of critical structures. If the adherence was to a structure (i.e., pelvic sidewall, diaphragm, psoas muscle), a 3- to 5-cm margin beyond the area of adherence is recommended. When tumor adherence to an organ or structure places nodal groups at risk, the acceptable superior-inferior extent of node inclusion is the same as tumor bed plus margin. For example, adherence to posterior abdominal wall would include the para-aortic nodes plus margin.

Initial Field

The tumor bed and the immediately adjacent para-aortic or pelvic nodes (depending on the site of the primary tumor) are treated to 45 Gy in 25 fractions. A margin of 3 cm of normal tissue should surround the tumor bed.

Boost Field

If small bowel contrast studies demonstrate the exclusion of small bowel from tumor bed such that no small bowel receives >45 Gy, a boost of 5.4 Gy in three fractions should be delivered to the tumor bed plus a 2-cm margin.

Critical Normal Tissues

The primary dose-limiting structures in patients receiving local/regional radiation therapy for colon cancer commonly include the small bowel, liver, kidney and the spinal cord. The tolerance of these organs using conventional fractionation include: (1) small bowel: maximum 45 Gy (30 Gy in patients receiving whole abdomen radiation); (2) liver: at least two thirds of the total liver volume must receive <30 Gy; (3) kidney: at least two thirds of one kidney must not receive a dose higher than 20 Gy (depending on the field size and anatomic location, most or all of one kidney may be in the radiation field. In such cases, a renal scan should be obtained in order to assure that the contralateral kidney has adequate function); (4) spinal cord: the maximum dose to the spinal cord must be <50 Gy.

Outcomes

Adjuvant Local/Regional Radiation Therapy

Although all the series are retrospective, the most comprehensive series examining the role of local/regional radiation in colon cancer is from the Massachusetts General Hospital (MGH).⁶⁶^,⁶⁷ Following potentially curative surgery for T3-4N0-2M0 colon cancer, 203 patients received postoperative adjuvant radiation therapy. Eligibility included the following patients: T4N0-2M0 regardless of anatomic site, T3N1-2M0 excluding mid sigmoid and transverse colon, and selected high risk T3N0M0 tumors with close margins. Patients received 45 Gy to the primary tumor bed with a 5-cm margin as well as the primary draining lymph nodes. This was followed by a shrinking field technique to 50.4 to 55 Gy, depending on the volume of small bowel which could be excluded from the high dose field. Of the 203, 173 were treated in the adjuvant setting and 30 after a subtotal resection. Sixty-three received bolus 5-FU with a variety of doses and schedules.

The results at 5 years were compared with a historical control group of 395 patients who underwent surgery only.⁶⁶ As seen in Table 40-6, three groups of patients appeared to benefit from postoperative radiation therapy. First, there was a significant improvement in local control and disease-free survival for patients with stages T4N0M0 or T4N1-2M0 disease. Second, patients with stage T4N0M0 disease with a perforation or fistula had improved local control and disease-free survival. Third, radiation therapy salvaged some patients with residual disease-following subtotal resection (37% 5-year disease free survival). There was no benefit in local control or disease-free survival in patients with stage T3N0M0 or T3N1-2M0 disease. It must be emphasized that the results may be biased against radiation therapy, because many patients were high-risk patients referred because of concerns about margins.

Table 40-6 Local Adjuvant Radiation Therapy in Colon Cancer—Massachusetts General Hospital

With 10-year follow-up, local control in patients with T4 disease was 78% with negative margins and 53% with positive margins.⁶⁷ For the 42 patients with positive margins, local control was 56% for the 30 with microscopically positive and 42% for the 12 with grossly positive margins.

Complications of treatment were acceptable. For the total patient group, the incidence of Grade 3+ acute bowel toxicity was 8%. Grade 3+ long-term bowel toxicity was 4.5%. These toxicity results are very similar to those reported from the Mayo Clinic/North Central Cancer Treatment Group postoperative adjuvant rectal trial 79-41-51.³¹ Therefore, with careful treatment techniques, the acute and long term bowel toxicity of postoperative local/regional radiation therapy (with or without chemotherapy) for colon cancer are comparable to those reported for rectal cancer.

On the basis of the retrospective data from the MGH, a randomized phase III intergroup trial coordinated by the Mayo/North Central Cancer Treatment Group (INT 0130) was developed. Patients with T4 or selected T3N1-2 colon tumors were randomized to 12 cycles of bolus 5-FU plus levamisole with or without local/regional radiation (45 to 50.4 Gy in 25 to 28 fractions) beginning with cycle 2 of chemotherapy. The trial was closed early because of poor accrual with only 222 of the anticipated 400 patients randomized, leaving 189 eligible patients.⁶⁸ Grade 3+ toxicity was modestly but not significantly higher in the combined modality therapy arm (43% versus 35%). With a median follow-up of 35 months, there was no significant difference in survival between the two arms. The patterns of failure data have not been reported.

In a phase I trial of 21 patients (four with colon cancers) who received upper abdominal radiation plus continuous infusion 5-FU, Martenson and associates reported a 40% grade 3+ toxicity rate.⁶⁹ Because of the large radiation field sizes, the dose of continuous infusion 5-FU needs to be attenuated in patients receiving combined modality therapy for upper abdominal malignancies.

Palermo and associates treated 45 patients with intraperitoneal 5-FU plus radiation to the tumor bed and para-aortic nodes.⁷⁰ Although local failure was only 11%, the 10-year survival was 53% which is not superior to conventional approaches.

In summary, the retrospective data from the MGH suggest that there are subsets of colon cancer patients with high local failure rates in whom the addition of postoperative local/regional radiation therapy may improve local control and disease free survival. The randomized INT 0130 trial did not show a survival advantage with combined modality therapy versus chemotherapy alone. It must be emphasized however, that the INT 0130 trial was closed before meeting its accrual goals and has not yet reported local control results.

Given the significant advances in adjuvant chemotherapy for colon cancer as well as the negative results of the INT 0130 trial, the role of radiation therapy in colon cancer is limited. Therefore, the details of the radiation fields which appeared in the colon cancer chapter from the second edition of this textbook will not be reproduced in this edition.⁷¹ However, there are two clinical situations where it is reasonable to use radiation for colon cancers. The first is in patients with close or positive resection margins; the second is in a patient who presents with a T4 colon cancer adherent to pelvic structures. These cancers (most commonly sigmoid or cecal primaries) have local failure rates similar to rectal cancers and it is reasonable to treat them as such preferably with preoperative combined modality therapy, surgery, and postoperative chemotherapy.⁷²

Whole Abdominal Radiation Therapy

The use of whole abdominal radiation therapy is limited by dose considerations. To treat the volume at risk with a potentially curative dose of radiation required for microscopic disease, the whole abdomen would need to receive 45 Gy. Although limited portions of the abdomen can tolerate this dose, the tolerance of the whole abdomen with conventional fractionation is 30 Gy. On the basis of the high incidence of abdominal failure in some colon cancers, a number of phase II adjuvant trials were designed to examine the efficacy of whole abdominal radiation therapy.⁷³^–⁷⁷

In general, patients received 20 to 30 Gy to the whole abdomen with or without a boost to the primary tumor bed. In three of the series, 5-FU was delivered with a variety of doses and schedules. The combined results revealed an in-field (abdominal) failure rate of 12% to 50%. Significant toxicity varied from 5% to 38%. Although the initial phase II results appeared promising, three of the series (Brenner et al.⁷⁴ Meek et al.⁷⁵ and Wong et al.⁷³) have not been updated.

The most encouraging data were reported by Fabian et al. from the Southwest Oncology Group (SWOG 8572).⁷⁶ In this phase II adjuvant pilot trial, 41 patients with T3N1-2M0 disease received whole abdominal radiation therapy plus continuous infusion 5-FU followed by nine monthly cycles of continuous infusion 5-FU. Because of unacceptable toxicity in the first six patients, the protocol was modified such that (1) the 5-FU was started on day 1 and radiation began concurrently on day 8, and (2) a 1-week treatment break from both the 5-FU and radiation was required at day 42. The tumor bed boost (1.6 Gy × 10 fractions) was delivered first followed by whole abdominal radiation therapy (1 Gy/day × 30 fractions) for a total dose of 30 Gy to the whole abdomen and 46 Gy to the tumor bed.

With a median follow-up of 5 years, the 5-year disease-free and overall survival rates were 58% and 67%, respectively. Limiting the analysis to the 20 patients with more than four positive nodes, the 5-year disease-free and overall survival rates were 55% and 74%, respectively. For the total patient group, the patterns of failure were: local = 12%; liver = 22%; and peritoneal and other abdominal = 15%. In contrast to other whole abdomen radiation therapy trials, toxicity during the combined modality segment was tolerable (17%, Grade 3; 7%, Grade 4). These results were encouraging but need further follow-up. Given the advances in systemic chemotherapy in colon cancer, there is little interest in whole abdominal radiation.