The fundamental role of environmental factors is supported by observations in migrant populations. Generally, migrants from low-incidence regions in Africa and Asia who relocate to high-incidence regions of North America or Australia assume the incidence of the host country within one generation.³ Specifically, a high-fat, low-fiber diet is associated with the development of colorectal cancer, although it is unclear if it is causative. Conversely, the ingestion of a high-fiber diet is associated with protection against colorectal cancer. Fiber causes the formation of a soft, bulky stool that dilutes out carcinogens; it also decreases colonic transit time, allowing less time for carcinogenic substances to contact the mucosa. The more sedentary lifestyle in Western countries, cigarette smoking, and alcohol consumption also appear to be linked with the risk of colorectal neoplasia.

Most colorectal cancers arise from benign adenomatous polyps lining the wall of the bowel. Those that grow to a large size (>2 cm) and have a villous appearance or contain dysplastic cells are most likely to progress to cancer. This progression from adenoma to carcinoma is associated with an accumulation of genetic alterations, including activation of oncogenes and inactivation of tumor suppressor genes.⁴ One of the early steps in this process is the interruption of the APC/?β-catenin/TCF-4 pathway, allowing unchecked cellular replication at the crypt surface.⁵ This can occur in the germline of FAP patients, with the second allele being inactivated somatically, or in sporadic cancers, in which both alleles are somatically inactivated.

There are likely three pathways that lead to colorectal cancer: chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP).⁶ CIN is the genetic reason for tumor formation in 50% to 70% of colorectal cancers and the mechanism operative in FAP. It is typically coupled with mutations in the KRAS, APC, and TP53 genes, ultimately leading to loss of heterozygosity of TP53 and malignant transformation. MSI is found in more than 90% of HNPCCs that carry a germline inactivation in DNA mismatch repair genes, but also in 15% of sporadic cancers, in which epigenetic hypermethylation silences gene transcription of hMLH1. With MSI, multiple frameshift mutations at microsatellite sequences occur, including those in exon coding sequences of the transforming growth factor-beta receptor II, the proapoptotic BAX gene, and the DNA mismatch repair genes (hMSH3 and hMSH6 genes). The third type, CIMP, is a relatively heterogeneous subgroup and occurs in approximately 10% to 30% of patients, is predominantly associated with KRAS gene mutations but sometimes with BRAF gene mutations, usually lacks chromosomal instability, and has the poorest prognosis of the three types and perhaps a poorer response to chemotherapy. Of the numerous molecular markers examined to date, MSI, 18q, thymidylate synthase, and TP53 overexpression are among those which appear to have the most prognostic significance in colon cancer.⁷ Although the markers are not currently incorporated into the staging system, they should be noted.

Colorectal cancer is the fourth commonest form of cancer worldwide, with an estimated 800,000 new cases diagnosed each year, accounting for roughly 10% of all cancers.⁸ Globally, the colorectal cancer incidence per 100,000 persons in 1990 was 19.4 for men and 15.3 for women. High incidence rates are found in North America, Western Europe, and Australia (40 to 45 cases per 100,000 population) and intermediate rates are found in Eastern Europe (26 cases per 100,000 population), with the lowest rates found in Africa (3 to 8 cases per 100,000 population). Approximately two-thirds of cases occur in the colon and one-third in the rectum. In the United States, 39,760 new cases of rectal cancer were estimated to occur in 2011 (22,620 in men, 17,050 in women),¹ there is little difference in incidence among whites, African Americans, and Asian Americans.

The occurrence of sporadic colorectal cancer increases continuously above the age of 45 to 50 years for both genders and peaks in the seventh decade. Subgroups of patients, including those with inherited syndromes such as familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC), or hamartomatous polyposis conditions (e.g., Peutz-Jeghers syndrome), can experience colorectal cancer at a much earlier age.⁹

Prevention and Early Detection

Primary Prevention

Primary prevention involves the identification and elimination of factors that cause or promote colorectal cancer or interfere with the adenoma-to-carcinoma cascade. Dietary and lifestyle approaches employ higher-fiber, lower-fat components and increased physical activity to inhibit the carcinogenic process. Other dietary components, such as selenium, carotenoids, and vitamins A, C, and E, may also have protective effects by scavenging free oxygen radicals. Folic acid, a component of fresh fruits and green vegetables, supplies methyl groups necessary for nucleotide synthesis and gene regulation. Prospective studies generally support an inverse association between folate intake and colorectal cancer risk.¹⁰

Chemopreventive strategies are based on population-based studies that strongly support an inverse relationship between the use of nonsteroidal anti-inflammatory drugs, such as aspirin, sulindac, or the new selective COX-2 inhibitors, and the risk of colorectal adenomas or carcinomas.¹¹ COX-2 is overexpressed in more than 50% of adenomas and 80% to 85% of adenocarcinomas. Trials are currently under way that focus on FAP patients, those with resection of early-stage colorectal carcinomas, and those with a history of adenomatous polyps.

Screening for Early Detection

The process of malignant transformation from adenoma to carcinoma takes several years. The goal of screening is to prevent rectal cancer deaths through the detection and treatment of benign or premalignant lesions and curable-stage cancers.^12,¹³ For the average-risk population, screening should begin at age 50 years and should follow one of the following testing options: fecal occult blood testing every year, flexible sigmoidoscopy every 5 years, yearly fecal blood testing and flexible sigmoidoscopy every 5 years, colonoscopy (preferably) every 10 years, or double-contrast barium enema studies every 5 years. If polyps are found, however, colonoscopy should be performed every year until the patient is polyp free.

Some individuals are at increased risk for colorectal cancer. For example, if there is an affected first-degree relative, a family history of FAP or HNPCC, or a personal history of adenomatous polyps, colorectal cancer, or chronic inflammatory bowel disease, screening should begin earlier (at age 40 years) and/or it should be done more often than in average-risk persons. In some settings such as a personal history of genetic predisposition, screening should be done at an even younger age.

Two promising but investigational approaches to screening include virtual colonoscopy and molecular stool testing.^7,¹⁴ Virtual colonoscopy employs virtual reality technology from cross-sectional CT or MRI scans. Molecular stool testing is based on the molecular detection of neoplasm-specific DNA from exfoliated cancer cells.

Biologic Characteristics and Molecular Biology

The most important prognostic factor for overall survival is the pathologic extent of disease as determined by the degree of bowel wall penetration by the tumor, and the presence or absence of lymph node metastases or distant metastases (TNM stage).¹⁵ Tumor differentiation is also prognostically important because poorly differentiated adenocarcinomas are associated with lymph node metastases in more than 50% of cases and also correlate with the likelihood of lymphatic and venous invasion.¹⁶ An elevated carcinoembryonic antigen (CEA) level at the time of presentation has an adverse impact on survival times independent of tumor stage.¹⁷ If the level is higher than 100 ng/mL, the patient has distant metastasis (most likely, to the liver or lung) until proven otherwise. Detection of occult metastases in lymph nodes, blood, or bone marrow by molecular techniques may allow further refinement in pathologic staging. Molecular strategies added to the more traditional histopathologic information may help in the future to identify patients at a lower stage whose tumors are likely to behave like higher-stage lesions, and vice versa. Several biologic markers, including allelic loss of 18q, alteration in KRAS, MSI, thymidylate synthase, thymidine phosphorylase, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), P21, P27, BCL2, BAX, and TP53, among others, are now being prospectively evaluated in clinical trials to determine their prognostic utility.² At the present time, however, the TNM staging system is the most reliable.

Pathology and Pathways of Spread

Histopathology

The majority (>90%) of colorectal cancers are adenocarcinomas. Some adenocarcinomas have mucin, which can be extracellular (colloid) or intracellular (signet-ring cell). Colloid cancer, which occurs in 15% to 20% of adenocarcinomas, is not an independent prognostic factor, whereas signet-ring cell carcinoma, which occurs in 1% to 2% of adenocarcinomas, is an independently poor prognostic factor for survival.^18,¹⁹ Other histologic types are rare and include carcinoid tumors,²⁰ leiomyosarcomas,^21,²² lymphomas,²³ and squamous cell cancers.²⁴ The grading system used for adenocarcinomas refers to the degree of differentiation. Some institutions use a three-grade system (well, moderate, poor), and others use a four-grade system. Despite substantial interobserver and intraobserver variability in tumor grading, poorly differentiated tumors have consistently been found to be associated with a worse prognosis in multivariate analysis.

Anatomy and Pathways of Spread

The rectum is about 15 cm long. In cancer staging, because of differences in treatment and prognosis, the rectum is subdivided into three parts according to the distance of the lower margin of the tumor from the anal verge (assessed by rigid sigmoidoscopy): upper third, 12 to 16 cm; middle third, 6 to 12 cm or less; and lower third, less than 6 cm. When reporting results, it should be stated whether the reference point is the anal verge (i.e., lowermost portion of the anal canal), the dentate line, or the anorectal ring. Distances measured from the anal verge are approximately 2 to 3 cm longer than distances from the dentate line. The anorectal ring is at the level of the puborectalis sling and levators, representing the pelvic floor from within the pelvis.

The anterior peritoneal reflexion represents the point at which the rectum exits the peritoneal cavity and becomes a retroperitoneal structure (approximately 12 to 15 cm from the anal verge). Below this level, there is a mesorectal, or circumferential, resection margin all around the rectum. The circumferential resection margin (CRM) is related more to the type of surgical procedure than to an anatomic landmark, however. While distal intramural spread usually extends no more than millimeters beyond the grossly recognizable margin of the tumor, microscopic tumor nodules (satellites) are found in the mesorectum, predominantly in a radial direction but also in a distal one, some centimeters from the lower tumor margin.²⁵ A layer of visceral fascia encloses both the rectum and mesorectum and thus forms a separate compartment within the pelvis. With total mesorectal excision (TME), the entire specimen is removed by sharp dissection along the mesorectal plane. Patients entered into postoperative adjuvant rectal trials in the United States were required to have tumors with the inferior aspect at or below the peritoneal reflection. For entry into preoperative trials, most use tumors with a distance of less than 12 cm from the anal verge for eligibility. The German trial allowed tumors at a distance of as much as 16 cm, however.²⁶

The major portion of the lymphatic drainage of the rectum passes along the superior hemorrhoidal arterial trunk toward the inferior mesenteric artery. Only a few lymphatics follow the inferior mesenteric vein. The pararectal nodes above the level of the middle rectal valve drain exclusively along the superior hemorrhoidal lymphatic chain. Below this level (≈7 to 8 cm above the anal verge), some lymphatics pass to the lateral rectal pedicle. These lymphatics are associated with nodes along the middle hemorrhoidal artery, obturator fossa, and hypogastric and common iliac arteries. The risk of their involvement increases with tumor stage, presence of mesorectal positive nodes, infiltration of mesorectal fascia, and low location of the primary tumor. Extensive lymphatics are also present in women contiguous with the rectovaginal septum and in men along Denonvilliers’ fascia.

The venous drainage of the upper rectum is to the inferior mesenteric vein via the superior hemorrhoidal vein and then to the portal system, whereas the lower rectum can, in addition, drain to the internal iliac veins and inferior vena cava. Therefore, liver or lung metastases, or both, can occur with rectal cancers.

Clinical Manifestations, Patient Evaluation, and Staging

Clinical Manifestations

Rectal cancer is usually symptomatic before diagnosis. Common symptoms include gross red blood (mixed or covering stool, or by itself, sometimes accompanied by the passage of mucus) and a change in bowel habits such as unexplained constipation, diarrhea, or reduction in stool caliber. Hemorrhoidal bleeding should always be a diagnosis of exclusion. Obstructing rectal cancers frequently present with diarrhea rather than constipation. In cases of locally advanced rectal cancer with circumferential growth and extensive transmural penetration, urgency, inadequate emptying, and tenesmus occur. Urinary symptoms and buttock or perineal pain from posterior extension are grave signs. Sciatic pain is indicative of tumor invasion into the sciatic notch, and surgery will likely leave gross disease.

Patient Evaluation

The standard diagnostic algorithm for rectal cancer is seen in Table 49-1. The pretreatment evaluation of a patient with rectal cancer should include a careful history and physical examination. By digital rectal examination (the average finger can reach approximately 7 to 8 cm), tumors can be assessed for size, ulceration, and fixation to surrounding structures. This examination also permits evaluation of sphincter function, which is critical when determining whether a patient is a candidate for a sphincter-sparing procedure. Rigid proctosigmoidoscopy allows direct visualization of the lesion and provides an estimation of the size of the lesion and degree of obstruction. This procedure is used to obtain biopsies and gives an accurate measurement of the distance of the lesion from the anal verge. A complete evaluation of the large bowel, preferably by colonoscopy, should be done to rule out synchronous neoplasms.

TABLE 49-1 Diagnostic Algorithm for Rectal Cancer

History	Including family history of colorectal cancer or polyps
Physical examination	Including assessment of size, minimum diameter of lumen, mobility, distance from anal verge, and cursory evaluation of sphincter function
Proctoscopy	Including assessment of mobility, minimum diameter of lumen, and distance from anal verge. Allows biopsy of the primary tumor.
Colonoscopy or barium enema	To detect possible synchronous neoplasm
Endorectal ultrasound	To assess extent of primary tumor, if considering local excision or preoperative therapy
Pelvic CT or MRI scanning	To assess extent of primary tumor and lymph node involvement (for accuracy of transrectal ultrasound, CT; MRI for T and N category) (see Table 49-2)
Chest radiograph and abdominal ultrasound	To detect possible metastatic disease
Abdominal CT/MRI scanning Lung CT scanning	To further investigate suspicious findings of chest radiographs and abdominal ultrasound
PET/CT scanning	To rule out metastatic blood-borne or nodal disease
CEA levels	To obtain baseline CEA level (a prognostic factor and important for follow-up)
Complete blood count	To check for anemia secondary to bleeding

CEA, carcinoembryonic antigen; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography.

The primary imaging modalities for assessing the extent of the primary tumor are endorectal ultrasound (ERUS), CT, positron emission tomography (PET), and MRI. ERUS and high-resolution pelvic MRI are the most accurate tools in predicting the T stage of rectal cancers (Fig. 49-1 and Table 49-2). With the shift to preoperative therapy, clinical staging to accurately identify both T stage and N stage is critical. Imaging techniques to assess the extent of the primary tumor include CT, MRI, PET with ¹⁸F-fluorodeoxyglucose (FDG-PET), and transrectal ultrasound. In the United States, ultrasound plus CT or MRI is commonly used, whereas in many European countries, high-resolution pelvic MRI is preferred. High-resolution MRI also allows for identification of patients likely to have close or positive radial margins if they undergo initial surgery and therefore they are selected to receive preoperative therapy.²⁷ For example, the Mercury trial, based in the United Kingdom, uses MRI to select for the intensity of preoperative therapy.²⁸ In a retrospective analysis of 504 patients reported by Bail and colleagues,²⁹ even following preoperative chemoradiation, those with positive radial margins still had a higher local recurrence rate (35% vs. 11%) and a lower 5-year survival rate (27% vs. 73%) compared with those with negative radial margins.

Figure 49-1 Endorectal ultrasound (ERUS) visualizes the rectal wall as alternating hyperechoic and hypoechoic layers of tissue. The first layer is the hyperechoic water-filled balloon or mucosal interface, which is bounded by the hypoechoic mucosa and muscularis mucosa, the hyperechoic submucosa, the hypoechoic muscularis propria, and, finally, the hyperechoic muscularis propria or perirectal fat interface. Depth of penetration is determined by identifying which of these layers is disrupted by the tumor. The figure shows a mass infiltrating beyond the muscularis propria (thick arrow) into the perirectal fat (bright area in the lower part), indicating a uT3 rectal tumor.

TABLE 49-2 Accuracy of Pelvic CT, MRI, and ERUS for T and N Category ²⁶⁷*

The overall accuracy of imaging studies in predicting disease extent varies by imaging modality and disease category (T vs. N vs. M). The accuracy for T category is approximately 50% to 90% with transrectal ultrasound ³⁰ or high-resolution MRI³¹ and 50% to 70% with CT or conventional MRI scanning.³² For identification of metastatic disease (M stage), FDG-PET/CT may be more accurate than CT alone.³³ The use of PET/CT to restage patients following preoperative chemoradiation remains controversial.³⁴^–³⁶

The identification of positive lymph nodes is more difficult. The overall accuracy in detecting positive pelvic lymph nodes with the above techniques is approximately 50% to 75%. The accuracy of MRI is similar to that of CT, but it is improved with the use of external and/or endorectal coils. Both CT and MRI can identify lymph nodes measuring 1 cm or more, although enlarged lymph nodes are not pathognomonic of tumor involvement. The accuracy of MRI is similar to that of CT and may be further enhanced with the use of superparamagnetic iron oxide particles.³⁷ Likewise, the accuracy of ultrasound for the detection of involved perirectal lymph nodes may be augmented if ultrasound is combined with fine-needle aspiration.³⁸ Despite these advances, the ability to accurately predict the pathologic stage following preoperative chemoradiation with MRI,^39,⁴⁰ ultrasound,^41,⁴² FDG-PET,³⁴ or physical examination⁴³ remains suboptimal. The tumor regression grade^44,45 may help predict lymph node positivity; patients would have already received preoperative chemoradiation, however.

Screening for distant metastatic disease is commonly performed with CT and/or MRI. The major advantage of a PET/CT scan is to differentiate between recurrent tumor and scar tissue by measuring tissue metabolism of an injected glucose-based substance.^46,⁴⁷ Scar tissue is inactive, whereas tumor tissue is generally hypermetabolic. At the present time, PET/CT is considered investigational for a routine preoperative metastatic workup in a patient who presents with primary disease,³³ but its use should be considered strongly for patients with presumed locoregional relapse who are being considered for aggressive treatment approaches with curative intent.³³

Imaging after Chemoradiation

Although ERUS, CT, and MRI can be used to assess downstaging of the tumor after neoadjuvant treatment, none is accurate in distinguishing among ypT0, ypT1, ypT2, or ypT3 tumors. Overstaging is common, especially when there is a fibrotic thickening of the rectal wall. A reasonably high level of accuracy has been observed by phased-array MRI for differentiating ypT0 to T2 versus ypT3 disease.⁴⁸ Both diffusion-weighted MRI and FDG-PET/CT have been used to monitor therapy response and to predict the outcome following preoperative therapy. Of the two, FDG-PET/CT has a larger role. Many studies have reported a significant decrease in standardized uptake values (SUVs) on postirradiation FDG-PET/CT scans in responders when compared with nonresponders, but the clinical value of this information remains to be determined.⁴⁹

Staging

The first practical staging system was the Dukes’ classification.⁵⁰ This system classified colorectal tumors from A to C, with stage A indicating penetration into but not through the bowel wall, stage B indicating penetration through the bowel wall, and stage C indicating involvement of lymph nodes, regardless of the extent of bowel wall penetration. The system 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 (B2m or C2m) or gross (B2m+g or C2m+g) penetration of tumor through the bowel wall.⁵¹ 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,⁵² with most confirming the predictive capability of this system.

In 1988, the American Joint Commission on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC) proposed a joint TNM staging system. It was based on the fifth edition of the AJCC TNM staging system. In the AJCC staging manuals up through the fifth edition, however, substaging was not used for colorectal cancer in spite of marked differences in outcomes by TN category of disease for patients with AJCC stage II and III disease.

In the sixth edition of the AJCC staging manual, stage II colorectal cancer was subdivided into IIA (T3N0) and IIB (T4N0) and stage III was subdivided into IIIA (T1-2N1M0), IIIB (T3-4N1M0), and IIIC (any TN2M0), based on improved outcomes for patients with IIA versus IIB disease and IIIA versus IIIB disease.⁵³ The prognostic validity of this change was supported by a subsequent pooled analysis of the U.S. GI Intergroup and National Surgical Adjuvant Breast and Bowel Project (NSABP) postoperative trials⁵⁴ and the retrospective analysis of the American College of Surgeons National Cancer Database (NCDB).⁵⁵ The placement of all TN2 patients into stage IIIC, however, was not based on in-depth outcomes analyses, because the impact of depth of bowel wall invasion (T category) in N2 patients had not been evaluated in detail.

Before making substantive changes in the AJCC seventh edition staging manual for colon and rectal cancer (Table 49-3), the AJCC Hindgut Task Force sought population-based validation that depth of invasion and nodal status interact to affect survival rates. Surveillance, Epidemiology, and End Results (SEER) survival data were obtained for patients with invasive colon and rectal cancer and evaluable TN category of disease (35,829 rectal and 109,953 colon cancer patients).⁵⁶ T4N0 cancers were stratified by “tumors that perforate visceral peritoneum” (T4a) versus “tumors that invade or are adherent to adjacent organs or structures” (T4b). N1 and N2 were stratified by number of involved nodes (N+): N1a/N1b (1 vs. 2 or 3 nodes), and N2a/N2b (4 to 6 vs. ≥7 nodes). Rates of 5-year observed and relative survival were obtained for each TN category. The analyses indicated the following information: survival rates are better for T1-2N0 cancers than T3N0 cancers, better for T3N0 cancers than T4N0 cancers, better for T1-2N2 cancers than T3-4N2 cancers, and similar for T4bN1 and T4N2 cancers. In addition, patients with T4a lesions have better survival rates than those with T4b lesions by N category, and the number of positive lymph nodes affects survival for each T category. The SEER population-based colon and rectal cancer analyses supported subdividing T4 (T4a/T4b), N1 (N1a/N1b), and N2 (N2a/N2b) and supported revised substaging of stages II and III (shift of T1-2N2 lesions from IIIC to IIIA/IIIB and T4bN1 lesions from IIIB to IIIC.^56,57

TABLE 49-3 AJCC TNM Staging System for Colorectal Cancer

There are additional descriptors that do not affect the stage grouping but 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.¹⁵

Clinical staging is designated as cTNM and is based on physical examination, radiologic imaging, and endoscopic, biopsy, and laboratory findings. Pathologic staging is designated as pTNM and depends on data acquired clinically in addition to surgical and pathologic findings. The prescript “y” is used to indicate that the tumor has been treated before surgical resection. Recurrent tumors are designated with the “r” prefix. If there is uncertainty regarding the appropriate T, N, or M stage, the lower (less advanced) category should be used.

The role of the pathologist is critical to proper staging. Following surgery alone, at least 12 pelvic nodes must be examined to obtain an accurate pN stage. Tumors treated with preoperative chemoradiation are downstaged, however, and it is commonly not possible to evaluate 12 lymph nodes for this purpose.^58,⁵⁹

Primary and Adjuvant Therapy for Resectable Disease

Adjuvant Irradiation without Chemotherapy

There are three general approaches in which radiation therapy has been used in the adjuvant treatment of resectable rectal cancer: postoperative treatment, preoperative treatment, and combined preoperative and postoperative treatment.

Postoperative Irradiation

Until 1990, most patients in the United States underwent surgery and, if needed, received postoperative external beam radiation therapy (EBRT). The primary advantage with this approach was pathologic staging and avoiding overtreatment with preoperative therapy. As confirmed by the German CAO/ARO/AIO 94 phase III trial that randomized preoperative versus postoperative chemoradiation, the disadvantage of postoperative therapy is significantly higher rates of local recurrence and acute and chronic toxicity, as well as a significantly lower chance of sphincter preservation.²⁶ Lastly, if the patient has undergone an APR, the radiation field must be extended to include the perineal scar.

Historical nonrandomized data from the Massachusetts General Hospital ⁶⁰ and M.D. Anderson Cancer Center⁶¹ reveal crude local failure rates of 4% to 31% in patients with stage pT3-4N0M0 disease and 8% to 53% in patients with stage pT3-4N1-2M0 disease who received 45 to 55 Gy without chemotherapy.

There are five randomized trials examining the use of adjuvant postoperative irradiation without chemotherapy in stage pT3 and/or N1-2 rectal cancer.62,63,64,65,66 None have shown an improvement in overall survival (OS). Two reveal a decrease in local failure rates; NSABP trial R-01 (16% vs. 25%; p = .06) and the Medical Research Council (MRC) trial (21% vs. 34%; p = .001).⁶⁵

Preoperative Irradiation

There are two approaches to preoperative therapy. The first, used most commonly in Northern Europe and Scandinavia, is the intensive short course (25 Gy in five fractions). In contrast, most other investigators recommend a standard course (50.4 Gy in 28 fractions) combined with concurrent systemic chemotherapy (chemoradiation).

Dose escalation has not shown a clear benefit. In the Lyon R96-02 trial, 88 patients with cT2 to T3 rectal cancer received 39 Gy in 13 fractions to the pelvis and were randomized to observation or a boost with contact irradiation to a total dose of 85 Gy.⁶⁷ A total of 23 patients were selected to receive postoperative chemotherapy. Patients who received the boost had a decrease in the local failure rate (2% vs. 7%) but there was no difference in 2-year disease-free survival (DFS) (92% vs. 88%).

A unique clinical situation in which preoperative radiation therapy alone is recommended is when a patient has a distal uT2N0 tumor and refuses an APR. Although APR is the standard therapy, an alternative treatment is preoperative irradiation followed by low anterior resection (LAR) and, if the pelvic nodes are positive, postoperative chemotherapy. In a series of 27 patients with cT2N0 distal rectal cancer who refused APR and received preoperative EBRT, 78%underwent a sphincter-sparing operation.⁶⁸ The incidence of 5-year actuarial local recurrence in those undergoing sphincter preservation was 13%; the colostomy-free survival rate, 100%; and the OS, 85%. Overall, 77% of those who underwent a sphincter-sparing procedure had good to excellent bowel function at 24 to 36 months after surgery.

The primary advantage of this approach is sphincter preservation. There are disadvantages, however. First, there is a chance of undertreatment, since approximately 50% of patients are downstaged from ypN+ to ypN0 after preoperative irradiation and therefore will not receive adjuvant chemotherapy. Although pretreatment high-resolution MRI can help predict which patients may have positive circumferential margins, neither MRI nor any other imaging modality or clinicopathologic factor can identify with a high degree of accuracy (>70%) those patients with N+ disease. Second, there is the additional toxicity of pelvic irradiation, which can adversely affect bowel, bladder, and sexual function.

Short-Course Preoperative Irradiation

There are 12 modern randomized trials of preoperative radiation therapy (without chemotherapy).⁶⁹ All use low to moderate doses of radiation. Most of the trials showed a decrease in local recurrence rates, and in five of the trials, this difference reached statistical significance. Although in some trials a subset analysis revealed a significant improvement in survival rates, the Swedish Rectal Cancer Trial is the only one that reported a survival advantage for the total treatment group. Two meta-analyses report conflicting results. Although both revealed a decrease in local recurrence rates, the analysis by Camma and associates⁷⁰ reported a survival advantage, whereas the analysis by the Colorectal Cancer Collaborative Group⁷¹ did not.

In the Swedish Rectal Cancer Trial, patients with cT1-3 rectal cancer were randomized to receive 25 Gy in 1 week followed by surgery 1 week later versus surgery alone.⁷² Those who received preoperative irradiation had a significant decrease in local recurrence rates (12% vs. 27%; p <.001) and a correspondingly significant improvement in 5-year OS (58% vs. 48%; p = .004). After 13 years, the OS is still significantly improved (38% vs. 30%; p = .008).⁷³ Of interest, the local recurrence rate in node-positive patients who underwent surgery alone was 46%, illustrating the inferior results of surgery before the adoption of TME.

The Dutch CKVO 95-04 trial randomized 1805 patients with cT1 to T3 disease to TME or intensive short-course preoperative radiation therapy followed by TME.⁷⁴ Irradiation significantly decreased the local recurrence rate (8% vs. 2%; p < .0001), but there was no difference in the 2-year survival rate (82%). With longer follow-up, the 5-year local failure rate was higher with TME (11%) but was still significantly decreased (to 6%) with preoperative irradiation.⁷⁵ The acute toxicity rates in the Dutch CKVO 95-04 trial included a 10% rate of neurotoxicity, a 29% rate of perineal wound complications, and a 12% rate of postoperative leaks.⁷⁶ Of the patients who developed postoperative leaks, 80% required surgery, resulting in death in 11%.

The presence of a positive circumferential margin is an important negative prognostic sign. In the Dutch CKVO trial, 17% had positive circumferential margins. Although they received 50 Gy postoperatively, this did not compensate for positive margins.⁷⁷ Few centers perform the necessary pathologic examination to detect positive circumferential margins.^29,⁷⁸ MRI can help identify patients who will have positive margins with surgery alone as well as select those who may benefit from preoperative therapy.⁷⁹^–⁸¹

It must be emphasized that chemoradiation trials cannot be compared with short-course irradiation trials because they exclude patients with cT1 to T2 disease. In contrast, short-course trials include patients with cT1 to T3 disease.

Preoperative plus Postoperative Irradiation

This approach, also known as the sandwich technique, includes a short preoperative course of radiation (5 to 15 Gy) followed by surgery, and in patients with pT3-4N1-2 disease, an additional 40 to 45 Gy postoperatively. The Radiation Therapy Oncology Group (RTOG) trial 81-15 randomized 350 patients (87% with rectal cancer) to preoperative irradiation with 5 Gy versus surgery alone.⁸² Patients with stage pT3 and/or N1-2 disease received a minimum dose of 45 Gy postoperatively. No chemotherapy was delivered. There were no differences in rates of local failure, distant failure, or OS between the arms. A retrospective analysis of 155 patients treated at the Institut Gustave Roussy also revealed no advantage of the sandwich technique compared with preoperative irradiation.⁸³ This approach is no longer used.

Adjuvant Combined-Modality Therapy

There are two conventional treatment approaches for clinically resectable rectal cancers. For patients with cT1-2N0 disease, the initial treatment is surgery, and if the tumor is pT3N0 or TanyN1-2, this is followed by postoperative chemoradiation.⁸⁴ For patients with cT3-4N0 or TanyN+ lesions, preoperative chemoradiation is given, followed by surgery and postoperative adjuvant chemotherapy.

Postoperative Chemoradiation

The National Cancer Institute (NCI) Consensus Conference concluded in 1990 that chemoradiation was the standard postoperative adjuvant treatment for patients with pT3 and/or N1-2 disease.⁸⁴ This recommendation was based on phase III trials that compared postoperative chemoradiation arms with control arms of either surgery alone or surgery plus postoperative irradiation (Mayo/NCCTG 79-47-51) and demonstrated improvements in both DFS and OS.⁸⁵ The standard design in U.S. trials was to deliver six cycles of bolus 5-fluorouracil (5-FU)–based chemotherapy; concurrent irradiation was also given during cycles 3 and 4.

The U.S. GI Intergroup 86-47-51 trial did not demonstrate an incremental benefit to semustine when it was added to postoperative irradiation plus concurrent and maintenance 5-FU.⁸⁶ However, a 2 × 2 component of the study demonstrated a positive benefit for giving protracted venous infusion (PVI) 5-FU rather than interrupted bolus 5-FU concurrently with pelvic irradiation. Patients randomized to receive concurrent PVI 5-FU (225 mg/m²/day, 7 days/week or until intolerance) had improvements in rates of disease control, DFS (at 4 years, 63% vs. 53%; p = .01), and OS (at 4 years, 70% vs. 60%; p = .005).

The successor INT 0114 four-arm trial randomized patients with pT3-4N0 and/or TanyN+ rectal cancer to postoperative irradiation and bolus 5-FU with or without leucovorin, levamisole, or leucovorin plus levamisole (INT 86-47-51 results were not available before INT0114 study design and completion). There was no significant difference in local control or survival rates among the four arms.⁸⁷ With longer follow-up, the study also revealed that local control and survival results continued to deteriorate after 5 years. At 7 years, the local failure rate was 17% and the survival rate was 56%, compared with 14% and 64%, respectively, at 5 years. Patients with high-risk (pT3N+ or T4) disease had a lower survival rate compared with lower-risk (pT1-2N+ or T3N0) disease (45% vs. 70%). Further analysis of the INT 0114 trial has revealed that body mass is related to outcome and treatment-related toxicity,⁸⁸ and both surgeons and hospitals with higher volumes of rectal cancer surgery have improved outcomes compared with those with lower volumes.⁸⁹

The subsequent INT 0144 postoperative adjuvant rectal trial was designed to follow up on the positive results achieved with concurrent PVI 5-FU during irradiation in trial 86-47-51.⁹⁰ Patients were randomized to three arms: arm 1, bolus 5-FU/PVI 5-FU + RT/bolus 5-FU (control arm from 86-47-51); arm 2, PVI 5-FU/PVI 5-FU + RT/PVI 5-FU; arm 3, bolus 5-FU–leucovorin(LV)–levamisole/bolus 5-FU–LV-levamisole + RT/bolus 5-FU–LV-levamisole. The concurrent PVI 5-FU arms did not confirm a survival benefit relative to the bolus 5FU/LV/levamisole arm, but arm 2 did report a lower incidence of grade 3+ hematologic toxicity. Based on these results, when 5-FU is used with either preoperative or postoperative chemoradiation, PVI has been the preferable standard.

Do Patients with Pathologic Node-Negative Rectal Cancer Require Pelvic Irradiation?

The 1990 NCI Consensus Conference recommendation for postoperative chemoradiation was published nearly 20 years ago and was based on trials where neither a TME nor an examination of 12 nodes or more was required. Retrospective data suggest that there may be a subset of patients with pT3N0 disease who may not require adjuvant therapy. Nissan and associates ⁹¹ reported results of 100 patients with uT2-3N0 disease who underwent TME alone and had 12 nodes or more examined.

In the subset of 49 patients with uT3N0 disease, the overall local recurrence rate was 4%. For the total group, the local recurrence rate was significantly higher in those with lymph vessel invasion tumors (32% vs. 6%; p = .006) and an elevated (>5 ng/mL preoperative CEA level (21% vs. 0%).

The sixth edition of the AJCC staging manual subdivided stage III into IIIA (T1-2N1), IIIB (T3-4N1), and IIIC (TanyN2). The prognostic validity of this change was supported by both the rectal pooled analysis of the U.S. GI Intergroup and NSABP postoperative trials ⁵⁴ and the retrospective analysis of the American College of Surgeons National Cancer Database.⁵⁵ The 5-year survival rates by stages IIIA, B, and C in the pooled analysis were 81%, 57%, and 49% and in the NCDB database were 55%, 35%, and 25%, respectively. These data provided further evidence that patients who undergo TME, have at least 12 nodes examined, and have stage pT3N0 disease may not need the radiation component of chemoradiation, dependent on the adequacy of radial and distal margins of resection. The approximately 3% to 4% benefit in local control with irradiation may not be worth the risks, especially in women of reproductive age. However, patients with pT3N0 tumors with adverse pathologic features, or who undergo resection without TME, or who have fewer than 12 nodes examined should still receive postoperative chemoradiation.

Although the number of nodes is defined in the AJCC staging system, the location of pelvic nodes is not. Leibold and associates ⁵⁹ treated 121 patients with preoperative chemoradiation and found that the incidence of metastatic disease was higher in those patients with positive nodes in the proximal pelvis compared with positive nodes anywhere in the pelvis (46% vs. 32%). Of note, the proximal nodes are above the superior border of the typical radiation field (L5/S1) because they are located along the apical and mid portion of the inferior mesenteric artery.

Preoperative Chemoradiation

Based on the German CAO/ARO/AIO 94 trial, preoperative chemoradiation is standard treatment for patients with cT3-4N0 or TanyN+ disease.²⁶ The disadvantage of preoperative therapy is the possible overtreatment of patients with either early-stage disease (pT1-2N0) or undetected metastatic disease. In the German trial that used CT and transrectal ultrasound, 18% of patients were overstaged. A number of questions and issues exist with regard to patient selection for preoperative chemoradiation and optimization of treatment that will be addressed in the following subsections.

The Need for Chemotherapy with Preoperative Irradiation

Almost every randomized trial for the past two decades has confirmed a 10% to 15% survival benefit of a total of 6 months of adjuvant 5-FU-based chemotherapy for patients with lymph node-positive colon or rectal cancer. Both retrospective ⁹² and randomized trials,^93,⁹⁴ however, question whether chemotherapy improves the results of preoperative irradiation in patients with cT3-4 rectal cancer.

The European Organization for Research and Treatment of Cancer (EORTC) trial 22921 was a four-arm randomized trial of 1011 patients who received preoperative irradiation of 45 Gy with or without a concurrent bolus of 5-FU/leucovorin followed by surgery with or without four cycles of postoperative 5-FU/leucovorin.⁹³ Only 37% had a TME. The EORTC trial revealed a significant decrease in the local failure rate in those patients who receive chemoradiation compared with irradiation (8% to 10% vs. 17%; p <.001) but no difference in the 5-year OS (65%). However, only 43% received 95% or more of the planned postoperative chemotherapy, which may explain the negative results. Furthermore, a subset analysis of the EORTC trial revealed that patients who responded to preoperative chemoradiation had a survival benefit from postoperative chemotherapy.⁹⁵

A trial by the Fédération Francophone de la Cancérologie Digestive (FFCD 9203) was a two-arm trial of 742 patients randomized to preoperative irradiation of 45 Gy with or without bolus 5-FU/leucovorin.⁹⁴ All patients were scheduled to receive postoperative chemotherapy, and 73% received such. The FFCD trial reported a similar decrease in local failure rates (8% vs. 17%; p <.05) and a corresponding increase in pathologic complete response (pCR) (11% vs. 4%; p <.05) with preoperative chemoradiation vs. irradiation alone, but no survival benefit (68% vs. 67%).

Because most patients did not receive adequate doses of postoperative chemotherapy in the EORTC trial and the FFCD trial only tested the impact of concurrent chemotherapy with preoperative irradiation, preoperative chemoradiation followed by surgery and 4 months of postoperative adjuvant chemotherapy remains the standard practice in North America. However, there remains considerable controversy in some European countries regarding its use. A recent consensus conference failed to reach a definitive recommendation regarding its use.⁹⁶

Potential Overtreatment with Preoperative Therapy

In the German CAO/ARO/AIO 94 rectal trial, 18% of patients clinically staged as cT3N0 preoperatively and who underwent initial surgery without preoperative therapy had pT1-2N0 disease.²⁶ Therefore, those patients would have been overtreated if they had received preoperative therapy. Although not ideal, preoperative therapy is still preferred to performing surgery first because even after preoperative chemoradiation (which downstages tumors), Guillem and coauthors⁹⁷ reported that 22% will have ypN+ disease at the time of surgery. In patients who undergo surgery alone, this number is as high as 40%.⁹⁸ These patients will then require postoperative chemoradiation, which, compared with preoperative chemoradiation, has inferior rates of local control, higher rates of acute and chronic toxicity, and, if a low anastomosis is performed, inferior functional results.

In the report by Guillem and coauthors,⁹⁷ the incidence of positive nodes was not dependent on the distance from the anal verge. Of the 103 patients with tumors that were 0 to 5 cm from the anal verge, 23% were ypN+, whereas of the 85 patients with tumors that were 6 to 12 cm from the anal verge, the incidence was 20%. These data suggest that in tumors up to 12 cm from the anal verge, the risk of positive nodes (and likely local recurrence) is similar.

Positive Radial (Circumferential) Margins

Although the distal margin is predictive of both local recurrence and the feasibility of a sphincter-preserving operation, the radial (circumferential) margin also has a substantial impact on the local recurrence rate.⁹⁹ An analysis of more than 17,500 pathologic specimens by Nagtegaal and associates⁹⁹ reported inferior survival rates in patients with positive CRMs after neoadjuvant treatment compared with immediate surgery (hazard ratio [HR], 6.3; 95% CI, 3.7 to 16.7 vs. HR, 2; 95% CI, 1.4 to 2.9, respectively).

In the Dutch CKVO trial, 17% of patients had positive circumferential margins. In a subset analysis by Nagtegaal and colleagues,¹⁰⁰ patients with positive radial margins who underwent TME alone had a local recurrence rate of 17% after an LAR and 30% after an APR.

Unfortunately, few centers perform the necessary pathologic examination to detect positive circumferential margins.⁷⁸ High-resolution MRI can help identify patients who will have positive margins.⁷⁹^–⁸¹ In a retrospective analysis reported by Bail and colleagues,²⁹ despite receiving preoperative chemoradiation, 504 patients with positive radial margins had a higher local recurrence rate (35% vs. 11%) and a lower 5-year OS (27% vs. 73%) compared with those with negative radial margins.

As reported with preoperative therapy, postoperative treatment has limited ability to control positive radial margins. In the MRC CR-07 trial, patients with positive radial margins who received postoperative chemoradiation had an 11% local recurrence rate.¹⁰¹ Likewise, in a subset analysis of the Dutch CKVO trial, 50 Gy postoperatively did not compensate for positive margins.⁷⁷

Distance from the Anal Verge

There are no prospective randomized data examining the impact of the distance from the anal verge on local recurrence. The available data are subset analyses from randomized trials that were not stratified by distance. Of the three trials, two used short-course preoperative irradiation and included patients with cT1-2N0 disease (Dutch CKVO ⁷⁵ and the Swedish Rectal Cancer Trial),⁷³ whereas the German trial used chemoradiation and was limited to patients with cT3N+ disease.^26,102 The MRC-C07 trial made a similar subset analysis, and the distance from the anal verge was determined by rigid sigmoidoscopy. There were additional variables that could have contributed to the differences in local failure rates. For example, TME (and its associated impact on radial margins) was used in the Dutch CKCO and German trials and not in the Swedish trial. All three trials included patients with tumors more than 12 cm from the anal verge in the “upper or high” category. Since the peritoneal reflection varies from 12 to 16 cm, some patients with tumors above the peritoneal reflection (colon cancer) were included in the three trials. Most investigators now limit preoperative treatment to tumors less than 12 cm from the anal verge.⁹⁷ Lastly, distance measurements using a flexible proctoscope are less accurate than straight proctoscope measurements. Flexible scopes were used in the Dutch CKVO trial. The German trial used a straight scope. In the Swedish trial, proctoscopic information was not mentioned. However, eligibility was limited to tumors “below the promontory as identified by barium enema.” The Polish trial is not discussed, because all tumors were palpable by digital examination.¹⁰³

As seen in Table 49-4, by univariate analysis, “high” tumors in both the Dutch CKVO and Swedish trials (defined as ≥10.1 cm and ≥11 cm, respectively) had a lower incidence of local recurrence compared with mid and lower tumors. Short-course irradiation did not significantly decrease local recurrence rates. By multivariate analysis, tumor location was an independent prognostic variable in the Dutch trial. It is interesting to note that irradiation did significantly decrease local recurrence rates for mid tumors in both trials, whereas for lower tumors it was helpful only in the Swedish trial.

TABLE 49-4 Impact of Distance from the Anal Verge by Univariate Analysis

In contrast, there was no significant difference between mid and upper tumors in the German trial.¹⁰⁴ However, data were not provided. In a recent subset analysis, patients with tumors above 6 cm had a lower local recurrence rate (Rödel, personal communication).

In summary, given the conflicting data combined with the report from Guillem and associates ⁹⁷ confirming that the incidence of positive nodes (ypN0 disease following preoperative chemoradiation) is the same from 0 to 12 cm from the anal verge, treatment decisions based on the current definitions of low versus mid versus high should not be used.

Patients with cT3N0 tumors should be examined with a straight proctoscope, and if the tumor is 12 cm or less from the anal verge be referred for preoperative chemoradiation. If the tumor is more than 12 cm from the anal verge, initial surgery is recommended. Following surgery, if the tumor is found to be either above the peritoneal reflection (colon cancer) or if it is a pT3N0 tumor at or below the reflection (rectal cancer), following a TME and the finding of at least 12 negative nodes, then irradiation is optional. If either the surgery or pathologic examination was not optimal, however, then postoperative chemoradiation is recommended.

Sphincter preservation without good function is of questionable benefit. In a series of 73 patients who underwent surgery, Grumann and associates ¹¹³ reported that the 23 patients who underwent an APR had a more favorable quality of life compared with the 50 who underwent an LAR. Krouse and colleagues¹¹⁴ reported that both men and women with ostomies had significantly worse social well-being compared with those without ostomies, however.

Although preoperative chemoradiation may adversely affect sphincter function,¹¹⁵ the impact is most likely less than postoperative chemoradiation.¹¹⁶ Most phase II trials that examine functional outcome report good to excellent results. Functional results continue to improve up to 1 year after surgery. Functional data from the German trial are pending.

Is Surgery Needed after Preoperative Chemoradiation?

In one series, the value of radical surgery in patients who had a biopsy-proven complete response was questioned.¹¹⁷ The trial included patients with cT1-3 disease, however, and has not been reproduced by other investigators. In series limited to patients with cT3 disease who received preoperative chemoradiation, radical surgery is still necessary to fully evaluate whether a pathologic response has been achieved. Neither post-treatment ultrasound^41,⁴² nor physical examination (which is only 25% accurate)¹¹⁸ is sufficient. The use of PET scanning^119,^120,³⁴ and diffusion MRI¹²¹ as noninvasive measures of response is being investigated, and reported results have been mixed. Although Kalff and associates³⁵ reported that postchemoradiation FDG-PET identification of residual viable tumor in 63 patients had a high positive predictive value (0.94; 95% CI, 85% to 99%), other groups have reported opposite results.

Glynne-Jones and colleagues ¹²² reviewed 218 phase II and 28 phase III trials of preoperative irradiation or chemoradiation and confirmed that a clinical and/or radiologic response does not sufficiently correlate with the pathologic response; they do not recommend a “wait and see” approach to surgery following preoperative therapy.

Randomized Trials of Preoperative Versus Postoperative Chemoradiation

Two randomized trials of preoperative versus postoperative chemoradiation for clinically resectable rectal cancer have been performed, NSABP R0-3 ¹²³ and the German CAO/ARO/AIO 94 trial.²⁶

The German trial completed the planned accrual of over 800 patients and randomized patients with uT3-4 and/or LN+ rectal cancers less than 16 cm from the anal verge to preoperative chemoradiation (with CI 5-FU during weeks 1 and 5) versus postoperative chemoradiation.²⁶ Patients were stratified by surgeon. Compared with postoperative chemoradiation, patients who received preoperative therapy had a significant decrease in rates of local failure (6% vs. 13%; p = .006), acute toxicity (27% vs. 40%; p = .001), and chronic toxicity (14% vs. 24%; p = .012), and in the 194 patients judged by the surgeon before treatment to require an APR, there was a significant increase in rates of sphincter preservation (39% vs. 20%; p = .004). With a median follow-up of 40 months, there was no difference in 5-year OS (74% vs. 76%). A subsequent analysis revealed that the treatment center, schedule, and gender were independent prognostic factors for local control.¹²⁴

The NSABP R-03 study accrued only 267 of a planned 900 patients with cT3-4 rectal cancers.¹²³ Patients received induction chemotherapy followed by conventional chemoradiation and were randomized to receive it either preoperatively or postoperatively. TME was not required, and some patients underwent local excision. Patients who received preoperative versus postoperative therapy had a significant improvement in 5-year DFS (65% vs. 53%; p = .011) and a borderline significant improvement in 5-year OS (75% vs. 66%; p = .065). There was no difference in 5-year local recurrence rates (11%). There was a correspondingly higher incidence of grade 4+ toxicity, almost all related to early diarrhea (33% vs. 23%), but the incidence of grade 3+ toxicity was lower (41% vs. 50%). Lastly, based on a prospective office assessment by the operating surgeon, there was no improvement in rates of sphincter preservation (48% vs. 39%). The results do not parallel the German trial, likely because of the fact that only 267 of the 900 planned patients were accrued, thereby limiting the statistical power to detect differences.

Given the improved local control rates, acute and long-term toxicity profiles, and sphincter preservation rates reported in the German trial, patients with cT3-4 rectal cancer who require chemoradiation should receive it preoperatively. In the German trial, 18% of patients who were clinically staged as cT3N0 preoperatively and underwent surgery without preoperative therapy had pT1-2N0 disease. Therefore, those patients would have been overtreated if they had received preoperative therapy. Although not ideal, this is preferred to performing surgery first because 20% to 40% will have LN+ disease at the time of surgery and require postoperative chemoradiation, which has inferior rates of local control, higher rates of acute and chronic toxicity, and, if a low anastomosis is performed, inferior functional results.⁹⁷

Clearly, the development of more accurate methods to identify LN+ disease, including imaging techniques and/or molecular markers, is essential because more patients are being treated with preoperative chemoradiation.^44,¹²⁵^–¹²⁸

The UK Medical Research Council trial (MRC C07) randomized 1350 patients with clinical stage I to III rectal cancer to preoperative irradiation of 5 Gy in five fractions or selective postoperative chemoradiation (45 Gy with concurrent 5-FU), which was delivered only to patients with a histologic CRM of less than 1 mm (12% of all patients with immediate surgery).¹³⁰ With a median follow-up of 4 years, patients who received preoperative compared with selective postoperative treatment had significantly lower 3-year local recurrence rates (4.4% vs. 10.6%; p <.0001) and higher 3-year DFS (77.5% vs. 71.5%; p = .013).

Short-Course Preoperative Irradiation Versus Standard-Course Preoperative Chemoradiation

Bujko and colleagues 103,129 performed a randomized trial of two preoperative approaches. A total of 316 patients with cT3 rectal cancer were randomized to 5 Gy in five fractions followed by surgery (median, 8 days) versus conventional preoperative chemoradiation (50.4 Gy plus bolus 5-FU/leucovorin daily for 5 days, during weeks 1 and 5) followed by surgery (median, 78 days). All tumors were above the anorectal ring; TME was performed for distal tumors; and there was no irradiation quality control review. The incidence of CRM positivity was lower following chemoradiation compared with irradiation alone (4% vs. 13%; p = .017).

Standard and Novel Combined-Modality Therapy Regimens and Issues

The NCCTG 85-47-51 postoperative adjuvant rectal trial revealed a 10% survival benefit for patients who received concurrent PVI versus bolus 5-FU.⁸⁶ Therefore, when 5-FU is combined with irradiation, either preoperatively or postoperatively, it should be delivered as a continuous infusion (CI). Although a survival benefit with CI 5-FU was not confirmed in the Intergroup 0144 trial, the CI 5-FU arm was associated with a lower incidence of hematologic toxicity.^90,¹³¹ Although it is just now being studied in rectal cancer, the combination of CI 5-FU and oxaliplatin (FOLFOX) has replaced CI 5-FU as a standard postoperative chemotherapy treatment based on the efficacy demonstrated in stage III colon cancer patients.¹³²

As an alternative, based on the X-ACT trial, which reported equivalence with the Mayo Clinic regimen in patients with stage II and III colon cancer, it is reasonable to substitute capecitabine for 5-FU.¹³³ However, capecitabine has not been directly compared with CI 5-FU, and this is one of the end points of the NSAPB R-04 rectal trial.

The Cancer and Leukemia Group B (CALGB) 89803 trial illustrated that the survival benefit of irinotecan in patients with metastatic disease does not necessarily translate into the adjuvant setting.¹³⁴ In contrast, based on the MOSAIC trial, which revealed a survival benefit with FOLFOX for node-positive colon cancer, oxaliplatin-based chemoradiation programs have been investigated. Many phase I and II trials have shown higher pCR rates compared with 5-FU-based chemoradiation regimens.

However, two phase III trials have reported significantly higher acute toxicity rates with no benefit in the pCR rate with the addition of oxaliplatin to CI 5-FU-based chemoradiation regimens in patients with cT3-4N+ rectal cancer (see Table 49-5). The STAR-01 trial randomized 747 patients to preoperative chemoradiation with 50.4 Gy plus CI 5-FU with or without oxaliplatin (60 mg/m² weekly).¹³⁵ There was a significant increase in grade 3+ toxicity with oxaliplatin (24% vs. 8%; p <.001) with no improvement in the pCR rate (15% vs. 16%). The ACCORD trial randomized 598 patients to preoperative chemoradiation with 50 Gy plus CAPOX versus 45 Gy plus capecitabine.¹³⁶ There was a similar significant increase in grade 3+ toxicity with oxaliplatin (25% vs. 11%; p <.001) with no improvement in the pCR rate (19% vs. 14%). Although local control and survival outcomes are pending, these early results underscore the importance of phase III data.

Most preoperative chemoradiation regimens have been developed somewhat empirically without clear criteria for timing of the irradiation. For example, in a retrospective analysis, Yu and colleagues ¹³⁷ reported a significantly improved pCR rate when capecitabine was delivered 1 hour before irradiation compared with other intervals (24% vs. 10%; p = .01). Most phase I to II chemoradiation trials do not control for this variable.

Both cytotoxic and targeted chemotherapeutic agents have been incorporated into phase I and II combined-modality programs, most commonly in the preoperative setting. Selected agents (alone or in combination with other agents) include tegafur-uracil (UFT), raltitrexed, oxaliplatin, irinotecan, gefitinib, tegafur-oteracil-gimeracil (S-1), bevacizumab, cetuximab, and capecitabine with pelvic radiation therapy. Selected series are seen in Table 49-5 (expanded version of Table 49-5 available on the Expert Consult website). Most of the regimens reveal higher pCR rates compared with 5-FU alone (10% in the German trial). For some agents, however, with this increased pCR rate is an associated increase in acute toxicity rates. Phase III trials are needed to determine if these regimens offer a local control or survival advantage compared with 5-FU or capecitabine chemoradiation regimens.

TABLE 49-5 Selected Novel Preoperative Chemoradiation Regimens

Only one randomized phase III trial, performed by the Hellenic Cooperative Oncology Group, compared concurrent postoperative chemoradiation with 5-FU/folinic acid plus irinotecan versus 5-FU/folinic acid alone.¹³⁸ There were no differences between the arms in rates of 3-year OS, DFS, and local relapse-free survival, whereas the incidence of severe leukopenia was significantly higher in the irinotecan-containing arm.

Chua and colleagues ¹³⁹ have examined the use of induction CAPOX followed by chemoradiation with capecitabine. This approach circumvents the need for the 4 months of postoperative chemotherapy. Their pilot trial of 77 patients reported a 24% pCR rate. Since there is a 6-month interval between diagnosis and surgery, the radiologic response rate was followed by MRI. After induction CAPOX, the overall response rate was 88%, which increased to 97% following the completion of chemoradiation, suggesting that there was no detriment in response rates. Based on these encouraging results, the Spanish GCR-3 randomized phase II trial was developed comparing this approach with conventional preoperative chemoradiation followed by surgery and postoperative chemotherapy.¹⁴⁰ A total of 108 patients received preoperative treatment with 50.4 Gy plus CAPOX and were randomized to receive 4 months of CAPOX either by induction or adjuvant (postoperative) administration. Although the pCR rates were not different (14% vs. 13%), the rate of grade 3+ toxicity was lower (17% vs. 51%; p = .00004) and the rate of ability to receive all four chemotherapy cycles was higher (93% vs. 51%; p = .0001) with the induction approach.

Choice of Adjuvant Chemotherapy

In colon cancer, the results of chemotherapy trials in metastatic disease cannot be extrapolated to the adjuvant setting. For example, trials using chemotherapeutic agents such as irinotecan and bevacizumab were positive in the metastatic setting but did not improve survival rates when tested in the adjuvant setting (CALGB 89803 ¹³⁴ and NSABP C-08,¹⁴¹ respectively).

Whether positive results from adjuvant colon cancer can be extrapolated to adjuvant rectal cancer is unknown. Most investigators think it is reasonable to do so and use the same adjuvant chemotherapy for adjuvant colon and rectal cancers.

FOLFOX has replaced bolus 5-FU/leucovorin as a standard postoperative chemotherapy treatment.⁸⁷ For patients who receive preoperative chemoradiation and are selected to receive postoperative adjuvant chemotherapy, four cycles of mFOLFOX6 is recommended.

Chemoradiation Using Targeted Therapies

The role of targeted biologic agents such as bevacizumab is the subject of ongoing clinical trials. Preliminary phase I trials from Duke University ¹⁴² and the M.D. Anderson Cancer Center¹⁴³ using preoperative chemoradiation with CAPOX plus bevacizumab reveal pCR rates of 18% and 24%, respectively. There is one report of three patients who received irradiation and when receiving bevacizumab 6 to 16 months later developed ischemic bowel complications.¹⁴⁴ These data underscore the caution needed when combining new agents with radiation therapy.

Phase I to II trials examining the addition of cetuximab to preoperative chemoradiation have had mixed results. Although the report from Heidelberg with CAPEIRI reported a pCR rate of 25%,¹⁴⁵ other trials with 5-FU, capecitabine, or CAPOX have more limited rates of 5% to 12%.^146,¹⁴⁷ Whether the benefit of patient selection based on wild versus mutated KRAS seen in patients with metastatic disease will be helpful in the adjuvant rectal setting is unknown, but it seems likely that the same biologic mechanisms will hold true.¹⁴³

In the metastatic setting, the addition of a second targeted therapy (panitumumab) to bevacizumab combined with cytotoxic chemotherapy (either irinotecan or oxaliplatin) had both higher toxicity rates and lower progression-free survival rates.¹⁴⁸ Other phase III trials have shown a similar lack of improvement. Therefore chemoradiation regimens with more than one targeted agent have not been developed.

RTOG Phase II Randomized Preoperative Chemoradiation Trials

The RTOG had reported two phase II randomized trials. RTOG 0012 enrolled 106 patients who received preoperative chemoradiation with either CI 5-FU plus twice-a-day irradiation versus FOLFIRI plus conventional daily fractionated irradiation.¹⁴⁹ Although the pCR rates were 26%, the grade 3+ toxicity rates were 42% and 55%, respectively. Neither of these preoperative regimens was moved into phase III trials.

In a more recent trial, the RTOG compared preoperative chemoradiation with CAPEIRI versus CAPOX in 101 patients with cT3-4 disease (RTOG 0247).¹⁵⁰ Although not statistically significant, patients who received CAPOX had a higher pCR rate (21% vs. 10%) with similar hematologic (4% vs. 8%) and nonhematologic toxicity rates (29% vs. 24%).

Impact of Tumor Response to Preoperative Chemoradiation

Although some series show no correlation,¹¹⁰ most series suggest that there is an improved outcome with increasing pathologic response to preoperative chemoradiation.^151,¹⁵² A retrospective review of 566 patients who achieved a pCR after receiving a variety of preoperative chemoradiation regimens at multiple European centers was reported by Capirci and associates.¹⁵³ With a median follow-up of 46 months, the local recurrence rate was only 1.6% and 5-year DFS and OS were 85% and 90%, respectively.

Analysis of biopsies examining selected molecular markers ¹⁵⁴^–¹⁵⁶ have had varying success in helping to select patients who may best respond to preoperative therapy. In a recent review, Kuremsky and colleagues¹⁵⁷ identified 1204 articles examining a total of 36 molecular biomarkers that may have predictive value. Restricting the analysis to patients treated with preoperative chemoradiation and to gene products examined by five or more studies, only TP53, epidermal growth factor receptor (EGFR), thymidylate synthase, Ki-67, P21, and BAX/BCL-2 met these criteria. Of these, quantitatively evaluated EGFR or EGFR polymorphisms, thymidylate synthase polymorphisms, and P21 have been identified as promising candidates that should be evaluated in larger prospective trials for their ability to guide preoperative therapy. Because the studies are limited retrospective trials and most do not examine multiple markers, the need for adjuvant therapy should still be based solely on T and N category.

Konski and associates ¹⁵⁸ performed pretreatment and post-treatment ¹⁸FDG-PET scans on 53 patients receiving preoperative chemoradiation. By multivariate analysis, the percentage of decrease in SUV was marginally significant in predicting pCR (p = .07).

The pCR rate may provide an alternative endpoint for assessing the efficacy of novel preoperative chemoradiation regimens. Because patients with rectal cancer who receive adjuvant chemoradiation can develop late relapses, however, a minimum follow-up of 7 years is needed.⁸⁸ Current intergroup rectal trials prospectively collect tissues for these and other markers.

Alternative Methods for Sphincter Preservation

Early localized tumors (3% to 5% of rectal cancers) include small, exophytic, mobile tumors without adverse pathologic factors (i.e., high grade, blood vessel invasion, lymphatic vessel invasion, colloid histologic type, or penetration of tumor into or through the bowel wall) and are adequately treated with a variety of local therapies such as local excision or endocavitary irradiation.

Endocavitary Irradiation

Endocavitary irradiation alone ¹⁵⁹^–¹⁶¹ has been used for early, noninvasive tumors. For more advanced tumors (cT2-3 and/or LN+), it is combined with a temporary iridium-192 (¹⁹²Ir) implant and/or pelvic irradiation.^67,¹⁶²^–¹⁶⁴ This technique is also known as the Papillion technique. Before delivery, the anus is dilated and a 4-cm proctoscope is introduced. A low-energy x-ray unit is placed through the scope almost against the tumor. Generally, 50-kV x rays are delivered at 30 Gy per fraction in three or four fractions over 1 month. Patients who develop local failure can successfully undergo surgical salvage.¹⁶⁶

Clinical outcomes with endocavitary irradiation alone or combined with EBRT have been reported. At the Mayo Clinic, 29 patients were treated with curative intent with endocavitary irradiation alone to a total dose of up to 155 Gy in one to five fractions. The local control rate was 76% at 10 years, and OS was 65% at 5 years and 42% at 10 years.¹⁵⁹ At Washington University, patients received pelvic irradiation (20 Gy in 5 fractions for those with cT1; the remainder received 45 Gy in 25 fractions) followed 6 to 7 weeks later by two endocavitary treatments of 30 Gy each.¹⁶⁴ Results by stage were uT1, 100% DFS; uT2, 85% local control rate; and uT3 (patients with uT3 tumors were not optimal candidates for surgery) or tethered uT2, 56% local control rate (67% after salvage surgery). Gerard and associates¹⁶⁶ have reported a similar experience in 44 patients. Because the 50-kVp radiation machine is not available, there are limited centers that continue to treat patients with contact irradiation.

Local Excision with or without Radiation Therapy

Given the morbidity of standard surgery as well as the frequent need for adjuvant therapy, the use of a more conservative approach such as local excision plus adjuvant therapy (radiation therapy usually combined with concurrent chemotherapy [chemoradiation]) as primary therapy for selected cases of rectal cancer has gained acceptance. Unfortunately, the data reported below confirm that this approach is a compromise treatment and in patients with long-term follow-up (>5 years), the local recurrence rates are substantially higher than with radical surgery, even with the addition of chemoradiation. Local recurrences occur both in the primary excision site and the pelvic nodes.

The results of local excision depend on a number of factors such as the type of surgery (full-thickness versus piecemeal excision) and clinicopathologic factors such as tumor size, T stage, grade, margins, and lymphatic and perineural invasion. Most series include some patients who have undergone suboptimal surgery such as a piecemeal excision or have positive or unassessable margins. Because few of the published series have adequate numbers to perform a meaningful multivariate analysis, it is difficult to determine the influence of these selected clinicopathologic features on one another.

Local excision has been performed both before and after radiation therapy. The advantage of performing a local excision before irradiation is that pathologic details can be well characterized. Highly selected patients with pT1 tumors without adverse pathologic factors have local failure rates of 5% to 10%. However, once adverse pathologic factors are present (high grade, vascular invasion, or signet-ring cells) or the tumor invades into or through the muscularis propria, the local failure rate is at least 17% and the incidence of positive mesorectal and/or pelvic nodes is at least 10% to 15%.¹⁶⁷ Nash and associates¹⁶⁸ reported that in 145 patients who underwent radical surgery for cT1N0 disease, 20% were found to have pathologically positive nodes.

There are a variety of surgical approaches, including transanal local excision, posterior proctotomy, and transsphincteric excision. Transanal endoscopic microsurgery (TEM) has emerged as another option for local treatment of rectal cancer, either alone for T1 tumors or combined with irradiation for selected patients with T2-3 disease.¹⁶⁹ Regardless of the technique, the excision should be full thickness and nonfragmented and should have negative margins.¹⁷⁰

Local Excision Alone

Local excision alone is recommended only for selected patients with pT1 tumors. Nash and colleagues performed a retrospective analysis of patients with cT1N0 disease who underwent a local excision (137 patients) or radical surgery (145 patients) and were found to have pT1Nx disease. With a median follow-up of 5 years, there was a significantly lower local recurrence rate (3% vs. 13%; p <.05) and a higher 5-year disease-specific survival rate (96% vs. 87%; p <.05) in those who underwent radical surgery versus a local excision. By multivariate analysis, both local excision and perineural invasion were independent prognostic factors associated with lower DFS.

Local Excision Followed by Postoperative Therapy

When all series are combined, the average crude local failure rate after local excision followed by postoperative radiation increases with T stage: pT1, 5%; pT2, 14%; and pT3, 22%.¹⁷¹^–¹⁸¹ However, when the analysis is limited to the series with a minimum of 4 years of follow-up,^175,^178,^181,¹⁸² the incidence of local recurrence for pT2 disease is 14% to 24% (Table 49-6). Therefore patients who are treated with local excision and postoperative adjuvant therapy require close follow-up beyond 5 years. Surgical salvage is possible, with most series reporting that approximately half of the patients who undergo an APR can be cured.¹⁸³

TABLE 49-6 Local Excision Plus Postoperative Therapy: Selected Series

The CALGB performed a phase II trial of local excision and selective postoperative chemoradiation (CALGB 8894).¹⁸⁴ A total of 91% underwent a full-thickness local excision. Patients with pT1 disease were observed, and pT2 patients received postoperative treatment with 54 Gy plus concurrent 5-FU. With a median follow-up of 4 years, the local recurrence rate in 59 patients with pT1 disease was 5% and with pT2 disease was 14%.

A separate analysis of the 110 patients who met the full eligibility criteria in CALGB 8894 was reported by Greenberg and colleagues.¹⁸⁵ These were limited to tumors less than 4 cm, full-thickness excision, and negative margins. Patients with pT1Nx tumors underwent local excision alone, and those with pT2Nx received postoperative chemoradiation. With a median follow-up of 7.1 years, the rates of local recurrence and 10-year actuarial survival were T1, 8% and 84%, and T2, 18% and 66%, respectively. The median time to failure was T1, 4 years, and T2, 2 years.

Sphincter Function

Prospective assessment of functional results after local excision and radiation therapy is limited. The groups from the Memorial Sloan-Kettering Cancer Center ¹⁷⁹ and Gemelli Hospital in Rome¹⁷⁶ report rates of 94% and 100%, respectively, for good to excellent function. Using a different scale, investigators from the Fox Chase Cancer Center¹⁷⁷ reported an 82% rate of good to excellent function; the University of Pennsylvania¹⁷⁴ reported a 92% rate of satisfactory function; and the M.D. Anderson Cancer Center¹⁷³ reported that all patients were continent. In the preoperative setting, sphincter function was reported as good to excellent in 88% to 91%.^186,¹⁸⁷

Preoperative Therapy Followed by Local Excision

Experience with preoperative chemoradiation followed by local excision is more limited.¹⁸⁶^–¹⁹² Most series selected patients with cT3 disease who were either medically inoperable or refused radical surgery. Local recurrence rates ranged from 0% to 20% and 5-year OS ranged from 78% to 90%. Borschitz and associates¹⁹² reported local recurrence rates by pathologic stage as ypT1, 2%, and ypT2, 6% to 20%. Rates were as high as 43% in ypT3 tumors that did not respond to chemoradiation.

This approach is being prospectively tested in the ACOSOG 06031 trial. In this phase II trial, patients with uT2N0 disease received preoperative CAPOX and radiation therapy. After local excision, if patients have stage ypT0-2 tumors with negative margins, they undergo observation only. If the postoperative stage is ypT3 or if the margins are positive, patients undergo radical surgery.

Chemotherapy

There are limited data examining the use of chemotherapy in patients who undergo local excision and preoperative or postoperative irradiation. In most series, concurrent 5-FU was delivered as a radiosensitizer rather than in the adjuvant setting. However, given the positive impact of chemotherapy on local control and survival rates in patients with resectable rectal cancer reported in the randomized postoperative rectal adjuvant trials,¹³¹ all patients should receive two cycles of 5-FU–based therapy concurrently with irradiation. For patients with pT2-3 disease where the incidence of pelvic lymph nodes is at least 20%, an additional four cycles of adjuvant chemotherapy for a total of six cycles is recommended.

Locally Advanced Disease and Palliation

Adenocarcinomas of the rectum usually present as clinically resectable tumors (cT1-3). Less commonly, they present as disease that is beyond the standard potentially curative surgical resection (cT4). In this setting, it is more difficult to obtain the significant improvements in local control and survival reported for resectable rectal cancer. The definition of resectability depends on the extent of the operation the surgeon is able to perform as well as the amount the patient is willing to undergo.

Locally unresectable rectal cancer is a heterogeneous disease. It can range from a tethered or “marginally resectable” cancer to a fixed cancer with adherence to or direct invasion of adjacent organs or vital structures. Furthermore, both primary unresectable and recurrent rectal cancers are commonly analyzed together. The heterogeneity of the disease and absence of uniform definition of resectability may explain some of the variation in results seen among the series.

The diagnostic workup must evaluate the local spread and the presence and location of pelvic nodes and of metastases. The choice of one or more imaging studies such as CT scan, MRI, or PET depends on the patient’s presenting symptoms. Involvement of the sciatic notch indicated by symptoms or scans predicts a situation unlikely to be helped by surgery alone. This has prognostic implications because patients with gross invasion of tumor into vital pelvic structures may be approached in a palliative rather than a curative fashion.

Standard Treatment

With the exception of the uncommon suture line-only recurrence, patients with locally unresectable primary or recurrent disease should receive preoperative chemoradiation. Braendengen and colleagues ¹⁹³ randomized 207 patients with locally nonresectable T4 primary rectal carcinomas or local recurrence from rectal carcinomas to chemotherapy (5-FU/leucovorin) concurrent with 50 Gy plus postoperative adjuvant therapy for 16 weeks versus 50 Gy alone. Patients who received chemoradiation had a higher R0 resection rate (84% vs. 68%; p = .009), pCR rate (16% vs. 7%), and 5-year local control rate (82% vs. 67%; p = .03) but a nonsignificant improvement in the OS (66% vs. 53%; p = .09).

Approximately 10% of rectal cancers require extensive surgery such as a pelvic exenteration to obtain negative margins.¹⁹⁴ These include tumors invading the prostate, the base of the bladder, or the uterus and vagina where the disease can be resected en bloc with negative margins. Midline posterior tumors adherent to or invading the distal sacrum may be resectable for cure with APR extended to include the sacrum. The 5-year OS range between 33% and 50%, with significant rates of morbidity and mortality up to 6%.¹⁹⁵ Improvements in perioperative care, patient selection, and surgical technique, such as vascularized tissue flaps to facilitate the healing of pelvic and perineal wounds, have improved the results.¹⁹⁶

Extended surgery to obtain negative margins is still recommended even if there is a favorable response after preoperative therapy. Given the limitation of the total EBRT dose that can be delivered to the bulky tumor in the pelvis ¹⁹⁵ and the frequent problem of local recurrence, the surgeon should be aggressive.¹⁹⁷

Tethered cancers have the most favorable outcome of all cT4 cancers. In a separate report from the Massachusetts General Hospital, the results of 28 patients with tethered rectal cancers treated with preoperative irradiation were presented.¹⁹⁸ Although a complete resection with negative margins was possible in 93%, the local failure rate was 24%. Tobin and colleagues¹⁹⁹ report a local failure rate of 14% and 5-year OS of 68% in 49 patients with tethered cancers treated with preoperative irradiation. The preoperative chemoradiation series do not report the results of cT4 tethered cancers separately.

Intraoperative Irradiation (IORT)

The primary advantage of IORT is that radiation can be delivered at the time of surgery to the site with the highest risk of local failure (the tumor bed) while decreasing the dose to the surrounding normal tissues. IORT can be delivered by two techniques: electron beam or brachytherapy. Brachytherapy is most commonly delivered by the high-dose-rate technique, and the dose rate is similar to that used for electron beam IORT.200,201,202 The results (and recommended dose) of IORT depend on whether the patient has primary unresectable or recurrent disease and on whether the margins of resection are negative or there is microscopic or gross residual disease. In general, series have used 10- to 20-Gy IORT depending on the volume of residual disease. For example, at the Mayo Clinic, patients with locally unresectable primary cancers receive 7.5 to 10 Gy after R0 resection with narrow margins, 10 to 12.5 Gy after R1 resection, and 15 to 20 Gy after R2 resection.²⁰³

It is difficult to clearly separate treatment-related complications from disease-related complications in patients with unresectable primary and/or recurrent rectal cancers. The total incidence ranges from 15% to 50% in most series and is highest in patients with the most advanced disease (recurrent unresectable tumors). Complications such as delayed healing, an increase in infection, fistula formation, and neuropathy may be the result of recurrent tumor, aggressive surgery, or radiation therapy, or a combination of these.

The incidence of IORT-related toxicity increases with IORT doses of 15 to 20 Gy. In a series from the Netherlands, 79 patients surveyed reported fatigue (44%), perineal pain (42%), sciatic pain (21%), walking difficulties (36%), and voiding dysfunction (42%).²⁰⁴ In addition, functional impairment consisted of requiring help with basic activities (15%), sexual inactivity (56%), the loss of former lifestyle (44%), and the loss of professional occupation (40%). The University of Navarra reported peripheral neuropathy up to 5 years after IORT.²⁰⁵ These consequences must be weighed against the chance of cure if the patient is treated and the disability eventually caused by uncontrolled tumor progression if the patient is not treated.

The long-term morbidity in the Mayo Clinic IORT series of 146 patients with locally unresectable colorectal cancers was 53% and included neuropathy (in 28 of 146 patients, or 19%), small bowel obstruction (14%), and ureteral obstruction (12%).²⁰³ Severe toxicity (grade 3 or 4) was evident in 32 of 146 patients (22%), with small bowel obstruction in 14 patients (9.5%) and severe neuropathy in only 3 (2%).

Although sphincter preservation is a major goal for patients with primary resectable disease, this should be a lesser goal for patients with locally recurrent cancers. In view of the extensive surgery required for patients with local recurrence and the likelihood of high-dose EBRT (prior adjuvant EBRT, repeat low-dose preoperative EBRT), patients may have a better functional outcome with a permanent colostomy than with coloanal anastomosis or a very low anterior resection.²⁰⁶

Primary Unresectable Disease

Results of selected series with or without IORT are seen in Table 49-7. The results of the series from Rotterdam,²⁸⁴ Madrid,²⁰⁷ and Eindhoven¹³⁹ include patients with both cT3 and cT4 disease and do not report the data separately. However, the Rotterdam and Eindhoven series examined outcome and did not find a significant difference. The overall incidence of local failure is approximately 10% to 15%, and central failure in the IORT field is uncommon (i.e., 2% in the Mayo Clinic IORT series of 146 patients with locally unresectable colorectal cancer).²⁰³

TABLE 49-7 Primary Locally Advanced/Unresectable Rectal Cancer with or without Intraoperative Radiation Therapy (IORT): Selected Series

The most favorable results are obtained in patients with gross total resection and negative margins (R0 resection) or microscopically positive margins (R1 resection). The 5-year local recurrence and OS in the Eindhoven IORT series were R0, 8% and 73%, and R1-2, 38% and 31%, respectively. Valentini and colleagues ²⁰⁸ treated 100 patients with primary, clinical, T4M0, extraperitoneal rectal cancer with preoperative chemoradiation with or without IORT. The R0 resection rate was 78%. The 5-year local control rates in R0 patients were 90% and 100% in the IORT group. The 5-year OS was 59%, and was better after an R0 versus an R1-2 resection (68% vs. 22%). Although the numbers are small, in the Rotterdam series, the 5-year local recurrence rate was lower in the 11 patients with positive margins who received IORT compared with the 8 who did not (58% vs. 100%; p = .016).

In the Mayo Clinic IORT series of 146 colorectal patients, R0-1 resection was accomplished in 128 patients and R2 resection in 18. Those with IORT after R0-1 resection had better 5-year OS than those with R2 resection (56% vs. 22%; p = .0006).²⁰³

In the Massachusetts General Hospital (MGH) series of 145 rectal patients,²⁰⁹ local failure in patients with negative margins decreased from 18% without IORT to 11% with IORT. In patients with positive margins, local failure was 83% without IORT versus 43% with IORT for gross residual disease and 32% with IORT for microscopic residual disease. For all patients in the series (with or without IORT), the 5-year DFS was 63% for patients with negative margins and 32% for patients with positive margins. These results underscore the importance of delivering preoperative therapy to help achieve negative margins. If negative margins cannot be obtained, then microscopic residual disease is preferable to gross residual disease. Reports from other centers (see Table 49-7) are similar.

At the MGH, of the 95 patients with T4 disease who received preoperative irradiation and underwent complete resection, 40 patients had an IORT boost and 55 did not, because it was not indicated secondary to either a favorable response or it was not technically feasible.210,211 Regardless of the response to preoperative therapy, higher local failure rates were seen in patients not receiving IORT (responders, 0% vs. 16%; nonresponders, 12% vs. 27%) These data suggest that IORT should be delivered independently of the extent of tumor downstaging.

Locally Recurrent Disease

In general, patients with local recurrence have an unfavorable prognosis. The median survival time ranges between 1 year and 2 years. Common symptoms include pain, hemorrhage, pelvic infection, and obstructive symptoms.

At the University of Wurzburg, sites of failure were analyzed in 155 patients.²¹² The incidence of failure sites was similar for APR versus LAR: local plus nodal disease, 61% versus 66%; isolated lymph node disease, 4% versus 5%; internal iliac and presacral node disease, 47% versus 59%; and external iliac disease, 7% versus 2%. Local recurrence was most commonly seen in the presacral pelvis and in patients who underwent an LAR; the anastomosis was involved in 93%.

Recurrences can be heterogeneous, and the pattern of extension is more infiltrative within the operative bed compared with primary rectal cancers. Localized pelvic recurrences may be classified according to the tumor location within the pelvis. At the Mayo Clinic, 106 patients with local recurrence, treated by subtotal resection alone or plus IORT (42 patients) and/or EBRT, were stratified during the surgical procedure according to no pelvic infiltration of the tumor (F0) or infiltration of the tumor to one pelvic site (F1), two pelvic sites (F2), or more than two pelvic sites (F3).²¹³ This classification system significantly correlated with survival. At the Catholic University of the Sacred Heart, Rome, 47 patients with locally recurrent, nonmetastatic rectal carcinoma were treated by preoperative chemoradiation plus IORT and were classified by CT scan according to the Mayo Clinic system.²¹⁴ A further (F4) class was added when tumor infiltrated small bowel or bone structures. The classification system significantly predicted R0 resectability (p = .01) and survival (p = .008).

Patients with local recurrence should receive preoperative combined-modality therapy, if feasible. However, some patients who present with locally recurrent disease series have had prior adjuvant EBRT and can receive only a limited dose or no EBRT for their locally recurrent cancer.

Results in selected series with or without IORT are seen in Table 49-8. As seen in patients treated for primary unresectable disease, the margin status and delivery or nondelivery of IORT have an impact on outcome for patients with locally recurrent disease.

TABLE 49-8 Role of IORT in Locally Recurrent Rectal Cancer: Selected Series

In the MGH IORT series of 49 patients, the overall 5-year local control rate was 35% and was higher with negative versus positive margins (56% vs. 13%).²¹¹ The 5-year OS for the total group was 27% and was higher in patients with negative versus positive margins (40% vs. 12%).

Kusters and colleagues ²¹⁵ from Eindhoven treated 170 patients with recurrent rectal cancer with preoperative irradiation with or without chemotherapy followed by surgery. The local recurrence rate in patients with negative margins was 32% and with positive margins was 71%. The 154 patients selected to receive IORT had a local recurrence rate of 47%. Consistent with other trials, patients with posterior (presacral) recurrences were more likely to have positive margins than those with anastomotic recurrences (72% vs. 23%) and the 5-year OS was only 19%.

The most recent Mayo Clinic Rochester analysis included 607 recurrent colorectal cancer patients receiving IOERT as a component of treatment (colon, 180 patients; rectum, 427 patients).²¹⁶ Survival at 5 years was 30% for the total group of patients. On multivariate analysis, complete resection, no prior chemotherapy, and treatment after 1996 were associated with improved survival rates. In patients with an R0 resection (227 patients) versus an R1 resection (224 patients) or R2 resection (156 patients), 5-year OS were 46%, 27%, and 16% (p <.0001, multivariate analysis), respectively.

Investigators at the M.D. Anderson Cancer Center and in Oslo reported no benefit of IORT for patients with positive margins.^217,²¹⁸ In the report from Oslo, 107 patients with isolated pelvic recurrence received 46 to 50 Gy preoperatively followed by resection alone or plus IORT.²¹⁸ Regardless of the volume of residual disease, there was no significant difference in local recurrence or survival rates whether or not patients received IORT.

In summary, in contrast to patients who have negative or microscopically positive margins, it is unclear if those with grossly positive margins benefit from aggressive therapy in view of differing results by series. However, although the Oslo study reported no long-term survivors for patients with R2 resection (gross residual disease), U.S. IORT series report 10% to 16% 5 year OS with these patients.

Reirradiation Followed by Surgery

The combination of chemoradiation and TME has appeared to significantly lower the incidence of local recurrence. However, there is a subset of patients who present with local recurrence only who have received previous pelvic irradiation. In these patients, the recurrence is often not resectable with clear margins and reirradiation would be expected to be associated with a high risk of late toxicity.

Few studies have analyzed the role of radiation retreatment in pelvic recurrence. Data from Mohiuddin and colleagues ²¹⁹ suggest that reirradiation with doses of 30 Gy (and if the small bowel can be excluded from the irradiation field, 40 Gy) can be used for limited volumes. A total of 103 patients with recurrent disease underwent reirradiation with concurrent 5-FU-based chemotherapy. The initial radiation dose to the pelvis ranged from 30 to 74 Gy, with a median dose of 50.4 Gy. Irradiation techniques consisted of two lateral fields with or without a posterior pelvic field to include recurrent tumor with a margin of 2 to 4 cm. Doses ranged from 15 Gy to 49.2 Gy (median, 34.8 Gy). After reirradiation, 34 underwent surgical resection for residual disease. For the total group, median survival was 26 months and 5-year OS was 19%. Patients who underwent resection had significantly higher median survival times (44 months vs. 14 months) and 5-year OS (22% vs. 15%) (p = .001). Late complications were seen in 22 patients and were unrelated to radiation dose.

A multicenter Italian trial of 59 patients with recurrent disease who had received less than 55 Gy were retreated preoperatively with concurrent CI 5-FU plus 30 Gy (1.2 Gy twice daily) to the gross tumor volume (GTV) plus a 4-cm margin.²²⁰ A boost was delivered, with the same fractionation schedule, to the GTV plus a 2-cm margin (10.8 Gy). Grade 3+ toxicity was 5% for acute toxicity and 12% for late toxicity. The prior median radiation dose was 50.4 Gy. The pCR rate was 9%, and 83% of those with pelvic pain before treatment had a symptomatic response. With a median follow-up of 36 months, the rate of local failure was 48%, median survival was 42 months, and 5-year OS was 39% (R0, 67% vs. R1-2, 22%). Multivariate analysis confirmed the impact of a longer DFS on local control (p = .016) and DFS (p = .002). Patients who underwent an R0 resection had improved local control and DFS (p = .016).

In the recent Mayo Clinic IORT analysis of 607 patients with locally recurrent colorectal cancer, 248 had received prior EBRT.²¹⁶ Additional EBRT was given in 228 patients (median, 27.5 Gy; range, 5 to 39.6 Gy). Prior in-field EBRT versus none was associated with an increased risk of local relapse (3-year rate, 31% vs. 17%; p <.0001) and trends for decreased 5-year OS that did not reach significance (28% vs. 34%; p = .07). Mayo Clinic investigators prefer to give preoperative EBRT (25 to 30 Gy in 1.8-Gy fractions) plus concurrent CI 5-FU or oral capecitabine before resection and IOERT in this group of patients.

Irradiation Alone for Locally Unresectable or Recurrent Disease

Some investigators have advocated the use of radiation therapy alone, most commonly in patients who are medically inoperable or refuse surgery.^162,^221,²²² A variety of techniques have been used, including various combinations of EBRT, brachytherapy, and intracavitary irradiation. In most series, patients received pelvic radiation therapy followed by a boost with EBRT and/or brachytherapy.

Brierley and colleagues ²²³ from the Princess Margaret Hospital reported the results of EBRT alone (40 to 60 Gy) in patients who refused surgery or had unresectable or medically inoperable disease. The 5-year OS was 27% for all patients; if the primary tumor was mobile, the rate was 47%; if partially fixed, 27%; and if fixed, 4%. These data suggest that patients with mobile or partially fixed rectal cancers who are medically inoperable should be treated aggressively with pelvic irradiation as a component of their therapy.

Gerard and associates ²²² reported the combination of EBRT, intracavitary therapy, and brachytherapy in 63 patients with uT2-3 tumors. For patients with uT3 disease, the 5-year local failure and survival rates were 20% and 35%, respectively.

Pelvic irradiation offers effective palliation. In a subset of 80 patients with metastatic disease who received pelvic irradiation, Crane and coauthors ²²⁴ reported that 94% had complete resolution of pelvic symptoms and the 2-year pelvic symptom-free control rate was 82%. The Princess Margaret Hospital series reported similar palliative benefits.²²³ In the subset of 84 patients who received more than 45 Gy, the following presenting symptoms were palliated by 6 to 8 weeks following the completion of radiation therapy: pain, 89%; bleeding, 79%; neurologic symptoms, 52%; mass effect, 71%; discharge, 50%; urologic symptoms, 22%; and other symptoms, 42%.²³⁰ In the Thomas Jefferson University series, complete plus partial symptomatic relief was achieved in the following categories: pain (65% + 28%), bleeding (100%), and mass effect (24% + 64%), respectively.²¹⁹ The duration of palliation was 8 to 10 months. In patients who are unable to receive irradiation, laser treatment or stenting²²⁵ offers some palliative benefit.

Treatment of Patients with Metastatic Disease

With the development of more effective systemic chemotherapy, the median survival of patients with metastatic colorectal cancer now approaches 2 years.²²⁶ Aggressive techniques to address liver metastasis with surgery and nonsurgical ablative techniques such as radiofrequency ablation, cryosurgery, microspheres, and EBRT have further improved median survival.²²⁷ More innovative radiation techniques such as stereotactic body radiotherapy of liver metastases are under investigation.²²⁸ With these advances, the historical notion that chemoradiation is not necessary because patients die before developing a local recurrence is being challenged. In the setting of disease presentation with distant metastasis, there is no standard of care and treatment should be decided on a case-by-case basis with the help of a multidisciplinary tumor board. In general, patients who respond to chemotherapy and have a risk of developing local recurrence should be considered for treatment consolidation with chemoradiation.

Irradiation Techniques and tolerance

Patterns of Relapse that Define Radiation Portals

The design of pelvic radiation therapy fields is mainly based on the pattern and incidence of local recurrence after surgery. For locally advanced disease, recurrences in the soft tissues may arise from tumor extension to the pelvic sidewall, the bladder, the prostate in men, the vagina in women, and the presacral space in all patients. This is especially true for tumors penetrating the mesorectal fascia or those with involved or close (<1 mm) circumferential margins. Incomplete mesorectal excision also has a higher risk of leaving residual microscopic tumor cells behind.

The major lymphatic spread is in a cephalad direction contained within the perirectal fascia and along the mesenteric system, which is commonly dissected by standard TME surgery. Outside the mesorectum is a space containing vessels, nerves, and lymphatics, which is not usually dissected. Tumors at or below the peritoneal reflexion tend to spread laterally along the internal iliac and obturator chains. The external iliac nodes only become at risk with anterior tumor extension and adjacent organ involvement. Lesions that extend to the anal canal or the lower third of the vagina can spread to the inguinal nodes. In this setting, the bilateral inguinal nodes should be considered for inclusion in the pelvic radiation fields.

The relative frequency and sites of pelvic failures were delineated by the seminal work of Gunderson and Sosin.⁵¹ In this reoperative series of 75 patients (initial APR), locoregional failures occurred in the soft tissue of the pelvis or the anastomotic site in 69%, pelvic lymph nodes in 42%, and perineum in 25%. A more contemporary series of 269 patients studied by Hruby and colleagues²²⁹ confirmed that the majority of local failures occurred in the posterior central pelvis (47%) or at the anastomosis (21%), while anterior recurrences (11%) were mainly restricted to T4 tumors. Perineal recurrences occurred in 16% of patients who underwent APR. Figure 49-2 depicts sites and frequency of recurrences in a German series of 123 patients diagnosed with rectal cancer recurrences between 1998 and 2001.²³⁰

Figure 49-2 Sites of recurrence after low anterior resection (LAR) (A) and abdominoperineal resection (APR) (B) in 123 patients with recurrent rectal cancer (areas involved in <10% excluded). Recurrent tumors are mainly situated in the posterior part of the bony pelvis. Note the higher percentage of recurrences in the lower part of the pelvis/perineum after APR.

Hocht S, Hammad R, Thiel HJ, et al: Recurrent rectal cancer within the pelvis. A multicenter analysis of 123 patients and recommendations for adjuvant radiotherapy. Strahlenther Onkol 180:15-20, 2004.

Irradiation Fields

The whole-pelvic radiation field should adequately cover the primary tumor and tumor bed as well as the primary nodes at risk. General guidelines for the design of pelvic radiation therapy fields are listed in Box 49-1. The intent of the boost is to treat the primary tumor and tumor bed and not to include the nodes. The exact size is determined by the size and location of the primary tumor. Whole-pelvic and boost fields are usually treated with a three-field (PA and laterals) or four-field technique. Field shaping by blocks is used to spare additional small intestine anteriorly and superiorly, the posterior muscle and soft tissue behind the sacrum, and the region inferior to the symphysis pubis. Specific examples of field arrangements with conventional techniques for a variety of presentations are seen in Figures 49-3 to 49-5.

Box 49-1 General Guidelines for Pelvic Radiation Therapy

Whole Pelvic Field

AP/PA

• Superior border: Sacral promontory (L5/S1 junction): The level of the attachment of the posterior peritoneum; above is little risk of soft tissue invasion by the primary tumor. Mesenteric lymphatics are adequately treated surgically. Para-aortic nodes are not treated, because they are stage M1 disease.²⁹⁰

• Lateral border: 1.5 cm lateral to the widest bony margin of the true pelvic walls to include possible lateral extension and the internal iliac chain.

• Distal border: 3 to 5 cm distal to the tumor for patients receiving preoperative irradiation (best determined by direct palpation, by an endoscopically placed clip, or by rectal contrast). For postoperative irradiation, the distal field edge must include the perineum (as indicated by a radiopaque marker) if the surgery was an APR or 2-3 cm beyond the anastomosis for an anterior resection with reanastomosis. NOTE: Bony anatomic landmarks such as the obturator foramina have no consistent relationship to the anal sphincter.

Lateral Fields

• Anterior border: T3 disease: Include the rectum with a generous margin (determined by placing contrast in the rectum at simulation); the posterior margin of the symphysis pubis is the bony landmark to treat the internal iliac nodes, the posterior border of the vagina, or the prostate. T4 disease: 2 to 3 cm anterior to the anterior extent of the primary tumor; the anterior margin of symphysis pubis is a bony landmark to treat the external iliac nodes. For anal canal involvement, the inguinal nodes may also be included; it is not clear that including them is beneficial, however.²⁹¹

• Posterior border: 1.5 cm behind the anterior bony sacral margin.

Boost Fields

• Primary tumor/tumor bed + 3-cm margin.

• In general, field sizes measure 10 × 10 cm or 12 × 12 cm, corner blocks.

• Oral contrast before simulation to exclude any small bowel within the boost volume.

Figure 49-3 Treatment fields following LAR for a T3N1M0 rectal cancer at 8 cm from the anal verge. In this example, the distal border is at the bottom of the obturator foramen and the perineum is blocked. Because the tumor was T3, the anterior field is at the posterior margin of the symphysis pubis (to treat only the internal iliac nodes).

Figure 49-4 Treatment fields following an APR for a T3N1M0 rectal cancer 2 cm from the anal verge. In this example, the distal border is extended to include the perineal scar. Because the distal border is being extended only to include the scar, the remaining normal tissues can be blocked.

Figure 49-5 Treatment fields for preoperative radiation therapy for a low-lying T3NxM0 (or following LAR for a T3N1M0) rectal cancer. In this example, the distal border is extended 3 cm beyond the primary tumor and the perineum is blocked. Because the tumor was T3, the anterior field is at the posterior margin of the symphysis pubis (to treat only the internal iliac nodes).

Three-Dimensional Treatment Planning and IMRT

Innovative techniques using three-dimensional (3D) treatment planning are being investigated. A major contribution of 3D treatment planning is the ability to plan and localize the target and normal tissues at all levels of the treatment volume and to obtain dose-volume histogram data. Examples of 3D and intensity-modulated radiation therapy (IMRT) treatment plans are seen in Figures 49-6 and 49-7, respectively.

Figure 49-6 Three-dimensional treatment plan for rectal cancer.

Figure 49-7 IMRT treatment plan for rectal cancer.

Using a 3D planning system, Koelbl and associates ²³¹ found that in patients receiving postoperative EBRT, the use of the prone position plus a belly board decreased the small bowel volume treated versus the supine position. Guidelines for the definition and delineation of the clinical target volumes (CTVs) are now available from a number of investigators.^232,²³³ Three-dimensional planned EBRT is desirable for patients who undergo reirradiation in order to limit the dose to previously irradiated critical structures.

The clinical utility of routine 3D and IMRT treatment planning techniques is being investigated.234,235 An analysis of 3D treatment planning techniques at the Massachusetts General Hospital suggests that the volume of small bowel in the radiation field is decreased with protons as compared with photons.²³⁶ IMRT treatment planning techniques can also decrease the volume of small bowel in the field when compared with 3D conformal techniques.²³⁷ The clinical benefit of IMRT compared with 3D or conventional treatment delivery remains to be determined, however.²³⁵

Irradiation Fractionation, Modality, and Dose

Hyperfractionated radiation has been examined in phase I and II trials.²³⁸ In general, the pCR rates may be improved but at the expense of increased acute toxicity. Coucke and colleagues²³⁹ treated 250 assessable patients with cT3-4 and/or N+ disease with 41.6 Gy at 1.6 Gy twice daily and reported a 92% actuarial 5-year local control rate but a survival rate of only 60%. The rate of acute grade 3+ toxicity was 42% in the 5-FU plus twice-a-day radiation arm of RTOG R-0012 (1.2 Gy to 45.6 Gy, with a boost of 9.6 to 14.4 Gy). Hyperfractionated and accelerated fractionated radiation, especially in combination with chemotherapy, remains investigational.

Other investigational approaches such as neutrons,²⁴⁰ carbon ions,²⁴¹ and hyperthermia²⁴²^–²⁴⁴ have been examined. None have shown a clear advantage compared with conventional pelvic EBRT.

A meta-analysis concluded that biologically effective preoperative doses above 30 Gy resulted in a statistically significant reduction in locoregional recurrence rates.⁷¹ With conventional fractionation, the doses necessary to treat microscopic disease with a high level of local control are in the range of 45 to 50.4 Gy in 5 to 6 weeks.²⁴⁵ A retrospective comparison of 143 patients treated in three phase II trials of chemoradiation with 40 Gy, 46 Gy, and 50 Gy revealed a significant improvement in 2-year OS for those receiving 46 and 50 Gy (94% and 92%, respectively) versus 40 Gy (72%; p = .03).²⁴⁶

A boost of 5.4 Gy to the primary tumor or tumor bed may be delivered if the small bowel is excluded from the high-dose field. However, it is not clear that doses higher than 50.4 Gy improve local control rates. Higher preoperative doses up to 60 Gy are associated with increased pCR rates; however, they may also significantly increase acute and long-term morbidity rates. The RTOG R-0012 phase II randomized trial compared twice-daily preoperative chemoradiation of up to 60 Gy (1.2 Gy to 45.6 Gy, with a boost of 9.6 to 14.4 Gy) with conventional fractionation (1.8 Gy to 45 Gy, with a boost of 5.4 to 9 Gy) plus 5-FU/irinotecan.¹⁴⁹ Both regimens resulted in a 28% pCR rate but were also associated with a more than 40% rate of grade 3 to 4 acute toxicity.

In the postoperative setting, if there is incomplete resection (R1 or R2 resection), radiation doses of more than 60 Gy are required. EBRT is limited by normal tissue tolerance, and results for patients with residual disease who received postoperative EBRT alone are disappointing.^77,²⁴⁷ As previously discussed, IORT may help to overcome this problem by direct visualization and irradiation of the persistent tumor.

Methods to Reduce Acute and Chronic Toxicity

Complications of pelvic radiation therapy are a function of the volume of the radiation field, overall treatment time, fraction size, radiation energy, total dose, technique, and sequence of radiotherapy.²⁴⁸ Acute side effects such as diarrhea and increased bowel frequency (small bowel), acute proctitis (large bowel), and dysuria are common during treatment.²⁴⁹ These conditions are usually transient and resolve within a few weeks following the completion of irradiation. The symptoms appear to be a function of the dose rate and fraction size rather than the total dose. The mechanism is primarily the depletion of actively dividing cells in what is otherwise a stable cell renewal system. In the small bowel, loss of the mucosal cells results in malabsorption of various substances, including fat, carbohydrate, protein, and bile salts. Examination during treatment frequently reveals an inflamed, edematous, and friable rectal mucosa. The bowel mucosa usually recovers completely in 1 to 3 months following irradiation. Management usually involves the use of antispasmodic and/or anticholinergic medications.

Small bowel-related complications are proportional to the volume of small bowel in the radiation field.²⁵⁰ In patients receiving combined irradiation and chemotherapy, the volume of small bowel in the radiation field limited the ability to escalate the dose of 5-FU.²⁴⁸

Delayed complications occur less frequently but are substantially more serious. The initial symptoms commonly occur 6 to 18 months following completion of irradiation. Complications may include persistent diarrhea and increased bowel frequency, proctitis and strictures at the anastomotic site, small bowel obstruction, perineal/scrotal tenderness, delayed perineal wound healing, urinary incontinence, and bladder atrophy and bleeding. Injury to the vascular and supporting stromal tissues is the presumed pathophysiology. Analysis of pooled patients from 1599 patients treated in Swedish rectal cancer trials revealed a 1.5% increase in in-field secondary tumors for those treated with irradiation compared with those not receiving irradiation.²⁵¹ Irradiation still had a positive effect on local control rates, however.

The most common delayed severe complications result from small bowel damage and include small bowel enteritis, adhesions, and small bowel obstruction requiring surgical intervention. The incidence of small bowel obstruction requiring surgery following postoperative pelvic irradiation for rectal cancer is 4% to 12% in historical series. In the Massachusetts General Hospital series, the incidence of small bowel obstruction with conventional postoperative radiation therapy was 6% as compared with 5% with surgery alone.⁶⁰ It was 2% in the preoperative chemoradiation arm of the German CAO/ARO/AIO-94 trial.²⁶

Even with appropriate doses and techniques of irradiation, approximately 1% of patients will have significant long-term toxicity of pelvic organs. Radiotherapeutic and surgical techniques as well as general methods to decrease treatment-related toxicity, especially small bowel complications, are seen in Box 49-2. Active inflammatory bowel disease is a relative contraindication to pelvic irradiation, although there are some reports of such patients who have tolerated EBRT.^252,²⁵³ Pelvic fractures following pelvic irradiation are rare.^254,²⁵⁵ Testosterone levels are decreased when the testicles are near or in the radiation field.^256,²⁵⁷ Radiation, alone or in combination with surgery can have a negative impact on sexual function.^258,259,260 In the Dutch CKVO trial, patients experienced new or worsening sexual dysfunction following treatment (men, 76%, and women, 62%).²⁶¹ By multivariate analysis, independent factors included irradiation in men and the psychological presence of a stoma in both men and women. The authors concluded that despite the additional effect of irradiation, sexual dysfunction was mainly caused by surgery.

Box 49-2 Techniques and Methods to Decrease Toxicity

Radiation Technique

Multiple-field techniques (preferably, PA plus laterals) using high-energy linear accelerators with computerized radiation dosimetry. Oral contrast to visualize the small bowel, rectal contrast and a wire at the perineal scar after APR help to guide field design. A three-field rather than a four-field technique will decrease the volume of small bowel in the pelvis, in males if the genitalia are in the treatment fields, and if there is a colostomy present. Shaped blocks and wedges on the lateral fields. The perineal scar after APR should be included in the pelvic radiation fields, the use of a separate perineal field should not be used. Treatment should be 5 days per week, with all fields treated each day. Split-course pelvic irradiation is associated with increased chronic bowel complications.

Physical Maneuvers

Prone position with abdominal wall compression and bladder distention and/or the use of immobilization molds or belly boards in the prone position generally decrease the volume of small bowel in the pelvis (though not consistently for all patients). Some physical maneuvers (especially, full bladder and the prone position for patients with a colostomy) may be associated with patient discomfort leading to increased movement and daily setup errors. The use of such techniques should be tailored to the individual patient.

Surgical Maneuvers in Patients Treated Postoperatively

Placing clips in the high-risk areas intraoperatively or at the inferior aspect of the tumor in the preoperative setting helps to better define tumor volume or the inferior border of the fields. For patients treated postoperatively, especially after APR, the use of an absorbable Dexon or Vicryl mesh may temporarily remove the small bowel from the pelvis. Other techniques such as an inflatable pelvic small bowel displacement prosthesis reconstruction of the pelvic floor, construction of an omental pedicle flap, and retroversion of the uterus have had variable success.

Sequencing of Radiotherapy and Surgery

Preoperative radiotherapy causes less acute and chronic toxicity compared with postoperative treatment. This is likely because of the fact that small bowel in an unviolated abdomen will be mobile and less likely to be within a pelvic radiation portal; the irradiated volume does not require coverage of the perineum following an APR. In the German CAO/ARO/AIO-94 trial, grade 3 to 4 gastrointestinal toxicity was significantly reduced with the preoperative approach (acute toxicity, 12% vs. 18%; p = .04; and long-term toxicity, 9% vs. 15%; p = .07).²⁶ Strictures at the anastomotic site were reduced (4% vs. 12%; p = .003).

Pharmacologic Approaches and Radioprotectors

Randomized trials have investigated the use of sucralfate enemas to decrease acute radiation proctitis, olsalazine and mesalazine to decrease acute enteritis, and butyric acid to decrease chronic radiation proctitis. All of these trials have been negative. The radioprotector WR-2721 did not reduce toxicity in early trials, but there is a suggestion of a benefit in a more recent study. Rectally administered amifostine is well tolerated, but its efficacy remains to be determined. Other trials of amifostine have not shown clear benefits.

Randomized trials have investigated the use of sucralfate enemas to decrease acute radiation proctitis, olsalazine and mesalazine to decrease acute enteritis, and butyric acid to decrease chronic radiation proctitis.²⁶² All of these trials have been negative. The radioprotector WR-2721 did not reduce toxicity in early trials, but there is a suggestion of a benefit in a more recent study.²⁶³ Rectally administered amifostine is well tolerated. However, its efficacy remains to be determined.²⁶⁴ Other trials of amifostine have not shown clear benefits.²⁶⁵

Treatment Algorithms, Controversies, Problems, Challenges, and Future Possibilities

Treatment Algorithms

The treatment of rectal cancer is multidisciplinary. It is important to develop treatment algorithms using a balanced approach with representation from all medical specialties, including radiation, medical, and surgical oncology as well as radiology, gastroenterology, and pathology. Treatment algorithms developed by representatives of a single modality or institution may be biased.

Treatment algorithms can be based on evidence or consensus, or both. Although purely evidence-based algorithms are the most rigorous, there are a variety of clinical settings where prospective trials do not specifically address a treatment controversy. Therefore multidisciplinary panels that use evidence from randomized trials as well as lower-level sources such as clinical experience reports offer a more practical approach. The National Comprehensive Cancer Network (NCCN) has published clinical practice guidelines for rectal cancer based on multidisciplinary panels that use evidence from randomized trials as well as lower-level sources such as clinical experience reports ²⁶⁶ (see web-only Fig. 49-1 on the Expert Consult website).

Web-Only Figure 49-1

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines for rectal cancer. Current guidelines can be found at www.nccn.org/professionals/physician_gls/f_guidelines.asp#site.

Finally, two caveats. All treatment guideline recommendations should be interpreted with caution. Radiation oncology, like other medical specialties, is both an art and a science. Therefore, guidelines should serve as a “guide” rather than a “cookbook.” Lastly, the ideal management for patients with rectal cancer is in a clinical trial, and participation in these is encouraged.

Controversies and Future Directions

Significant progress has been made in the three conventional modalities used to treat rectal cancer: surgery, irradiation, and chemotherapy. Identification of radial microscopic lymphatic spread within the mesorectum has led to the use of TME. With this type of surgery, local recurrence rates have appeared to decrease. However, in patients with pN+ disease there is still a 21% local recurrence rate and adjuvant chemoradiation remains standard. Technical advances in irradiation planning and delivery techniques as well as refinements in the sequencing of radiotherapy, chemotherapy, and surgery will likely lead to further improvements. Moreover, cytotoxic chemotherapeutic agents as well as novel targeted therapies, such as bevacizumab and cetuximab, which have improved results of patients treated in the adjuvant and/or metastatic setting, are currently being studied in chemoradiation programs. Clinicopathologic and molecular features as well as the development of more accurate preoperative imaging and staging methods will also play an important and integrative part in the multimodality treatment of rectal cancer.

Recent data from phase III trials are helping to clarify some of the issues about both the benefit and type of concurrent/maintenance chemotherapy in chemoradiation regimens.²⁹²^–²⁹⁷ In NSABP RO4, chemoradiation regimens using PVI 5-FU and capecitabine had similar pCR rates and tolerance.²⁹² In three separate phase III trials, the addition of oxaliplatin to either PVI 5F-U or capecitabine did not improve pCR but added toxicity. Accordingly, the current standard is not to include oxaliplatin in preoperative chemoradiation regimens, pending longer term outcomes of local control and survival.²⁹²^–²⁹⁴ Additional text is found on the Expert Consult website with regard to the benefit of concurrent chemoradiation, sequencing with surgery, and the impact of type of concurrent chemotherapy on outcomes.

There are many controversies remaining, which lead to the following questions: Should patients receive short-course irradiation or chemoradiation? Is postoperative adjuvant chemotherapy necessary for all patients? Should the type of surgery following chemoradiation be based on the response rate? Can we develop more accurate imaging techniques and/or molecular markers to identify patients with positive pelvic nodes to reduce the chance of overtreatment with preoperative therapy? Will more effective systemic agents improve the results of chemoradiation as well as modify the need for pelvic irradiation in some TN categories of disease? These questions and others remain active areas of clinical investigation.

Preoperative Chemoradiation: Update of Controversies

Chemoradiation versus Radiation Alone: Sequencing

The benefits of concurrent chemoradiation and the issue of sequencing with surgery have been addressed in updates of prior phase III trials. The EORTC and FFCD trials of preoperative radiation versus chemoradiation have been updated with a median follow-up of 5.6 years. A pooled analysis of the two trials confirmed that patients who received preoperative chemoradiation versus radiation alone had a significant decrease in local recurrence (11% vs. 15%, p = .0001) but no difference in 5-year OS (66%).²⁹² With regard to sequencing, the results of the German CAO/ARO/AIO 94 trial were updated with a median follow-up of 11.2 years. At 10 years the local control benefit of preoperative versus postoperative therapy was sustained (6% vs 10%) with no difference in OS (60%).²⁹³

Chemoradiation: Type of Chemotherapy

The NSABP R-04 trial compared preoperative chemoradiation with CI 5-FU versus capecitabine (with or without oxaliplatin). Compared with CI 5-FU, capecitabine had similar rates of pCR (22% vs. 19%), sphincter-sparing surgery (63% vs. 61%), and grade 3+ diarrhea (11%).²⁹⁴ Therefore, chemoradiation regimens using CI 5-FU or capecitabine have similar response rates.

Four randomized trials have examined the impact of addition of oxaliplatin to 5-FU– or capecitabine-based CMT on response rates and acute toxicity in patients with cT3-4N+ rectal cancer. The STAR-01 trial randomized 747 patients to preoperative chemoradiation with 50.4 Gy/28 fractions + CI 5-FU with or without oxaliplatin.²⁹⁵ There was a significant increase in grade 3+ toxicity with oxaliplatin (24% vs. 8%, p <.001), but no improvement in the pCR rate (15% vs. 16%).

In the ACCORD trial, 598 patients were randomized to preoperative chemoradiation with 50 Gy plus capecitabine + oxaliplatin (CAPOX) versus 45 Gy plus capecitibine.²⁹⁶ There was a similar significant increase in grade 3+ toxicity with oxaliplatin (25% vs. 11%, p <.001) with no improvement in the pCR rate (19% vs. 14%).

The NSABP R-04 trial was a four-arm trial (2 × 2 comparison) of CI 5-FU– vs. capecitabine-based preoperative chemoradiation (50.4 Gy/28 fractions) with or without oxaliplatin.²⁹⁴ A total of 1606 patients with cT3 and/or N+ disease were randomized. The addition of oxaliplatin (to either 5-FU or capecitabine) was associated with a significantly higher incidence of grade 3+ diarrhea (15% vs. 7%, p = .0001) with no improvement in the incidence of pCR (21% vs. 19%) or sphincter-sparing surgery (60% vs. 64%).

The German CAO/ARO/AIO-04 randomized 1265 patients with cT3-4 and/or N+ disease to the preoperative arm of CAO/ARO/AIO-94 (50.4 Gy/28 fractions + 5-FU) versus 50.4 Gy/5-FU+ oxaliplatin (50 mg/m² weekly).²⁹⁷ In contrast with the STAR-01, ACCORD, and NSABP R-04 trials, patients who received oxaliplatin-based CMT had a significant improvement in pCR (17% vs. 13%, p = .045) with no corresponding increase in acute grade 3+ toxicity (23% vs. 22%). The results of a similar trial (PETACC-6) are pending.

Because three of four randomized trials reveal an increase in acute toxicity with no benefit in the pCR rate, the current standard is not to include oxaliplatin in preoperative CMT regimens. However, local control and survival data are not available and this recommendation may need to be modified once these data are reported.

Critical References

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