Nuclear Oncology, 1 Ed.

CHAPTER 9

COLORECTAL CARCINOMA

Gregory C. Ravizzini • Revathy B. Iyer • Homer A. Macapinlac

INTRODUCTION

Worldwide, colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females.1 In the United States, it is estimated that 143,460 new cases of CRC will be diagnosed in 2012, including approximately 1,030,170 colon and 40,290 rectal cancers.2 On an annual basis, 51,690 Americans die of CRC, accounting for approximately 9% of all cancer deaths. Approximately 85% of CRCs are adenocarcinomas (not otherwise specified), 10% are mucinous adenocarcinomas, and the remaining are rare histologic types, such as papillary carcinoma, adenosquamous carcinoma, and signet cell carcinoma. The risk of developing CRC is influenced by both environmental and genetic factors, with the majority of cases being sporadic.3 As many as 20% to 30% of CRCs have a potentially definable inherited cause, and 3% to 5% of colon cancers occur in genetically defined high-risk colon cancer family syndromes such as familial adenomatous polyposis and Lynch syndrome.3,4

Once the diagnosis is established, the local and distant extent of disease spread will provide the scaffold for therapy planning and prognosis, with resection being the mainstay of treatment for curative intent. Following surgical exploration of the abdomen, histopathologic staging is performed. This will frequently include evaluation of the grade of the tumor; depth of penetration and extension to adjacent structures (T); number of regional lymph nodes evaluated and number involved (N); status of proximal, distal, and radial margins; lymphovascular invasion; perineural invasion; and assessment of distant metastases to other organs, peritoneum, or nonregional lymph nodes (M).5Symptoms of CRC are most frequently related to tumor growth into the bowel lumen or direct invasion into adjacent structures. As a result, patients present typically at relatively advanced stage. Among the newly diagnosed CRCs in the United States, approximately 39% of cases are localized at diagnosis, and an additional 37% have locoregional metastases.2 Unfortunately, nearly 20% of patients have distant metastatic disease at the time of presentation, most commonly to lymph nodes, liver, lungs, and peritoneum.2 In approximately 75% of patients presenting with CRC deemed to be resectable, only two-thirds are cured by surgical intervention, whereas one-third will recur following primary therapy. Recent data support that early diagnosis of recurrent disease results in more favorable outcome. Some cases of isolated locoregional recurrence may be amenable to surgical resection alone or benefit from multimodality therapy. Surgery may also have curative potential in patients with distant metastases, such as hepatic metastases or limited extrahepatic disease.6,7 Ablative techniques may be considered alone or in conjunction with surgery in selected patients with distant metastases.8

Modern imaging techniques play a critical role in the management of patients with CRC and help in selection of patients who would benefit most from surgical or invasive approaches. Postoperatively, surveillance by imaging is usually performed in tandem with serum carcinoembryonic antigen (CEA) assays. When CEA levels rise during postoperative surveillance, imaging is performed in an attempt to identify the presence and location of recurrence to facilitate prompt treatment.

SCREENING

The usual symptoms of CRC are typically because of tumor penetration into the lumen or adjacent structures. This symptomatic presentation is often a manifestation of relatively advanced CRC. Patients may suffer from abdominal pain, change in bowel habits, hematochezia or melena, or unexplained iron-deficiency anemia.9,10 There is substantial evidence that the majority of cases of CRC arise from benign adenomatous polyps which grow slowly over time.11 As the polyp size increases, the risk of malignancy also increases. Systematic screening of a target population of appropriate age has the potential to reduce morbidity and mortality of CRC by detecting asymptomatic lesions and by cancer prevention through polypectomy.12,13 The American Cancer Society recommendations for colon cancer screening in adults 50 years of age with average risk include tests to find polyps and cancer. The available diagnostic tests include flexible sigmoidoscopy every 5 years, or double-contrast barium enema examination every 5 years or computed tomography (CT) colonography every 5 years, or colonoscopy every 10 years.14 The American Cancer Society also recommends the following screening tests to detect cancer: Fecal occult blood test (FOBT) every year, or fecal immunochemical test (FIT) every year, or stool DNA test (sDNA).14

More rigorous testing is required for patients with increased or high risk of developing CRC. Emerging technologies such as sDNA show promise as a reasonable screening test, but to date, there are limited data to support it as a first-line screening test. The FOBT is a guaiac-based test for peroxidase activity used to detect blood in the stool. Mandel et al.15 present evidence that the FOBT decreases mortality secondary to colon cancer. The sensitivity of the FOBT is in the range of 72% to 81.8%.16,17 With flexible sigmoidoscopy, it is possible to examine up to 60 cm of the colon, and thus limiting the number of detectable lesions to just 40% to 65% of all possible lesions.18 Some authors report sensitivities of 71% to 95% in the detection of colon carcinoma with double-contrast barium enema examination.19 However, the sensitivity decreases to as low as 50% to 75% as reported in prospective studies.20Therefore, some organizations such as the National Comprehensive Cancer Network (NCCN) discourage the use of double-contrast barium enema for screening, unless patients are unable to undergo colonoscopy or if colonoscopy is technically incomplete. In the United States, colonoscopy is the primary method employed for CRC screening in patients with average and increased risk. Unfortunately, adherence to CRC screening recommendations is poor, with only approximately 50% to 60% of the eligible patient population undergoing any kind of screening examination.21 Rex et al.22 compared colonoscopic procedures in the same day back-to-back. The overall miss rate was 24% for adenomas, 27% for adenomas 5 mm in diameter or smaller, 13% for adenomas 6 to 9 mm in diameter, and 6% for adenomas 10 mm in diameter or larger.

More recently, CT colonography has been proposed as an alternative noninvasive method for screening CRC. CT colonography combines the data from multidetector helical CT with advanced graphical software to reconstruct two-dimensional and three-dimensional endoluminal views of the colon. Reconstructed endoluminal images can be viewed dynamically and interactively, simulating what is seen at conventional colonoscopy. Current studies have shown that CT colonography and conventional colonoscopy show equivalent sensitivity in the detection of polyps of 10-mm diameter or larger, that are considered to be clinically significant.13 Moreover, CT colonography permits the complete exploration of the colonic lumen and evaluation of eventual areas of tumor stenosis.23 Colonography can also be performed combining fluorine-18-fluorodeoxyglucose ([18F]FDG) positron emission tomography PET/CT and magnetic resonance imaging (MRI) techniques. According to Veit-Haibach et al.,24 PET/CT colonography showed improved T staging in patients with CRC compared with CT colonography. This study determined that PET/CT colonography correctly localized 74% of colorectal tumors, CT and PET 64% of lesions, and CT alone localized 52% of lesions. PET/CT colonography helped significantly in defining TNM staging compared to optimized abdominal CT staging alone, a difference mainly based on a more accurate definition of the T stage. Consequently, in this study, whole-body PET/CT colonography changed therapy management in 9% of patients.24,25 In addition to optical colonoscopy, as an all-in-one staging modality, whole-body PET/CT colonography is capable of providing an alternative to the multimodality, multistep staging in patients with CRC.24 The concept of whole-body PET/CT colonography demonstrated high detection rates for CRC, metastatic lymph nodes, as well as distant metastases.25

The analysis of the differences between CT, MRI, and PET/CT colonography shows that these techniques present both advantages and disadvantages, such as the difficulty to perform MRI in patients with pacemakers or in claustrophobic patients and the risk to perform CT with iodinated contrast in patients with history of adverse reactions or renal failure.26

PATTERNS OF TUMOR SPREAD

Tumors spread in certain patterns: Local, nodal, and peritoneal spread (well described by Tan27)

Local Spread

Tumors may spread either intramurally or transmurally. Intramural spread of tumor usually occurs longitudinally along the bowel wall or superficially toward the serosa. Preferentially, tumor grows in a circumferential pattern, resulting in luminal narrowing. Longitudinal spread is not common and is generally approximately 2 cm from the primary site of disease. This supports the practice of a 5-cm surgical margin.28 Transmural spread is present in more advanced disease. Lesions in the ascending colon, descending colon, and rectum, which are primarily retroperitoneal in location, can directly invade the adjacent retroperitoneal organs such as the kidneys and pancreas via this mode of spread. Locally advanced rectal cancer often involves the pelvic viscera including the bladder base, prostate gland, and vagina.29 Disease can also spread along the neurovascular structures. Extramural venous invasion is associated with increased metastastic burden and result in the worst overall prognosis. Perineural spread in rectal cancer can result in tumor deposits along the perineural spaces more than 10 cm from the primary tumor. This has been reported in as many as 35% of cases.30

Nodal Spread

Distant spread of disease most commonly occurs in the liver, followed by lymph nodes.31 Nodal spread from carcinomas of the right colon follow along the marginal vessels of the cecum and ascending colon and then along the ileocolic vessels to the root of the superior mesenteric artery. Tumors of the proximal transverse colon tend to spread along the marginal vessels on the mesocolic side of the colon. These marginal vessels in turn drain to the right or middle colic vessels and to the root of the mesocolon, anterior to the head of the pancreas. Lymphatics from the distal transverse colon and splenic flexure follow the left middle colic vessels to the inferior mesenteric vein just caudal to the body and tail of the pancreas. Cancers of the descending colon and sigmoid colon spread to nodes along the left ascending colic and sigmoidal vessels that can then be followed to the origin of the inferior mesenteric artery.32Proximal rectal tumors spread cranially via the superior hemorrhoidal nodes antegrade to the inferior mesenteric lymph nodes. The more distal rectal tumors spread laterally along the internal iliac lymph nodes antegrade to the common iliac and retroperitoneal chains. Those located at the rectosigmoid junction tend to spread to the perirectal lymph nodes rather than along the sigmoid mesenteric chain.33

Peritoneal Spread

Peritoneal spread of disease is seen in up to 43% of patients.29 Tumor cells can spread throughout the peritoneal cavity and implant on the omentum and peritoneal surfaces. This pattern of spread is seen more commonly in the intraperitoneal portions of the colon, including the cecum and transverse and sigmoid colon.29 The ovaries are a common site of involvement by peritoneal dissemination.28 In animal models, injection of neoplastic cells into the mesenteric border tend to give rise to nodal metastases whereas injection into the antimesenteric border gives rise to peritoneal metastases, alluding to the role of tumor location to the method of dissemination.34 The presence of peritoneal involvement predicts higher local recurrence and is strongly associated with a mucinous tumor phenotype (signet-ring feature).35 Hematogenous spread of colonic and upper rectal tumors initially occur via the portal circulation. The liver is often the first site of metastatic disease and may be the only site of spread in as many as 30% to 40% of patients with advanced disease.36 Twenty percent to 25% of patients will have clinically detectable liver metastases at the time of initial diagnosis and an additional 40% to 50% of patients eventually develop liver metastases after resection of the primary tumor. Approximately 20% to 30% of patients with metastatic CRC have disease that is confined to the liver and is potentially resectable.37 In low rectal tumors, venous drainage occurs through the systemic circulation via the iliac vessels. This may explain the higher propensity of pulmonary metastases in low rectal cancers compared with tumors from the more proximal parts of the colon and rectum.29 In the appropriate clinical setting, aggressive surgical resection of distant metastases (including the liver, lung, adrenal gland, and spleen) has been shown to confer survival benefit.38 Therefore, early detection of metastastic disease by imaging procedures is important.

DIAGNOSIS AND INITIAL STAGING OF COLORECTAL CANCER

Several modalities have been used in the preoperative staging of CRC: CT, MRI with endorectal or phased array coils, endorectal ultrasonography with rigid or flexible probes, and PET/CT imaging. Usually, a combination of these modalities provides complete staging information. Frequently, barium enema is still performed, having the advantage of permitting the examination of the entire colon. The sensitivity of double-contrast barium enema for detecting polyps 1 cm or larger has been estimated to range from 50% to 90%.39,40 However, the sensitivity declines with decreasing lesion size, and is less sensitive than colonoscopy for identifying smaller lesions.41 CT imaging is routinely used in the staging of CRC, permitting the visualization of the entire abdomen and pelvis. Most protocols involve the administration of iodine-containing intravenous contrast, which gives information on perfusion and the relationship of tumors to blood vessels. In addition, intravenous contrast frequently makes metastases easier to discriminate from background tissues. Iodine- or barium-containing oral contrast is often used to highlight loops of bowel, allowing a higher degree of diagnostic certainty when evaluating adjacent soft tissue masses. CT is useful for identifying the primary tumor, local and distant lymph nodes, and the presence of liver and lung metastases.42

Based on the American Joint Committee on Cancer (AJCC) staging system, the T stage of CRC is determined by degree of involvement of the bowel wall, whereas that of the anus is determined by the size of the primary tumor. Also, the N stage of CRC is defined by the number of involved nodes, as opposed to the location of nodes in anal cancer. T-staging accuracy of 59% to 88% has been reported for MRI in CRC and was similar to that reported for CT imaging.4345 The improvement in T-staging accuracy of CRC to 71% to 91% was achieved after development of endorectal coils.46,47 As is common with other modalities, the primary staging inaccuracy of MRI occurs in differentiating T2 from T3 lesions. Because of the desmoplastic reaction seen adjacent to tumors, MRI typically overstages T2 lesions,48 thus making it difficult to determine whether an irregular outer border of the rectal wall represents perirectal fat being invaded by inflammation alone or a combination of tumor and peritumoral fibrosis. Difficulties of N staging in CRC occur mainly by the fact that micrometastases could present as normal-sized lymph nodes.49,50 Even though MRI may localize nodes as small as 2 to 3 mm in size, morphologic criteria alone are a poor predictor of whether a node is reactive or metastatic. Consequently, the N-staging accuracy of MRI has been highly variable, ranging from 39% to 95%.43,44,51,52

Diffusion-weighted MRI (DW-MRI) can provide unique information, as contrast is dependent on the molecular motion of water, which may be substantially altered by disease. The method was introduced into clinical practice in the mid-1990s, but because it requires high-performance magnetic field gradients, it has only recently undergone widespread dissemination.53 For instance, in the application of CRCs, DW-MRI improves the detection rate of metastases in normal-sized lymph nodes from 7% to 76% by calculation of the apparent diffusion coefficient.54 Another MRI technique, dynamic contrast-enhanced MRI (DCE-MRI), has become an attractive modality for evaluating response to therapy. Rapid acquisition of images is performed before and after intravenous contrast administration, providing information about tumor neovascularization by calculating the different fractions of tumor perfusion.55 A study by Gore et al.56 suggests that quantitative DCE-MRI could be helpful for differentiating benign from malignant breast tumors and could assess the effects of antiangiogenic medications. The combination of DWI, magnetic resonance spectroscopy, and DCE-MRI data with PET, has become an interesting research topic recently. Further attempts were made to combine MRI and FDG PET, by means of software fusion, for primary staging of CRC. In the study by Kam et al.,57 23 patients were evaluated with MRI of the pelvis, whole-body 18F-FDG PET, and MRI-PET fusion. All patients subsequently underwent anterior resection. In T staging, MRI correctly staged 14 of 22 T2/T3 tumors. MRI-PET identified metastases in three patients, but provided little additional value over CT. Indeed, CT was more useful in identifying comorbid conditions (such as an abdominal aortic aneurysm).57 In lymph node assessment, MRI-PET fusion had a sensitivity of 44%, with a specificity and positive predictive value (PPV) of 100%, and thus, MRI-PET fusion added little to conventional investigations for staging colorectal carcinoma.

PET/MR Systems

The development of PET/MR scanners has been restricted because of the mutual incompatibilities between PET and MRI systems. To combine these two systems, several technical challenges had to be solved. The PET detectors needed to be able to function within a high static magnetic field as well as with quickly changing gradient fields and radiofrequency signals from the MRI scanner. Similarly, techniques to prevent degradation of the MR image quality by inhomogeneities in the magnetic field and electromagnetic interference caused by the PET detector needed to be created. One ingenious solution was the replacement of the traditional photomultiplier tubes in the PET detector with avalanche photo diodes (APDs).58,59 PET detectors were also integrated between the MRI body coil and the gradient coils, thus rendering simultaneous acquisition of PET and MRI possible. Siemens AG and Philips Healthcare recently launched PET/MR scanners for clinical examinations, which use very different engineering approaches. Philips unveiled a solution, which involves a 3-tesla MR and a high resolution PET scanner with a rotating table that transfers the patient from one machine immediately into the other. The system combines time-of-flight technology with state-of-the-art 3-tesla MRI in a whole-body footprint for sequential imaging acquisition. The PET gantry was redesigned to introduce magnetic shielding for the photomultiplier tubes, which ensured their operation in “normal” flux levels close to the Earth’s magnetic field. Siemens addressed the mentioned challenging issues by developing a new electro-optical readout scheme for a PET scintillation detector module that relays the signals using optical telecommunications grade lasers and fibers rather than shielded coaxial or high-density ribbon cables, while preserving the high detector signal-to-noise ratio and signal integrity of the PET.59 In the Siemens 3-tesla hybrid system, named Biograph mMR (m = molecular), the photomultipliers were replaced with APDs that are only a fraction of the size of electron tubes. Even though the APDs measure an electron flow that is caused by photons, this takes place within a semiconductor layer system that does not suffer much interference from external magnetic fields. This technology permits fast simultaneous imaging acquisition in an integrated system.

PET/CT for Initial Staging

PET with [18F]FDG is widely used for diagnosing, staging, restaging, and assessing the therapeutic response in a number of tumors (Fig. 9.1).60

Two different patterns of colorectal [18F]FDG uptake have been defined on PET examination: Focal and nonfocal.61 Nonfocal uptake of [18F]FDG is generally correlated with physiologic uptake by smooth muscles of the gastrointestinal tract or with radiotracer excretion and intraluminal concentration, whereas there is evidence from the literature that focal uptake of [18F]FDG can be associated with endoscopically detectable lesions.62 A study by Treglia et al.62 evaluated 6,000 patients and recommends the use of colonoscopy for further characterization of incidental focal colorectal uptake of [18F]FDG, given the high incidence of malignant and premalignant lesions (Fig. 9.2).

One of the challenges of older generation dedicated [18F]FDG PET systems in the detection of tumors in the abdomen was related to the poor ability to properly localize the lesions. Bowel has variable uptake that can be sometimes intense. Even though physiologic activity within the bowel most often has a linear pattern, focal activity is not rarely seen in normal patients (Fig. 9.3).63 In addition, physiologic radiotracer activity along the colon can easily obscure primary lesions in patients with CRC.64 It has been shown that patients treated with metformin have significantly increased [18F]FDG PET uptake in the colon and to a lesser extend in the small intestine. This increase is typically intense, diffuse, and continuous along the bowel wall and lumen and may mask underlying malignant lesions. Stopping metformin before PET/CT imaging significantly decreases this unwanted uptake, especially in the colon, and should be considered in patient undergoing scans for the evaluation of CRC (Fig. 9.4).

Other sources of misinterpretation with dedicated PET scanners were related to excreted radiotracer in the genitourinary tract. Urinary activity can be confounding, particularly if focal retention in the ureters is misinterpreted as nodal involvement. Diuretics and hydration have been suggested to decrease urinary activity but are not invariably successful and seldom used.64 Hybrid [18F]FDG PET/CT imaging, providing precise anatomical landmarks, has permitted better localization of suspicious colorectal uptake, and has been a useful guide to direct further investigations with endoscopy and biopsy.62 However, there are several limitations for detection of small tumors with PET/CT. The main disadvantage is the inherent limited spatial resolution of PET/CT imaging.65 In addition, certain types of tumors such as mucinous adenocarcinomas do not demonstrate significant metabolic activity. There is still a lack of data supporting the usefulness of [18F]FDG PET/CT imaging in the routine staging of patients diagnosed with primary CRC. In a study that included 37 patients, Gearhart et al.,66 were able to identify [18F]FDG PET/CT involved nodes within the mesorectal fascia that were not seen with standard imaging. In particular, in low rectal tumors, where frequently, iliac and inguinofemoral nodes were involved. This resulted in patient management changes in 27% of cases, and thus improved the accuracy of pretreatment staging.66 In addition, two studies by Tsunoda et al.67 and Tateishi et al.68 suggest that [18F]FDG PET/CT is able to identify N-stage disease remote from the primary site suggesting that [18F]FDG PET/CT should be considered in the preoperative staging of primary rectal cancer. In proximal nodal staging, based on analysis with an SUVmax threshold of 1.5, [18F]FDG PET/CT demonstrated a sensitivity of 51% (95% CI: 36% to 66%) and a specificity of 85% (95% CI: 72% to 92%). For distal nodal staging (lymph node metastases of CRC) using an SUVmax threshold of 1.5, the sensitivity of [18F]FDG PET/CT was 62% (95% CI: 30% to 86%) and specificity was 92% (95% CI: 84% to 96%). [18F]FDG PET/CT was found to have a sensitivity of 28% (95% CI: 18% to 42%) and specificity of 92% (95% CI: 87% to 96%) when used for nodal staging of proximal and distal lymph nodes (n = 176), and data were compared with findings from surgical excisions and dissection.67 If a threshold of nodal maximum axial diameter of lymph nodes was set for ≥10 mm, tumor detection with [18F]FDG PET/CT had a sensitivity of 30% (95% CI: 19% to 44%) and a specificity of 95% (95% CI: 90% to 97%).67 When the optimal cutoff value of 1.5 SUVmax was analyzed, the sensitivity of [18F]FDG PET/CT was 53% (95% CI: 39% to 66%) and the specificity was 90% (95% CI: 84% to 94%). With increased SUV value to 2.5, the sensitivity of [18F]FDG PET/CT was 38% (95% CI: 26% to 53%) and the specificity was 94% (95% CI: 89% to 97%), and, at a threshold of 3.5, the sensitivity was 24% (95% CI: 15% to 38%) and the specificity was 100% (95% CI: Not calculable).67

FIGURE 9.1. A 39-year-old female with newly diagnosed moderately to poorly differentiated adenocarcinoma of the rectosigmoid undergoing PET/CT for initial staging. Axial PET (A), CT (B), fused PET/CT (C), and MIP (D)images demonstrating a hypermetabolic mass in the rectosigmoid region with an SUVmax of 12.6, compatible with the known primary tumor (arrows ). The MIP image also demonstrates bilobar liver metastases (arrowheads ).

As mentioned earlier in this chapter, most protocols for CT imaging involve the administration of iodine-containing intravenous contrast for detection of CRCs. Similarly, PET/CT can be performed with intravenous contrast to improve diagnostic accuracy without significant artifacts from attenuation correction.69 There is also the possibility to use iodine-based or diluted barium oral contrast to better delineate loops of bowel and thus improve the visibility of soft tissue masses. Tateishi et al.68 reported improved accuracy in diagnosing N staging by adding contrast enhancement to the [18F]FDG PET/CT with sensitivity of 85% (95% CI: 69% to 93%) and a specificity of 42% (95% CI: 23% to 67%) in 53 patients. They reported accuracy of contrast-enhanced [18F]FDG PET/CT was 85% (95% CI: 69% to 93%) and 68% (95% CI: 46% to 84%). However, the accuracy data to support the use of [18F]FDG PET/CT or contrast-enhanced [18F]FDG PET/CT in the preoperative staging for primary CRC are very limited because of the small number of patients involved in the study. Contrast-enhanced [18F]FDG PET/CT was favorable in imaging all lymph nodes. For imaging of pararectal nodes, contrast-enhanced [18F]FDG PET/CT increased sensitivity to 90% (95% CI: 76% to 97%) and specificity to 76% (95% CI: 55% to 89%) compared to nonenhanced [18F]FDG PET/CT, where is reported sensitivity of 75% (95% CI: 57% to 87%) and a specificity of 52% (95% CI: 32% to 71%).67,68 Imaging of internal iliac nodes with contrast-enhanced [18F]FDG PET/CT demonstrated 75% sensitivity (95% CI: 50% to 90%) and 86% specificity (95% CI: 72% to 94%); a sensitivity of 31% (95% CI: 14% to 55%) and specificity of 81% (95% CI: 66% to 90%) for [18F]FDG PET/CT. Obturator node detection had a sensitivity of 67% (95% CI: 39% to 86%) and a specificity of 95% (95% CI: 84% to 99%) for contrast-enhanced [18F]FDG PET/CT in comparison to sensitivity of 67% (95% CI: 39% to 86%) and a specificity of 61% (95% CI: 46% to 74%) for [18F]FDG PET/CT.67,68

FIGURE 9.2. A 55-year-old male with head and neck squamous cell carcinoma undergoing initial staging. Axial PET (A), CT (B), fused PET/CT (C), and MIP (D) images demonstrating an incidental hypermetabolic lesion (arrows) in the left colon (SUVmax 9.3). Follow-up colonoscopy revealed an ulcerated colonic mass compatible with moderately differentiated adenocarcinoma of the colon.

[18F]FDG is limited in the evaluation of mucinous tumors, particularly in hypocellular lesions with abundant mucin. Mucinous carcinomas are commonly found in the gastrointestinal tract and represent approximately 17% of colonic tumors.70 These tumors contain clear, gelatinous fluid (mucin), which may be intracellular or extracellular. In one study, [18F]FDG PET detected mucinous carcinoma in only 13 of 22 patients, resulting in an unusually high percentage of false-negative results (41%).71 Further studies with [18F]FDG PET/CT imaging confirmed that the technique is not sensitive in detecting mucinous colon cancers and can be a cause of false-negative results.72

PET/MRI for Initial Staging

PET/MRI systems are now available with only a limited number of studies describing its potential clinical applications.73,74 MR imaging combined with PET may provide unique information for staging of CRC. This new approach may enhance the T-staging accuracy in those tumors that could not dispense with MRI and the N-staging and M-staging performance in body compartments that are superiorly depicted by PET.75 However, current evidence indicates that PET/MR technique provides no significant additional value in the preoperative staging of patients with rectal cancer, compared with pelvic MRI in conjunction with abdominal CT and chest radiography.57 In a study of 23 patients, MRI localized 100% of all rectal tumors; however, it was insufficient for the determination of tumor stage, because 11 out of 23 patients were overstaged. Based on the results of a recent meta-analysis, the sensitivity and specificity of MRI for the T staging of rectal cancer are 87% and 75%, respectively (Figs. 9.5 and 9.6) in locally advanced colon cancer.76 As previously published, [18F]FDG PET does not add to the accuracy of T staging in rectal cancer.77 It remains to be determined if PET/MRI will be superior to MRI alone in the assessment of local tumor extent in CRC patients.78

FIGURE 9.3. A 30-year-old female with sarcoma involving the mediastinum. Axial PET (A), CT (B), fused PET/CT (C), and MIP (D) images demonstrate a focus of increased [18F]FDG activity (SUVmax 6) in the right colon (arrows ). On the follow-up PET/CT scan obtained 2 months later (not shown), the previously seen focal activity in the right colon resolved, suggesting it was physiologic in nature.

A study by Kam et al.57 reported only 44% sensitivity of PET/MRI for the detection of lymph node metastases in preoperative rectal carcinoma patients.57 The same study also reported a specificity of 100%, a PPV of 100%, and a negative predictive value (NPV) of 74%. The authors reported that PET was never positive in the absence of positive lymph nodes on MRI; the pathologically determined size of metastases within lymph nodes rated positively on MRI ranged from 8 to 17 mm in that study.57 In a meta-analysis by Al-Sukhni et al.,76 they reported a sensitivity of 77% and a specificity of 71% on the diagnostic performance of MRI for the metastases N stage.76 It was expected that a combination of anatomical MRI or CT and functional [18F]FDG PET would increase the diagnostic accuracy in N staging. A confirmation came from Kim et al.,79 where 90% of lymph node metastasis was detected when [18F]FDG and MRI/CT were combined; the sensitivity, specificity, PPV, and NPV of combined MRI and [18F]FDG PET/CT were 94%, 83%, 89%, and 91%, respectively. However, these initial experiences with PET/MRI still reflect inaccuracy of lymph node micrometastasis localization with any imaging modality.

For accurate quantification and clinical presentation of PET/MRI systems, appropriate attenuation-correction algorithms needed to be developed. A study of Marshall et al.80 describes the use of MRI to infer patient-specific attenuation coefficients to be applied to augment whole-body MRI-based attenuation μ-maps. This technique has been shown to improve the quantitative fidelity of PET images. Although μ-map choice did not influence quantification in soft tissue or bone when averaged over the whole thorax, it did affect structures near the lungs, notably the vena cava and peripheral left ventricle. This could be especially useful for staging and imaging of recurrences, but because of the dearth of published data, the clinical use of PET/MRI in CRC remains to be explored.

FIGURE 9.4. A 73-year-old female with diabetes mellitus type 2 and lymphoma status post chemotherapy undergoing restaging. Axial PET (A), CT (B), and fused PET/CT (C), and MIP (D) images demonstrate diffusely increased [18F]FDG activity throughout the colon compatible with patient use of metformin.

IMAGING OF RECURRENCE AND RESTAGING

PET/CT

[18F]FDG PET/CT has an established role in restaging patients before surgical resection of locally recurrent cancer and metastases and in the assessment of residual masses after treatment (Figs. 9.7 and 9.8). It is also accurate for detection of hepatic and extrahepatic tumors (Fig. 9.9).

PET/CT has provided significant improvement in comparison with PET alone, especially in patients with hepatic recurrence considered for surgical resection, because PET may demonstrate uptake not only in tumors, but also in inflammatory changes, which include postoperative healing scars and postradiation therapy.81 A number of studies have indicated a possible role of [18F]FDG PET/CT for prediction and evaluation of treatment response,8183 as metabolic alterations in tumor cells may occur before changes in tumor size.55 In a study by Capirci et al.,84 the accuracy of PET was determined as 81% for the detection of residual rectal cancer after neoadjuvant CRT (using a response index cutoff of 65% for defining response to the therapy). Guillem et al.85 showed that rectal cancer patients who were disease free and remained at a median follow-up of 42 months, presented a greater decrease in SUVmax after neoadjuvant treatment than patients who eventually developed recurrence. Therefore, [18F]FDG PET/CT may provide crucial data for the development of strategies for long-term monitoring of postoperative patients who have an increased risk of recurrence.

Since the recurrence rate of CRC is generally high, it is imperative to closely monitor patients, particularly those at an increased risk.86 In the relatively short follow-up period of 2 to 3 years, up to 40% of patients will have recurrent disease.87,88 The location of recurrent tumors typically is in the liver or lungs but also can occur at the site of the previous tumor. Local recurrence of colon cancer is less common than recurrent rectal cancer, because the surgical removal of primary tumors of the colon involves extensive lymph node dissection.89 In general, hepatic metastases are the first presentation of recurrence in 20% to 40% of patients,89 and in two of the studies90,91 metastases were detected in patients suspected of recurrence. A sensitivity and specificity of detection of local recurrences is relatively high with [18F]FDG PET/CT (the sensitivity of [18F]FDG PET/CT was 93% [95% CI: 70% to 99%] and the specificity 98% [95% CI: 89% to 100%]) as reported by Bellomi et al.90 This group demonstrated that in 67 patients, the accuracy of detection of distant recurrence of resected rectal cancer is even higher with multidetector CT, where sensitivity was 100% (95% CI: Not calculable) and the specificity was 98% (95% CI: 90% to 100%).90

FIGURE 9.5. A 54-year-old male with newly diagnosed rectal cancer. Axial PET (A), CT (B), and PET/CT (C), and PET sagittal (D) images demonstrate a hypermetabolic rectal mass (SUVmax 9.8) extending to the anal canal (arrows ).

FIGURE 9.6. Axial (A) and sagittal (B) T2-weighted images demonstrate a locally advanced rectal cancer involving the distal rectum abutting the posterior wall of the prostate gland (asterisks ).

FIGURE 9.7. A 59-year-old male with rectal cancer status post low anterior resection. Axial PET (A), CT (B), and fused PET/CT (C) images as well as a PET sagittal image (D) obtained 2 years after the initial resection demonstrate a hypermetabolic presacral mass (SUVmax 7.1) at the anastomosis (arrows), compatible with local recurrence.

In the detection of extra-abdominal recurrence of CRC, data by Kim et al.92 showed a sensitivity of 100% (95% CI: 70% to 100%) and a specificity of 97% (95% CI: 86% to 99%) for the accuracy of [18F]FDG PET/CT whereas [18F]FDG PET alone had lower sensitivity of 78% (95% CI: 45% to 93%) and a specificity of 86% (95% CI: 72% to 94%), respectively. With regard to the accuracy of staging pelvic recurrence, a study by Even-Sapir et al.93demonstrated on 62 patients that a sensitivity of 98% (95% CI: 88% to 99%) and a specificity of 97% (95% CI: 85% to 99%) for [18F]FDG PET/CT were higher than for [18F]FDG PET alone, where lesion-level data had a sensitivity of 88% (95% CI: 69% to 95%) and a specificity of 70% (95% CI: 57% to 85%) in the detection of pelvic recurrence of rectal cancer. In general, as reported in multiple studies, [18F]FDG PET/CT was repeatedly more accurate in preoperative staging than [18F]FDG PET alone.9294 If patient-level analyses are considered in the detection of recurrent CRC, the study by Votrubova et al.94 on 84 patients reported a sensitivity of 89% (95% CI: 76% to 95%) and a specificity of 92% (95% CI: 80% to 97%) for [18F]FDG PET/CT, whereas the corresponding [18F]FDG PET sensitivity was 80% (95% CI: 66% to 89%), and specificity was 69% (95% CI: 53% to 81%). A study by Kim et al.92reported patient-level analyses on 51 patients, where [18F]FDG PET/CT sensitivity was 83% (95% CI: 64% to 93%) and specificity was 93% (95% CI: 76% to 97%). In contrast, for [18F]FDG PET alone, sensitivity was 67% (95% CI: 47% to 82%) and specificity was 74% (95% CI: 60% to 86%). A third study reporting patient-level analysis was conducted by Even-Sapir et al. They presented [18F]FDG PET/CT sensitivity of 96% (95% CI: 80% to 99%) and specificity of 89% (95% CI: 76% to 96%) compared to sensitivity of 87% (95% CI: 69% to 96%), and specificity of 74% (95% CI: 58% to 80%)93 using [18F]FDG PET alone. A study by Schmidt et al.95 compared [18F]FDG PET/CT with whole-body MRI and reported equally high sensitivities and specificities in the detection of all recurrent lesions in 24 patients with CRC. Lesion-level analyses for the detection of nodal recurrence reported by the same group had greater accuracy for [18F]FDG PET/CT with a sensitivity of 93% (95% CI: 78% to 98%) and a specificity of 100% (92% to 100%) compared to whole-body MRI, where sensitivity and specificity were 62% (95% CI: 44% to 77%) and 91% (95% CI: 80% to 96%), respectively.95

FIGURE 9.8. Axial (A) and sagittal (B) T2-weighted MR images of the same patient demonstrate a presacral soft tissue mass (arrows ), consistent with tumor recurrence.

FIGURE 9.9. A 66-year-old male with history of moderately differentiated adenocarcinoma of the rectum status post low anterior resection. PET/CT scan obtained 2 years after the initial diagnosis for restaging. Axial PET (A), CT (B), and MIP (C) images demonstrating a large hypermetabolic mass centered in the left hepatic lobe (arrow ), compatible with liver metastasis. Additional hypermetabolic metastases are also seen in the right hepatic lobe and in the lungs bilaterally (small arrows ).

The benefits of PET/CT over PET appeared to be more marked for the evaluation of extrahepatic disease, both intra-abdominal and extra-abdominal, than for liver evaluation. In these regions, better localization of [18F]FDG avid lesions is potentially more beneficial.72 Interesting results were presented by Kula et al.,96 where detection possibility of CRC was compared between serum levels of CEA and [18F]FDG PET/CT imaging in 120 patients. Data revealed [18F]FDG PET/CT to be more accurate for detection of recurrent colorectal tumors than the blood test for CEA levels. The sensitivity of 98% (95% CI: 90% to 100%) and specificity of 95% (95% CI: 82% to 99%) were reported for [18F]FDG PET/CT; for CEA levels, sensitivity of 68% (95% CI: 55% to 79%) and specificity of 82% (95% CI: 64% to 92%) was presented for recurrence.96 In another study, Strunk et al. looked at comparing [18F]FDG PET/CT with CT in patients with an unexplained elevated CEA levels with suspicion of recurrent CRC. This study demonstrated that, [18F]FDG PET/CT had a sensitivity of 79% (95% CI: 69% to 86%) and a specificity of 83% (95% CI: 61% to 94%) whereas CT had a sensitivity of 85% (95% CI: 76% to 92%) and a specificity of 76% (95% CI: 55% to 89%), based on lesion-level data.91 Another, more recent study by Ozkan et al.97 followed 69 patients with elevated CEA compared to the [18F]FDG PET/CT in the detection of CRC recurrences. They showed there was no correlation between patient serum CEA levels and lesion’s SUVmax. In the evaluation of separate patient groups, the sensitivity and specificity values of [18F]FDG PET/CT were different: In the group whose CEA-level elevation was less than twofold (5 to 9.9 ng/mL), the sensitivity and specificity were 100% and 60%, respectively. The sensitivity and specificity were 100% and 75% in the group with CEA elevation less than threefold (10 to 14.9 ng/mL) and least in the group, where elevation was more than threefold (≥15 ng/mL), the sensitivity and specificity were 95% and 62%. The sensitivity and specificity of [18F]FDG PET/CT were computed as 98% and 85% in the lesion-based evaluation. The sensitivity and specificity of contrast-enhanced CT were 73% and 86%, respectively. These studies indicate that [18F]FDG PET/CT is a safe imaging method that should be used in the determination of CRC recurrence in patients with elevated CEA levels, regardless of the degree of CEA elevation.97

MRI and PET/MRI Imaging

The biggest advantage of combined PET/MRI is expected in the assessment of therapeutic response and tumor relapse. Evaluation of 68 patients with rectal cancer demonstrated that the tumor-free margin on preoperative MRI is predictive of tumor recurrence and patient survival.98 MRI was shown to be reliable for the assessment of tumor-free distance to the mesorectal fascia, with reported sensitivity of 77% and specificity of 94%.76 MR DWI may predict the tumor clearance of the mesorectal fascia in locally advanced rectal cancer99 and was reported to provide an imaging biomarker for tumor invasiveness. Lower apparent diffusion coefficient values correlated significantly with more aggressive tumor profiles, including high grades, high frequency of lymph node metastases, and invasion of the mesorectal fascia.100 In patients with clinically suspected local recurrence, sensitivity ranged from 84% to 100% and specificity from 74% to 83% for conventional MRI, and an increase of diagnostic performance by adding functional MRI information (DWI) has been reported.101 Residual tumor or locally recurrent tumors are sometimes difficult to identify on the basis of morphologic criteria. This is in part because of potential postsurgical changes or alterations related to chemoradiation that can lead to scar tissue or desmoplastic reactions.102 In this case, metabolic information of [18F]FDG activity should be considered for correct restaging. It is also known that tissue in process of regeneration and inflammation may present with increased [18F]FDG uptake. This is a real limitation of [18F]FDG PET/CT in prediction of histopathologic tumor response after chemoradiation when scanning is performed shortly after therapy.102 The reported sensitivity, specificity, accuracy, PPV, and NPV of [18F]FDG PET/CT for the detection of local CRC recurrence were 84%, 88%, 87%, 76%, and 92%, respectively.103 PET/MRI integrates the advantages of MRI and [18F]FDG PET and thus may evolve as the first-line restaging modality in CRC patients with suspected tumor relapse or newly developed metastases.78

DCE-MRI

The utility of DCE-MRI has already been explored in animal experiments104107 as well as in several clinical trials,99,108,109 and it was suggested that DCE-MRI is useful as a pharmacodynamic biomarker.110,111 A study by De Bruyne et al.55 compared the role of DCE-MRI and [18F]FDG PET/CT for evaluation of response and for prediction of long-term outcome in patients with potentially resectable colorectal liver metastases treated with bevacizumab before surgery. In this study, the area under the enhancement curve (AUC) and initial AUC (iAUC) were calculated from 19 patients diagnosed with mCRC who underwent treatment with FOLFOX/FOLFIRI and bevacizumab followed by surgery. Microvessel density (MVD) and proliferation index were also measured. After the fifth treatment cycle, DCE-MRI and [18F]FDG PET/CT were performed. [18F]FDG PET uptake was evaluated by calculating SUVmax. A major finding from this study was the delineation of a potentially important role of DCE-MRI in predicting outcome, both early during treatment and after treatment.55 Both AUC and iAUC were significantly decreased following bevacizumab therapy (median change of 22% [p = 0.002] and 40% [p = 0.001] for AUC and iAUC, respectively). Progression-free (PF) survival benefit was shown for patients with more than 40% reduction in Ktrans (p = 0.019). An increase in Ktrans (the endothelial transfer constant) of at least 40% after one cycle of bevacizumab-containing chemotherapy directly correlated with worse progression-free survival (PFS). Other studies presented similar results.108,112 Baseline [18F]FDG PET on the other hand, could predict the probability of an objective response according to De Bruyne et al.,55 and did not predict the probability of a metabolic response. However, they demonstrated that higher [18F]FDG uptake at follow-up scan correlated with worse PFS (p = 0.012), as was observed also by Riedl et al.113 Pathology confirmed median MVD as 10.9. PFS was significantly shorter in patients with an MVD greater than 10, compared with patients with lower MVD (10 months compared with 16 months, p = 0.016).55 Altogether, their data indicate that after neoadjuvant chemotherapy, high [18F]FDG uptake in liver metastases of CRC is a negative prognostic marker. This study also reflects that no correlation between DCE-MRI parameters and the standardized [18F]FDG uptake value was found. The lack of correlation between DCE-MRI parameters, anatomical tumor response, and SUVmax suggests that tumor blood flow, tumor shrinkage, and tumor glucose metabolism are potentially independent predictors of outcome and that both imaging techniques may provide complementary information.55 In conclusion, if a decrease in Ktrans, low SUVmax on follow-up PET scan, complete metabolic response, and low MVD are observed, then these parameters provide for a favorable prognosis for mCRC patients.

FIGURE 9.10. A 65-year-old male with colorectal cancer and lung metastases. Axial PET (A), CT (B), and fused PET/CT (C) images demonstrate a pleural-based nodule (arrows ) with only mild [18F]FLT activity (SUVmax 3.1), compatible with viable malignancy.

OTHER RADIOPHARMACEUTICALS FOR IMAGING OF COLORECTAL CANCER

CEA Scan

CEA is a cell surface 180-kDd glycoprotein overexpressed in a variety of cancers.114 To date, few compounds utilizing radiolabeled monoclonal antibodies (mAbs) and fragments directed against CEA have been developed for single photon emission imaging. The most promising, CEA-Scan (arcitumomab; Immunomedics, Morris Plains, New Jersey) is an antibody (Fab′) fragment labeled with 99mTc pertechnetate, previously approved for imaging of recurrent colorectal tumors in patients with rising CEA levels.115,116 Because of its relative small size and rapid renal excretion, imaging could be performed within 5 hours after administration. The fragment was derived from a murine antibody, but elicited lower rates of human antimouse antibody (HAMA) in comparison to intact mAbs.115 Even though results from clinical trials indicated that the 99mTc anti-CEA Fab′ agent was suitable for the diagnosis of local recurrence of colorectal carcinoma, [18F]FDG PET is clearly superior in the detection of distant metastases (liver, bone, and lungs).117 Therefore, in 2005, the marketing authorization of CEA-Scan was withdrawn at the request of Immunomedics, Inc.

11C-Choline PET/CT

Choline is a marker of phospholipid synthesis. 11C-choline has been considered as a potential PET radiopharmaceutical for tumor detection since Hara et al.118 reported on the usefulness of 11C-choline PET for detection of brain tumors. Ramírez de Molina et al.119 reported that choline kinase, which catalyzes the phosphorylation of choline, is upregulated in lung, prostate, and CRCs. Therefore, 11C-choline PET may be a reasonable approach for detection of CRC. Terauchi et al.120 reported a single case of a patient who underwent surgical resection for advanced colon cancer depicted by 11C-choline PET. A 50-year-old woman presented with melena and abdominal discomfort. The colonoscopy showed an elevated lesion in the sigmoid colon. Abnormal uptake of 11C-choline was observed in the sigmoid colon, corresponding to an area of wall thickening. In this case, lymph node metastases were not detected by 11C-choline PET, probably because of their small size (less than 10 mm in diameter). Even though further studies are necessary, the authors hypothesized that 11C-choline PET/CT might be useful for the detection of the primary lesions. Because of the high level of physiologic 11C-choline activity in the liver, the visualization of hepatic metastasis is challenging. However, 11C-choline PET might be useful for detecting other metastases of CRC such as brain, lung, and bone metastases, with less interference from background activity.120

18F-FLT

18F-fluoro-3′-deoxy-3-L-fluorothymidine ([18F]FLT) permits the assessment of tumor proliferative activity, a key feature of malignancy. Uptake of [18F]FLT reflects proliferation by reporting the activity of thymidine salvage, a mechanism that provides dividing cells with DNA precursors from the extracellular environment. On internalization, [18F]FLT is monophosphorylated by the cytosolic enzyme thymidine kinase 1 (TK1), resulting in intracellular trapping and accumulation.121 Recently published data by Yamamoto et al.,122 reported on 26 patients with newly diagnosed CRC comparing [18F]FLT and [18F]FDG PET. The mean (± SD) values of [18F]FLT SUV in colon cancer (5.4 ± 2.4) and in rectal cancer (5.6 ± 1.3) were significantly lower than the corresponding values of [18F]FDG SUV (12.4 ± 6.3 and 12.5 ± 4.7, respectively) (P < 0.003).122 Two other studies described that primary tumors were well depicted using [18F]FLT;123,124 however, in 17 patients with 50 primary or metastatic CRC lesions, [18F]FDG revealed on average twice the uptake of [18F]FLT.123 For visualization of extrahepatic lesions, [18F]FLT PET and [18F]FDG PET demonstrated comparable sensitivities. However, of the 32 liver lesions present, only 11 were visualized with [18F]FLT. The poor sensitivity of [18F]FLT for detection of hepatic lesions is probably because of high physiologic background activity seen in the liver, secondary to the metabolism of [18F]FLT via glucuronidation. The prognostic implications of [18F]FLT imaging need to be further investigated, particularly in regard to the assessment of response to therapy and ultimately, patient survival (Fig. 9.10).123

RADIOIMMUNOTHERAPY IN COLORECTAL CANCERS

Radioimmunotherapy (RIT) utilizes radiolabeled mAbs or antibody fragments against tumor-specific antigens to deliver targeted radiation to cancer cells. Currently, there are two Food and Drug Administration approved RIT agents, 90Y-Zevalin (Spectrum Pharmaceuticals, Inc., Irvine, CA) and 131I-Bexxar (GlaxoSmithKline, Research Triangle Park, NC), both for the treatment of non-Hodgkin lymphoma. However, RIT has not produced sufficient evidence of efficacy in the treatment of more radioresistant solid tumors to be considered a major therapeutic option.

Anti-CEA Radioimmunotherapy

As a cell surface epitope overexpressed in patients with CRC, CEA presents as an interesting target for RIT. Early publications investigated the use of 131I-labeled anti-CEA antibodies and fragments in xenograft models of metastatic CRCs. These studies revealed that 131I-labeled anti-CEA successfully inhibited the growth of colon cancer xenografts in a rodent model in a dose-dependent manner. Moreover, the absorbed dose to the tumor dose was inversely proportional to the size of the tumor. Thus, treatment of larger tumors was ineffective, but promising for micrometastases.125128 Early clinical trials with murine 131I-A5B7 anti-CEA antibody and neutrophil proteinase-4 (131I-NP-4), a murine IgG1 antibody presented only modest results in regard to treatment response.129,130

More recently, Juweid et al.,131 described a new murine IgG mAb against CEA (MN-14), which has greater affinity for the antigen than NP-4. Subsequently, a radiolabeled form of this MAb (188Re-MN-14) was investigated in a phase I trial and determined to have less toxic effects than seen with 131I-labeled antibodies. However, two of the patients from that study developed human anti-murine antibodies (HAMAs). A humanized version of MN-14 (hMN-14) was later investigated in two clinical studies. In both, 42% to 45% of patients developed mixed or minor responses.132,133

Antiglycoprotein Radioimmunotherapy

Tumor-associated glycoprotein 72 (TAG-72) is a cell surface and secreted antigen expressed in more than 80% of CRCs and is another potential candidate for targeted RIT. Radiolabeled mAbs against TAG-72 (131I-CC49) was investigated in several studies by Divgi et al.134 and Murray et al.,135 resulting in minor responses in 20% to 25% of patients but with significant development of HAMA response. Epithelial cellular adhesion molecule (Ep-CAM) is another interesting contender for RIT, because antibodies binding to Ep-CAM tend to be rapidly internalized into the cell, leading to excellent intratumoral retention of the antibody.136 NR-LU-10 is a murine IgG against Ep-CAM, which has been evaluated in the phase I setting of 15 patients with no objective responses and with all patients developing HAMAs.137 The chimeric version of this antibody (NR-LU-13) labeled with 186Re, also demonstrated significant immunogenicity in patients, despite the chimeric nature of the antibody.138

Pretargeting Radioimmunotherapy

Pretargeting is a novel concept in RIT, whereas an unlabeled immunoconjugate is first used to target cancer cells and later followed by a radiolabeled compound with high affinity for the immunoconjugate that prelocalized to the tumor. In a phase I trial, Kraeber-Bodéré et al.139 investigated the antitumor efficacy of targeted preradioimmunotherapy using anti-CEA, hMN-14 × m734 bispecific antibody (BsmAb), followed by the injection of 131I-di-diethylenetriamine pentaacetic acid (DTPA)-indium hapten. Toxicity and tumor response rates were assessed in 20 patients with CEA overexpressing tumors (medullary thyroid carcinoma, and colorectal, stomach, esophagus, pancreas, gallbladder, breast, or lung cancers). A BsmAb dose of 40 mg/m2 at a 5-day interval from the radiolabeled hapten appeared to be a better dose/schedule regimen, with acceptable toxicity. Under these conditions, the overall rate of disease stabilization was 22%.139 However, further validation of these results in a larger population of patients with CRC needs to be performed.

Future Directions in Radioimmunotherapy

The epidermal growth factor receptor (EGFR, HER1) is a transmembrane glycoprotein that is a member of a subfamily of type I tyrosine kinase receptor overexpressed in certain human cancers, including approximately 75% of CRCs. To date, two HER1 targeted mAbs are currently used as second- or third-line therapy for metastatic CRC: Cetuximab (ImClone, Somerville, NJ), an IgG1 chimeric mAb, and panitumumab (Amgen, Thousand Oaks, CA), a fully humanized IgG2 antibody.

Imaging HER1-positive tumors utilizing optical imaging as well as single photon and positron emitting probes has proved to be a feasible approach to evaluate the extent of disease in the preclinical settings. Therefore, the development of an imaging surrogate may help select and screen patients for subsequent HER1-targeted RIT.140143 Panitumumab specifically binds to the extracellular domain of EGFR.144146 A critical factor in screening patients for targeted therapy is evaluating the presence and amount of the specific target in the tumor and its relevance to the disease state. To date, antibody-based imaging has been limited by high background levels related to slow clearance, making such imaging challenging. Therefore, smaller molecules such as antibody fragments are extremely appealing. The average molecular weight of intact panitumumab is 147 kD. In comparison, the panitumumab F(ab′)2 fragment is approximately 110 kDa. Wong et al.147 evaluated the preclinical properties of panitumumab F(ab′)2 fragment and successfully assessed its utility as a targeting agent in radioimmunodiagnostic and radioimmunotherapeutic protocols. Therefore, their preliminary results confirm that the smaller panitumumab F(ab′)2 fragment is more effective in tumor penetration and HER1 targeting. The rapid clearance of the F(ab′)2 from the blood compartment results in a higher signal-to-noise ratio at earlier time points, permitting optimal patient imaging and more favorable dosimetry.

The smaller size and rapid clearance of antibody fragments such as F(ab′)2 should also lower their immunogenicity potential, reducing the risk of patients developing a humoral response against the conjugate, and potentially permitting repeated treatment of patients.148 Noninvasive imaging and later RIT using panitumumab F(ab′)2 fragments may prove to be a powerful tool for the treatment of patients with metastatic colorectal carcinoma.

CONCLUSIONS

Imaging plays an important role in screening, initial staging, and restaging of patients with CRC. Combined PET/CT and PET/MRI merge advantages of functional and anatomical techniques. To this day, data supporting the usefulness of [18F]FDG PET/CT imaging in the routine staging of patients diagnosed with primary CRC is insufficient. Similarly, the clinical use of PET/MRI in CRC is yet to be explored. PET/CT has an established role in evaluating tumor recurrence in the setting of rising CEA levels. PET/CT significantly improves localization of lesions in patients with hepatic recurrence and is recommended for monitoring response to treatment. The biggest advantage of combined PET/MRI is expected to be in the assessment of therapeutic response and tumor relapse or in identification of newly developed metastases.

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