Introduction
Colorectal cancer (CRC) is the third most commonly diagnosed cancer globally and in the United States. Although the incidence and mortality rates have been steadily declining over the last several decades likely due to earlier detection from standardized screening and mitigation of risk factors, there are still roughly 130,000 newly diagnosed cases and 50,000 deaths every year in the United States. The incidence is higher in people over the age of 65 and among males compared to females. Other risk factors for nonhereditary disease include smoking, obesity, sedentary lifestyle, inflammatory bowel disease, and race, with African Americans having the highest incidence rate among all ethnic groups in the United States. , Although the vast majority of new CRC cases are sporadic, there are a number of hereditary conditions that confer additional risk, including variants of familial adenomatous polyposis, MUTYH-associated polyposis, and Lynch syndrome.
Compared to their global counterparts, the United States has a higher survival rate for CRC at 60%–65%. These patients not only face challenges with pain management when they are being treated for their active disease, but a growing population of survivors faces the unexpected burden of treatment-related chronic pain syndromes as well. Almost one-third of cancer survivors experience chronic pain following curative treatment, and there are very few guidelines for the treatment of chronic pain syndromes following cancer survivorship.
Etiology and Pathogenesis
As previously stated, the majority of CRC cases occur sporadically with no known genetic predisposition. Sporadic carcinogenesis is secondary to progressive accumulation of genetic instabilities of the tumor suppressor genes and oncogenes. Tumors develop from polyps, which are generally benign in nature. Although most hyperplastic polyps are nonneoplastic lesions, adenomas and a subset of hyperplastic polyps called serrated adenomas are considered precursors for CRC. The majority of all CRCs are adenocarcinomas, although lesions can infrequently be mucinous adenocarcinomas, sarcomas, lymphomas, and carcinoid tumors. Most cases occur in the proximal colon (41%) and rectum (28%).
Tumor invasion into the bowel wall is seen with local disease. Direct invasion of neighboring organs occurs with more aggressive disease. Extension to the blood and lymphatic vessels leads to metastatic lesions, including involvement of the liver, lungs, bone, and brain. Patients with local disease expectedly have a better prognosis with a 5-year survival rate of roughly 90% compared to patients with metastases to distant organs, with a survival rate of 12.5%.
The prevalence of pain among patients with CRC is high, with reported rates of 64%–79%. , Tumor infiltration causes luminal distention of the intestinal wall and nearby viscera, releasing inflammatory markers and activating nociceptors. Compression or invasion of the peripheral and central nervous system may also lead to neuropathic pain syndromes. The small intestine and colon up to the splenic flexure receives parasympathetic innervation from the vagus nerve and sympathetic innervation from the greater (T5–T9) and lesser (T10–T11) thoracic splanchnic nerves. These nerves then synapse via the celiac and superior mesenteric plexuses. The gastrointestinal tract distal to the splenic flexure has sympathetic innervation from the lumbar splanchnic nerves (L1–L2) via the inferior mesenteric plexus.
Clinical Features
Patients with early-stage CRC are frequently asymptomatic and identified through screening.
Signs and symptoms of CRC are often due to tumor growth into the intestinal lumen or neighboring viscera, thereby indicating relatively advanced disease. The most common symptom is change in bowel habits. Large masses lead to narrow-caliber stools or even complete bowel obstruction, particularly if the tumor is located near the transition zone of the small and large bowels. Patients with rectal cancers often present with loose stools with sensations of inadequate evacuation. Colicky abdominal pain is common, which may be due to partial bowel obstruction or peritoneal disease. Patients can also have hematochezia or melena depending on the location of the tumor. Darker red stools (melena) suggest a more proximal source whereas bright-red rectal bleeding (hematochezia) indicates a distal source. Alternatively, many patients present with iron deficiency anemia from occult bleeding. Other general warning signs include fatigue, unintended weight loss, anorexia, nausea, and vomiting.
Patients with hepatic involvement can have right upper quadrant abdominal pain consistent with hepatic distention syndrome. Those with bone metastases may have deep, aching bony pain that is worse with movement and even pathologic fractures. Tumor infiltration into the posterior abdominal wall or peritoneum is experienced as epigastric or midback pain that is worse when lying down and improved when sitting up.
As previously mentioned, many patients who are successfully treated with their disease experience chronic pain syndromes as a sequelae. Chemotherapy-induced peripheral neuropathy (CIPN) secondary to demyelination or axonal injury from exposure to platinum (i.e., oxaliplatin) and taxane (docetaxel) based compounds are known to cause numbness and dysesthesias in the lower extremities in a “stocking-glove” distribution. Other potential neurologic deficits include weakness and ataxias.
Radiation therapy also causes axonal nerve injury and tissue ischemia. Although recent advancements in conformal radiation therapy have been able to reduce the amount of exposure to normal tissue, injury to the lumbosacral plexus during abdominal radiation can present as neuropathic pain and weakness of the lower extremities. Radiation-induced enteropathy also presents as chronic abdominal pain, bowel obstruction, and malabsorption. These symptoms may not appear for years after the last radiation treatment.
Postsurgical pain is common and often a result of cutaneous nerve entrapment at the lateral border of the rectus abdominis muscle. Patients classically present with very localized anterior abdominal wall pain that is exacerbated with Valsalva maneuvers (Carnett’s sign). Iatrogenic injury to other peripheral nerves may also occur during surgery and repeated procedures lead to the formation of intraabdominal adhesions and bowel obstruction.
Diagnosis
When CRC is suspected, colonoscopy is a versatile diagnostic tool and the gold standard for identifying lesions through direct visualization. Biopsies may also be taken and polyps can be removed during the same procedure.
Computed tomography (CT) colonography, also known as virtual colonoscopy, utilizes cross-sectional CT images to produce three-dimensional views of the interior of the colon to simulate the views that might be obtained with traditional colonoscopy. Ingestible capsule endoscopy also allows direct visualization of the colon. Equipped with a miniature video camera and the ability to take images as the capsule passes through the gastrointestinal tract, capsule endoscopy has been approved in the United States by the Food and Drug Administration (FDA) for patients who have had an incomplete colonoscopy.
When a diagnosis of CRC has been confirmed, additional imaging modalities are used for clinical staging. CT imaging of the chest, abdomen, and pelvis is obtained for surgical planning before resection surgery. Magnetic resonance imaging may also be used to identify hepatic lesions if liver metastases are suspected given its superior sensitivity compared to CT. Positron emission tomography-CT is another imaging modality that assesses distant and occult disease; this is utilized when assessing for recurrent disease and is rarely used at the time of initial diagnosis.
Laboratory testing of serum markers, such as carcinoembryonic antigen (CEA), assesses tumor burden and monitors for recurrence after curative treatment. However, given that CEA levels are not always elevated at the time of diagnosis, it is not recommended as a screening or staging tool.
The newest screening guidelines by the American Cancer Society recommends that individuals with an average risk of CRC should undergo regular screening starting at the age of 45 with either a stool-based test (i.e., guaiac-based fecal occult blood test or fecal immunochemical test) or visual exam (colonoscopy, flexible sigmoidoscopy).
Differential Diagnosis
Several nonmalignant syndromes present with similar symptoms as CRC. Patients with irritable bowel syndrome have recurrent abdominal discomfort with changes in stool frequency and consistency. Inflammatory bowel disease is also associated with weight loss, hematochezia/melena, abdominal discomfort, and changes in bowel consistency. It is important to note that the average age of onset for inflammatory bowel disease at 20–40 years is younger than with CRC. Other sources of rectal bleeding, such as hemorrhoids and diverticulosis, should also be ruled out.
Metastatic disease from other primary cancers also presents almost identically to CRC. Therefore, the primary source must be identified when there is suspicion for disseminated disease.
Physical Exam
A comprehensive physical exam should be completed with a focus on the abdominal and rectal exams. Although early-stage disease may not reveal exam findings, the advanced disease presents with the general appearance of pallor, jaundice, and lethargy. A physical exam can demonstrate abdominal tenderness, palpable abdominal or rectal masses, lymphadenopathy, hepatomegaly, ascites, and macroscopic rectal bleeding.
Treatment
Opioids
Opioid-based therapy is still considered the mainstay treatment for patients with moderate to severe CRC-related pain. The World Health Organization (WHO) analgesic ladder ( Fig. 13.1 ) is the conventionally accepted approach for opioid treatment. ,
Opioids are administered to patients with moderate-to-severe pain, with oral opioids being the most common route of delivery. Although morphine-based medications have traditionally been the most accepted agents, the recognition that individuals have varying responses to different μ-agonists has led practitioners to adopt opioid rotation to identify the most effective agent that minimizes side effects. , Therefore, while the WHO analgesic ladder generally recommends the use of weak opioids such as tramadol and codeine for moderate pain, stronger opioids such as oxycodone or morphine at lower doses should be considered as an alternative. There is no significant difference in the analgesic effect or tolerability of oxycodone compared to morphine for moderate-to-severe cancer pain.
For opioid-naive patients, immediate-release (IR) oral opioids are recommended for break-through pain . The dose should be carefully titrated if the patient endorses inadequate relief. The frequency of administration may also be adjusted if the patient complains of a short duration of relief. The general duration of action for immediate-release formulations is 4 h with some variation depending on renal and hepatic function. Fixed scheduled dosing of extended-release opioids should then be considered for patients with inadequate control with as needed (PRN) usage of IR formulations. This provides maintenance relief while allowing for PRN doses for breakthrough pain. If a patient is unable to tolerate oral medications and a long-acting opioid is desired, then transdermal fentanyl should be considered. Other routes of rapid fentanyl delivery for breakthrough pain include transmucosal lozenge, sublingual tablet, and nasal spray.
If patients experience intolerable side effects or inadequate relief, the opioid rotation should be considered. In these cases, the equianalgesic dose of the new opioid should be reduced by 20%–30% to account for incomplete cross-tolerance. Attention to a patient’s neuropsychological function and tolerance to side effects is essential to provide individualized therapy.
Chronic opioid use in cancer survivors remains controversial. Survivors often experience psychosocial hardship, including depression and anxiety, which increases their risk for dependency and misuse. All attempts should be made to reduce opioid use while utilizing adjuvant medications and interventions when appropriate. When these alternative modalities have failed, the benefits and risks of continuing chronic opioids must be weighed. Should opioid use be deemed appropriate, use of a low dose regimen (<90 mg/day morphine equivalence) is recommended with close follow-up. If worsening pain is encountered, tumor relapse should be ruled out.
Nonopioid Analgesics
Nonopioid analgesics should be utilized when possible. Acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs) may be used alone or in conjunction with opioids. NSAIDs, which have antiinflammatory and antipyretic properties, are more efficacious for bone and inflammatory pains. The efficacy of NSAIDs with opioids is unclear, with some studies demonstrating benefit and others showing no additional efficacy compared to the use of NSAID or opioid alone. , The use of these medications may be limited due to their renal, gastrointestinal, hematological, and cardiac toxicity profiles.
Corticosteroids are commonly used in late-stage disease for anorexia, analgesia, and nausea. Bisphosphonates are also often given in conjunction with glucocorticoids, such as dexamethasone and prednisone, for malignant bone pain.
CIPN remains a debilitating problem for patients who receive chemotherapy. The overall incidence rate is estimated to be 38% in survivors, and the mainstay pharmacologic options include antidepressants and anticonvulsants. Duloxetine and venlafaxine, both serotonin and norepinephrine reuptake inhibitors, have been shown to be superior to placebo in treating CIPN. Tricyclic antidepressants (TCAs), such as amitriptyline and nortriptyline, are also used for treating neuropathic pain, though their efficacy for CIPN remains inconclusive. Gabapentinoids, such as gabapentin and pregabalin, are anticonvulsants used for treating nonmalignant neuropathic pain and should be considered as well. In fact, pregabalin has been shown to provide greater analgesia with significantly improved opioid-sparing effects compared to gabapentin and TCAs.
Intranasal ketamine may be considered to reduce oral opioid requirements or if patients do not tolerate opioids. The nares and sinus cavities have an abundant vascular supply, which allows for efficient systemic absorption. Additionally, intranasal delivery has greater bioavailability compared to oral delivery due to the absence of the first-pass metabolism. The data is limited to intranasal ketamine for cancer pain. Intranasal ketamine is typically made from a compound pharmacy with a specially prepared nasal spray to deliver a mist of atomized medication. Dosing can be used with 100 mg ketamine per ml, with 10 mg or 0.1 mL administered per puff, given 3–4 times per day.
Celiac Plexus Block, Neurolysis
The celiac plexus carries the afferent, parasympathetic, and sympathetic innervation of the upper abdominal viscera, including the ascending and transverse colon. It lies in the retroperitoneum on the anterolateral surface of the aorta at the level of the T12 and L1 vertebrae. Image-guided block and neurolysis of the celiac plexus is used to treat intractable abdominal pain from CRC of the ascending or transverse colon as well as metastatic disease to other abdominal viscera (i.e., liver).
Celiac plexus neurolysis may be performed with an anterior or posterior approach with fluoroscopic or CT-guided imaging. Posterior approaches are performed with the patient lying prone, most commonly utilizing the antecrural or retrocrural techniques, which refers to the site of injection. The antecrural and retrocrural sites are the spaces anterior and posterior, respectively, to the crura of the diaphragm. The antecrural approach is effective for targeting the celiac plexus while the retrocrural approach targets the splanchnic nerves.
When performing the posterior retrocrural technique under fluoroscopy, the needle is inserted at the level of the L1 transverse process and advanced until the tip is just past the anterior surface of the T12–L1 vertebral bodies. For the antecrural technique, a single needle is inserted using a left posterior paramedian approach and advanced through the posterior and anterior walls of the aorta to get access to the plexus ( Fig. 13.2 ). The use of CT has become increasingly popular as well because of the ability to visualize the retroperitoneal anatomy and spread of the neurolytic agent. The bilateral posterior antecrural approach ( Fig. 13.3 ) is the most commonly performed technique for CT-guided neurolysis.
