Gastric Cancer Pain

Introduction

Gastric cancers are organized based on histologic morphology, with the adenocarcinoma subtype being the most common. Gastric cancers also include gastrointestinal lymphomas. Interestingly, there is a dichotomous distribution of gastric cancer subtypes related to geography. As of 2019, an estimated 27,510 annual new cases and 11,140 annual deaths occur in the United States due to gastric cancers. In Asian countries, distal gastric cancers are more common, and in some countries like South Korea are prevalent enough to mandate screening programs. In the West, proximal tumors are more common and present later at more advanced stages.

Risk factors include H. pylori infection and associated chronic mucosal inflammation, pernicious anemia, smoking, genetic mutations in cell adhesion proteins, and diets high in salted or smoked foods. The pain associated with advanced gastric cancer is visceral in character and in the epigastric region, owing to the stomach’s location. It is often chronic and lifelong in the case of an advanced cancer diagnosis. In addition, due to the mechanical effects of the tumor, symptoms of obstruction can be seen including nausea, vomiting, early satiety, and preclusion of enteral feeding in severe cases. Medical management of gastric cancer pain is guided by the World Health Organization (WHO) pain ladder ( Fig. 12.1 ), which serves as a framework for the escalation of opioids. Consideration should be given to coexisting gastritis, and caution should be taken when considering the use of nonsteroidal antiinflammatory drugs (NSAIDs) for pain. For associated refractory chronic pain syndromes where the pain is poorly controlled with opioids and nonopioid adjuvants, celiac plexus blocks are often performed. Additionally, interventions such as spinal cord stimulators or intrathecal drug delivery systems or epidural devices can be used to reduce pain, improve function, and lower opioid consumption.

Etiology and Pathogenesis

The afferent nerve fibers of the gastrointestinal tract (GI) travel with sympathetic and parasympathetic nerve fibers via a complex collection of ganglia and plexuses en route to the spinal cord. These visceral nerve axons are almost completely comprised of unmyelinated C and thinly myelinated Aδ fibers. The stomach specifically receives its sympathetic innervation from the celiac plexus via the greater thoracic splanchnic nerves (T5–T9) and parasympathetic innervation from the anterior and posterior trunks of the vagus nerve. Sympathetic communication with the enteric nervous system can be bidirectional, suggesting the role of sympathetic plexus blockade on enteric nociception. The GI tract’s sensory innervation involves the mucosa, muscularis mucosa, and the serosa. Several nociceptors have been identified, including mechanoreceptors of varying thresholds, and silent nociceptors, which respond to chemical tissue insult and may be critical in the development of peripheral sensitization and the development of chronic visceral pain.

Biochemical messengers seen in elevated amounts in gastric neoplasms, including cancer-associated trypsins, have been implicated in the activation of primary afferent nociceptors. These species are important to the maintenance of the neoplastic cell matrix and have a secondary effect of inducing substance P and calcitonin gene-related protein from peripheral C fibers. In addition, these molecules can induce hyperalgesia to mechanical stimuli. ^, The inflammatory milieu seen in carcinomatous proliferation likely contributes to silent nociceptor-induced peripheral and central sensitization. As seen with many other cancer pain syndromes, perineural invasion of gastric cancers portends a poorer prognosis and is a significant source of neuropathic pain.

Thus, it is expected that gastric neoplasms, like many other enteric neoplasms, cause pain through visceral mechanical afferents, inflammatory-mediated pain and associated hyperalgesia, and sympathetically mediated mechanisms given the communication between the enteric nervous system and sympathetic plexuses. Unfortunately, sympathetically mediated pain remains a poorly understood topic in the realm of pain management, but the benefits of interventional sympathectomy in managing gastric cancer pain are apparent.

Clinical Features

The presentation of pain associated with gastric cancer depends on the individual patient’s tumor burden with respect to tumor size, perineural invasion, and the presence or absence of obstructive symptoms. The associated pain is generally visceral in nature and can result both from primary tumor burden and from metastatic disease. Mechanical stimuli, such as torsion or distension, stretching of serosal and mucosal surfaces, and compression of nearby nerve structures produce pain. Pain is often constant and epigastric due to the mechanical nociceptive stimulus from a fixed neoplastic mass. Breakthrough abdominal pain has also been characterized as a worsening of background visceral pain secondary to acute changes in visceral lumen distention, commonly observed with food intake. As with any visceral pain, the character is described as “deep,” “crampy,” and “gnawing,” among other terms. It is important to note that the severity of pain does not always reflect the severity of inciting cancer.

Visceral breakthrough pain is worsened by undertreatment or underoptimization of one’s antinociceptive regimen. In addition, visceral abdominal breakthrough pain is quite common, with a cited rate of 55% of patients experiencing breakthrough pain, even with well-controlled background pain. ^, Breakthrough pain may afflict patients several times per day, with episodes varying in both onset and duration.

Attention should also be given to pain induced by therapeutics as well. Chemotherapy agents including the microtubule inhibitors (docetaxel, paclitaxel) have been linked to myalgias, arthralgias, and neuropathic pain syndromes, as have other agents such as anthracyclines. Radiation therapy can cause mucosal irritation when applied to gastrointestinal organs and is a source of chronic enteropathy and neuropathy.

Diagnosis

Many of the signs and symptoms of gastric malignancy are indolent or mimic other less serious pathologies. Typically, patients remain asymptomatic until they develop more advanced disease, often experiencing weight loss, anorexia, nausea, early satiety, and dysphagia. As often seen with the hypercoagulable state of other malignancies, migratory phlebitis (Trousseau’s syndrome) can also be seen. Occult upper GI bleeding may accompany symptoms. Pain, if even present during the early stages of the disease, is typically epigastric, vague, and mild early in the disease course. Diagnosis is made definitively with upper endoscopy and tissue biopsies with adjunct barium contrast imaging. When the diagnosis of a gastric malignancy is confirmed, computed tomography (CT) imaging and positron emission tomography (PET) CT are frequently utilized for staging and to assess for distant metastatic disease. Genetic screening is also useful in cases of familial subtypes of gastric cancer.

Differential Diagnosis

Many of the symptoms of gastric cancer are both vague and indolent, and are seen in other GI pathologies including acute gastritis, peptic ulcer disease, atrophic gastritis, gastroenteritis, esophagitis, and esophageal cancer. In addition, many of these conditions can mimic the endoscopic appearance of gastric cancer and are excluded after biopsy. Other primary GI malignancies, such as pancreatic cancer and colorectal cancer, can also present with similar symptomatology and should be considered.

Physical Exam Findings

Physical exam is usually unrevealing except in cases of advanced disease. Melena, especially in combination with anemia or weight loss, should raise one’s clinical suspicion for neoplasm. Physical palpation of an abdominal mass is occasionally seen, as are signs of lymph nodal spread (Virchow node), or from paraneoplastic syndromes including acanthosis nigricans and diffuse seborrheic keratoses.

Treatment

As one could expect in the treatment of any malignancy pain syndrome, the psychological aspects of a gastric cancer diagnosis interplay with a patient’s management and expectations of his or her pain. As our understanding of the precise mechanisms and development of chronic visceral pain improve, novel pharmacologic agents and their mechanisms remain a topic of significant interest. The optimal treatment of chronic gastric cancer pain involves multimodal pharmacologic therapy including opioid and nonopioid adjuvants and the use of more invasive interventions when appropriate.

Many different agents have been used to treat chronic abdominal visceral pain. However, given the often advanced and terminal nature of many gastric cancer diagnoses, opioids remain the staple pharmacologic choice. Other nonopioid options include NSAIDs, acetaminophen, and neuropathic agents. ^, ^,

Nonopioid Analgesics

Acetaminophen is a nonopioid analgesic that can be dosed 325–1000 mg by mouth every 4–6 h as needed, up to a maximum of 4000 mg/day. Care should be taken not to exceed this maximum dose due to the risk of hepatotoxicity. Acetaminophen is a common first step analgesic for mild-to-moderate pain and is almost universally tolerated.

NSAIDs are part of the WHO approach to cancer-pain management and are a staple in the management of both acute and chronic pain. In patients with gastric cancer, the use of NSAIDs may be complicated by the exacerbation of comorbid gastritis, chronic GI bleeding, or ulcerative disease. Individual clinical judgment should be taken regarding the use of chronic NSAID therapy in these patients, including the consideration of patients’ renal function. Examples of nonselective cyclooxygenase (COX) inhibitors include ibuprofen, naproxen, indomethacin, and ketorolac. These agents have a ceiling effect that limits their utility in controlling cancer pain. COX-2 inhibitors remain an option due to their improved safety profile with regard to GI side effects and thus make them better options for GI cancer pain. Examples include rofecoxib and celecoxib. Celecoxib can be started typically at 200 mg by mouth, twice daily.

Adjuvant analgesics have varying degrees of data supporting their use for chronic cancer pain. These agents include antidepressants, muscle relaxants, antiepileptics, and steroids. They have several advantages including reducing the opioid burden and addressing pain less amenable to opioid pharmacotherapy.

Tricyclic antidepressants (TCAs) can be effective in the treatment of neuropathic pain. Cancer pain syndromes often have neuropathic components due to neural invasion. Although TCAs have been less rigorously studied in the treatment of chronic cancer pain, small studies and clinical experiences have shown them to be beneficial. Common agents include amitriptyline, nortriptyline, and desipramine, which can be started at 10–25 mg, by mouth, nightly. Care should be taken with the significant side effects of cardiotoxicity and anticholinergic effects.

Other antidepressants, including selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, have less rigorous data supporting their use in neuropathic and cancer pain syndromes but can be considered in the holistic treatment of the cancer patient with psychiatric comorbidities. ^,

Low dose steroids can be used for the pain caused by GI tract distention from gastric cancer, and a typical regimen is dexamethasone, 2–4 mg orally, once or twice daily. Adverse effects including mood disturbances, cushingoid changes, fluid retention, and immunosuppression should be weighed against the benefits, which can include a reduction in nausea and improved appetite.

Ketamine administered by monitored intravenous (IV) infusion is effective for allaying cancer pain. ^, This is a medical approach to refractory pain, and if administered under regularly scheduled intervals, can reduce basal opioid requirements for patients. Ketamine has been given IV or through 3–5-day continuous intramuscular infusions of 100–500 mg/24 h in monitored palliative care units, and has been shown to reduce opioid requirements and baseline pain scores. Chung and Pharo showed that IV ketamine at 0.2–0.65 mg/kg/h for 30 days in a palliative home care setting resulted in significant improvements in pain with concurrent opioid-sparing effects. Care should be taken to note side effects including hallucinations or dysphoria, nausea, and vomiting, and an increase in oral secretions.

As an outpatient, intranasal ketamine can be considered to reduce oral opioid requirements. The nares and sinus cavities have increased vascular supple and great absorption. In addition, the intranasal route has greater bioavailability compared to the oral route due to the absence of the first-pass metabolism. The data is limited to intranasal ketamine for cancer pain. Intranasal ketamine will have to be 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 with three times per day or four times per day.

Opioids

Opioids are still considered the mainstay treatment for chronic malignant visceral pain, and the WHO analgesic ladder ( Fig. 12.1 ) is the conventionally accepted approach for opioid treatment. Although they carry many adverse effects, opioids are effective if the appropriate regimen is tailored to the individual patient. There is no evidence to suggest the therapeutic superiority of one opioid over another for cancer pain ; therefore, given that individuals may have varying responses to different μ-agonists, the opioid rotation should be considered to identify the most effective agent. Sustained-release formulations should be used when appropriate for patients with inadequate pain control with as needed usage of immediate-release (IR) formulations. If oral medications are not well-tolerated and long-acting agents are needed, transdermal fentanyl should be considered.

Less emphasized side effects of chronic opioid use include impairments to fertility and libido, and immunosuppression. ^, Doses of commonly used agents are shown in Table 12.1 , and both extended-release and immediate-release formulations should be appropriately tailored to the individual patient to provide basal and breakthrough pain relief. ^,

Table 12.1

Commonly Used Opioids for the Treatment of Gastric Cancer Pain.

Medication	Initial Dosing	Comments
Codeine	15–60 mg every 4–6 h	CYP2D6 metabolism. Not recommended in renal failure.
Tramadol	50–100 mg every 4–6 h	Weak inhibitor of norepinephrine and serotonin reuptake
Hydrocodone	5–10 mg every 4–6 h,	Combined with 300–325 mg acetaminophen depending on formulation
Morphine	15–30 mg every 4–6 h	Available in immediate-release tablet, suppository, oral liquid, IV, and subcutaneous use Metabolites morphine-3 and morphine-6-gluconoride may accumulate in renal failure and alter reliable kinetics
Oxycodone	5–15 mg every 4–6 h	Available in combination with acetaminophen or standalone
Methadone	2–5 mg every 8 h	Unpredictable half-life requires patient individualization in titration. QTc prolonging. NMDA antagonism confers multifactorial analgesia and theoretical protection against opioid-induced hyperalgesia. Relatively safe in renal failure.
Hydromorphone	2–4 mg every 4–6 h	Safer than morphine in renal insufficiency.
Buprenorphine	Buccal film: 75 mcg daily Transdermal patch: 5 mcg/h	Partial mu agonism confers the analgesic ceiling effect. Limited experience in cancer pain.
Fentanyl	Individualized based on daily morphine consumption, mostly used in cancer pain in transdermal formulations. Transdermal fentanyl dose typically starts at 12–25 mcg/h	Intranasal formulations, buccal, and sublingual tablets and lozenges exist for breakthrough cancer pain. Safe for use in renal failure.