Gastrointestinal malignancies are the most commonly diagnosed cancers in the world. Before any management decisions are made with this patient population, it is critical to understand the patient’s expected overall survival ( Table 29-1 ), potential further antineoplastic therapy that may be available, the amazing variability of each tumor’s biology, and how all these features and other factors result in the intent of the therapy (curative vs. palliative or something in between). Care must be individualized to the patient and not to the statistics. For example, it is possible to find a patient with metastatic pancreatic cancer alive years after the diagnosis or, alternatively, a patient with metastatic neuroendocrine tumor who only survives months after their diagnosis despite aggressive chemotherapy.
| Cancer | Median Overall Survival for Advanced Disease (with Treatment) |
|---|---|
| Gastric | 8–10 months |
| Neuroendocrine | >5 years |
| Hepatocellular | 6–8 months |
| Pancreatic | 6 months |
| Colorectal | 2+ years |
| Esophageal | 8–10 months |
Because patients’ symptoms vary widely and are often exacerbated by tumor-directed therapy as well as disease progression, those caring for patients with gastrointestinal malignancies must be cognizant of each malignancy’s and each treatment’s unique manifestations and their effect on the patient’s quality of life. This chapter provides approaches to palliative management, including antineoplastic therapy, of patients with various advanced gastrointestinal cancers. The National Collaborative Cancer Network (NCCN), listed in Resources at the end of this chapter, provides more detailed information about each malignancy discussed.
Gastric Cancer
Background
Gastric cancer remains one of the most common forms of cancer worldwide, as well as one of the most deadly. In the United States, patients present more than half the time with symptoms of weight loss, abdominal pain, and dysphagia but unfortunately the majority of patients have disease too advanced to receive curative therapy. Cancers that affect the gastroesophageal junction (GEJ) are included in this classification. Histologically, squamous cell carcinoma is felt to be more chemosensitive and radiosensitive than adenocarcinoma. In recent years, there has been a rapid rise in GEJ adenocarcinoma.
Role of Chemotherapy
Chemotherapy has a definitive role in the palliative care of advanced gastric cancer patients with a good performance status. In patients with metastatic disease, chemotherapy regimens not only offer a doubling of survival (3–4 months vs. 8–9 months) compared with best supportive care but also appears to delay the time to deterioration of functional status and quality of life.
Common Palliative Care Issues
Abdominal pain in this population could be caused by peritoneal carcinomatosis (even if there is no evidence of it on imaging) and/or gastric distention, called malignant gastroparesis. Pain associated with increased hiccups, early satiety, and relieved by vomiting occurs with and may be the first suggestion of malignant gastroparesis. Peritoneal carcinomatosis pain tends to respond to anti-inflammatory agents, including steroids (e.g., Decadron 4–16 mg PO/IV every morning) or nonsteroidal anti-inflammatory drugs (NSAIDs), either alone or given as an adjuvant to opioids. Mechanical relief of malignant gastroparesis can be achieved with prokinetic therapy aimed at improving dysfunctional gastric motility. Metoclopramide (Reglan), a dopamine antagonist that sensitizes gastric tissue to the effects of acetylcholine, at doses of 5 to 20 mg PO/IV every 6 hours around the clock, improved pain, nausea, and vomiting, reduced the use of other antiemetics, and even led to weight gain compared with placebo. In addition, erythromycin stimulates motilin receptors at a dose of 150 to 250 mg PO every 8 hours and has been shown to be as effective as Reglan.
Radiation therapy should be considered in patients who present with bleeding that is refractory and significant; dysphagia (usually GEJ cancers); or pain that is refractory to systemic management. An option for relieving dysphagia in patients who are not good radiation candidates is the placement of an esophageal self-expanding metallic stent (SEMS). These stents give almost immediate relief of dysphagia in 86% to 100% of patients, leading to improved quality-of-life scores. Generally, smaller diameter stents are favored, despite an increased need for further intervention as a result of stent migration or recurrent or refractory dysphagia when compared with larger diameter stents (42% vs. 13%), because of the increased risk of hemorrhage (2%–14%), perforation (2%–6%), fistula, and chest pain (15%–27%) with the larger stents. Stents that cross the GEJ have a 30% chance of causing gastroesophageal reflux symptoms; if this occurs, consideration of a proton pump inhibitor would be warranted. Endoscopic stent placement should be done by an experienced interventional gastroenterologist.
At select centers, two other options exist for patients who have a recurrence of cancer after radiation therapy (and are unable to safely get more) or who are unable to tolerate radiotherapy: neodymium yttrium aluminum garnet (Nd : YAG) laser therapy, ideal for accurate and localized coagulation, and photodynamic therapy. Photodynamic therapy (PDT) uses an intravenous photosensitizer (called porfimer in the United States) and an endoscopic nonthermal laser for ablation. In a prospective, randomized controlled trial of these two therapies in 236 patients, although they were of similar efficacies for relieving dysphagia, PDT worked better for larger lesions (>8 cm) and for lesions in the upper and mid-esophagus and was better tolerated (termination of treatment 3% for PDT and 19% for Nd : YAG).
Gastric outlet obstruction can also occur in this population if the malignancy involves the distal portion of the stomach. This tends to cause almost immediate postprandial vomiting, but symptoms can be quite similar to malignant gastroparesis. Options for treating this symptom include creation of a gastrojejunostomy, placement of a SEMS, or placement of a venting gastrostomy tube, which is similar to a feeding gastrostomy tube but used solely to decompress the stomach. A recent systemic review of the literature comparing gastrojejunostomy with SEMS revealed similar success and complication rates; however, although gastrojejunostomy yielded fewer recurrent obstructive symptoms compared with SEMS (1% vs. 18%), it was associated with a longer hospital stay (164 days vs. 105 days). SEMS may be best for patients with shorter life expectancies, but gastrojejunostomy may be best for patients with longer life expectancies if they are able to tolerate this procedure. Venting gastrostomy tubes should be considered for patients not amenable to SEMS placement, but caution should be taken if there is a large burden of ascites or peritoneal carcinomatosis, which increases the potential technical difficulty of the procedure. Because of the availability of SEMS, gastrojejunostomy, and venting gastrostomy tubes to relieve symptoms, partial gastrectomy procedures for patients with metastatic disease should only be performed by the surgeon on a case-by-case basis.
Neuroendocrine Tumors
Background
Carcinoid tumors are the most common neuroendocrine tumors of the gastrointestinal tract, but they are quite rare in terms of overall gastrointestinal malignancies. Carcinoid tumors are generally well differentiated and therefore are comparatively less aggressive than small-bowel adenocarcinomas. In patients with metastatic disease, a 70% 5-year survival rate has been reported. Approximately 90% of patients presenting with symptomatic carcinoid tumors have advanced disease with liver metastases, even though some patients will have normal imaging. It is also worth noting that islet cell carcinoma falls in the category of neuroendocrine tumors; even though it does not produce carcinoid syndrome, it can secrete a hormone that causes symptoms such as excessive insulin.
Role of Chemotherapy
The first-line therapy in malignant, metastatic neuroendocrine tumors is a somatostatin analogue, which acts by specifically binding to the somatostatin receptors commonly expressed on these tumors. These receptors can be measured using an imaging study called an OctreoScan, which can be helpful in determining the utility of a somatostatin analogue in these patients. Although historically this therapy was used almost exclusively in patients with carcinoid syndrome and was purely for symptom management, recently it has been recognized that using octreotide, a somatostatin analogue, in all patients with advanced neuroendocrine tumors may delay progression of disease by more than a year. If somatostatin analogues fail to control the disease, other options include the addition of interferon, traditional chemotherapy agents, and new agents that target cell signaling pathways.
Common Palliative Care Issues
Carcinoid syndrome is a collection of symptoms that results from secretion of excessive serotonin and other biologically active amines and generally is a consequence of metastatic disease that involves the liver. The syndrome is often associated with flushing, diarrhea, abdominal cramping, wheezing, fatigue, and heart disease as a result of carcinoid infiltration, and the syndrome can significantly impact a patient’s quality of life. Carcinoid syndrome can be significantly improved with initiation of somatostatin analogue therapy, usually octreotide long-acting release (LAR) 20 to 40 mg subcutaneously every 2 to 4 weeks. In approximately 50% of patients, treatment with this single agent provides a response duration ranging from 3 to 60 months. In refractory carcinoid syndrome, octreotide continuous infusion pump or other somatostatin analogues can be considered, as well as more aggressive therapy, including chemotherapy and targeted agents (noted in the previous section) and liver-directed therapies as listed next.
An emerging strategy for maintaining disease control and improving symptoms associated with neuroendocrine tumors has been liver-directed therapy. This can be with transarterial chemoembolization (TACE), which involves infusing chemotherapy and embolizing material locally to the tumor via the hepatic arterial system, or radioactive beads infused via the hepatic arterial system.
Causes of abdominal pain secondary to neuroendocrine tumors that should be considered include stretching or irritation of the hepatic capsule, mesenteric ischemia from compression of vessels with mesenteric masses or lymph nodes, and bowel obstruction. Stretch or irritation of the hepatic capsule responds well to anti-inflammatory management with NSAIDs or steroids (e.g., Decadron 4–16 mg IV/PO every morning). Because of the relatively lengthy survival of most patients with neuroendocrine tumors, if pain from vascular compromise or bowel obstruction is amenable to surgical intervention, this should be strongly considered.
Hepatocellular Carcinoma
Background
Hepatocellular carcinoma is the leading cause of cancer death worldwide, with a median overall survival of around 8 months. The main risk factor for the development of hepatocellular carcinoma remains hepatocellular injury resulting from chronic liver disease or cirrhosis. Caring for these patients can be challenging for several reasons, including potential underlying substance abuse issues (which may have been the reason for their chronic liver disease), morbidity associated with their underlying liver disease, and altered clearance of medications, including opioids. The current mainstay of therapy for cure is surgery (resection or liver transplant), or loco-regional control can be achieved with percutaneous ablation, transarterial chemoembolization, or radioactive beads. However, only about 30% to 40% of patients present at an early enough stage to consider these techniques.
Role of Chemotherapy
Traditional chemotherapy has not been effective in advanced hepatocellular carcinoma, but recently a targeted molecular agent, sorafenib, has been shown to improve survival by a median of 3 months for those with good liver function (e.g., those with a Child-Pugh score of class A). No quality-of-life assessments were performed, but about 37% of patients discontinued sorafenib because of adverse effects, and the most common symptoms of any grade were diarrhea (55%), hand-foot syndrome (21%), rash (19%), and weight loss. Palliative clinicians caring for patients receiving this therapy should pay attention to these side effects and discuss potential dose modifications or other supportive care with the oncologist.
Common Palliative Care Issues
A retrospective study of 991 patients with hepatocellular carcinoma in a hospital-based hospice ward in Taiwan demonstrated that the most common symptoms at admission were pain, fatigue, weakness, anorexia or vomiting, peripheral edema, cachexia, and ascites. Pain is likely to be from stretching or irritation of the hepatic capsule but can also result from bulky retroperitoneal adenopathy that causes stretching of the retroperitoneal cavity. Therefore, treatment with potent anti-inflammatory medications (e.g., steroids and/or NSAIDs) is appropriate before the addition to an opioid to limit adverse effects from the latter. However, because of the thrombocytopenia in this population and high rate of potential bleeding varices, caution should be taken with use of NSAIDs.
Caution should also be used with opioid administration because of liver dysfunction and potential decreased clearance, as well as the potential for renal dysfunction from hepatorenal syndrome. Generally, start with lower doses and titrate slowly. In patients with decompensated liver failure, avoid using long-acting formulations (including transdermal patches) and use immediate-release preparations as needed until the steady-state dynamics are evident. Opioids metabolized by glucuronidation (e.g., morphine, hydromorphone) are preferred to those metabolized by the cytochrome P450 (CYP) system (e.g., fentanyl, methadone, oxycodone) in patients with liver dysfunction because the half-life is more predictably related to liver function measured by bilirubin, prothrombin time, albumin, presence of ascites, or encephalopathy. Monitor for neurotoxicity from the opioids and opioid byproducts, especially from glucuronidated byproducts of morphine and hydromorphone, which can be exacerbated by renal failure, leading to myoclonus, confusion, sedation, and even seizure. See Table 29-2 for a summary of opioid metabolism, as well as recommendations for dosing.
| Opioid | Liver Metabolism | Ascites Accumulation | Renally Cleared | Dosing Recommendation in Liver Failure |
|---|---|---|---|---|
| Morphine | Glucuronidation | Yes | Yes | Lower starting doses and dosing intervals (q6–8h) |
| Hydromorphone | Glucuronidation | Yes | Yes | Lower starting doses and dosing intervals (q6–8h) |
| Fentanyl | CYP system | No | Yes | Avoid long-acting transdermal preparation |
| Methadone | CYP system | No | Minor | Hepatitis C virus increases clearance |
| Oxycodone | CYP system | Yes | Yes | Immediate release same half-life as sustained release formulation |
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