Palliative options in advanced pancreatic cancer

E. Osman
Moderator Dr. A. De Beer Palliative cares goal is to relieve suffering and improve quality of life in the context of an individuals family and society. The Three pillars of palliative care are: 1. Pain and non-pain symptoms management 2. Communication between patients, families and care providers 3. Continuity of care across a range of clinical settings and services. The indications for palliative care are based on the need for these services, not prognosis. The modern hospice movement was pioneered by Dame Cicely Saunders who demonstrated that quality of life of terminally ill patients could be improved significantly with scheduled morphine administration. Balfour Mount a surgeon introduced the term palliative care and surgeons were among his earliest and steady referrers. In an increasingly aging population 28% of all medical care costs are incurred in the last 2 years of life; half of this is spent during the last 2 months of life. The study to understand prognosis and preference for outcomes and risks of treatment (support) showed that seriously ill hospitalized patients in the last 6 months of life, in addition to never getting better, frequently were undertreated for pain and their preferences for care often were unknown or even ignored. Palliative care and the surgical institution The first endorsement of the concept of palliative care was by the American college of surgeons (ACS) 1998 in its statement of principles guiding care at end of life. In 2003 the (ACS) published the ACS code of professional conduct. They wrote, We singled out terminally ill patients as worthy of specific mention. Most surgeons are uncomfortable with death; it is an outcome that might be equated with defeat. Many surgeons are also uncomfortable with the transition from curative to palliative care. The American board of surgery included palliative care as one of the domains in which a certified surgeon must acquire knowledge and experience. The royal college has similar expectations for those sitting for its qualifying exams. A survey of oncologic surgeons showed that palliative surgery is a significant part of practice, 21% of operations were described as palliative. Thomas Russell executive director of the ACS pointed out No longer it is my patient, but it is our patient. this shared responsibility for surgical patient has positive application in the interdisciplinary model of palliative care.

Background: In the United States, approximately 30,000 people die of pancreatic cancer each year. Among cancers of the gastrointestinal tract, it is the third most common malignancy and the fifth leading cause of cancer-related mortality. The disease is difficult to diagnose in its early stages, and most patients have incurable disease by the time they present with symptoms. The overall 5-year survival rate for this disease is less than 5%. Approximately 75% of all pancreatic carcinomas occur within the head or neck of the pancreas, 15-20% occurs in the body of the pancreas, and 5-10% occurs in the tail. Typically, pancreatic cancer first metastasizes to regional lymph nodes, then to the liver, and less commonly, to the

lungs. It can also directly invades surrounding visceral organs such as the duodenum, stomach, and colon.

The highest incidence rate is approximately 13 cases per 100,000 persons per year in black males in the United States. While the incidence in India is less than 2 cases per 100,000 persons per year. The median age at diagnosis is 69 years in whites and 65 years in blacks.

The male-to-female ratio for pancreatic cancer is 1.2-1.5:1. Causes: Overall, estimates indicate that 40% of pancreatic cancer cases are sporadic in nature. Another 30% are related to smoking, and 20% are associated with dietary factors. Only 5-10% is hereditary in nature. Fewer than 5% of all pancreatic cancers are related to underlying chronic pancreatitis. Mortality/Morbidity:

Pancreatic carcinoma is usually a fatal disease. Most patients eventually succumb to the consequences of local invasion and metastatic cancer, and true long-term cures are rare. Overall, fewer than 5% of all patients are still alive 5 years after initial diagnosis. The collective median survival time of all patients is 4-6 months. In patients able to undergo a successful curative resection (only 20% of patients), median survival time ranges from 12-19 months, and the 5-year survival rate is 15-20%.

History: The early clinical diagnosis of pancreatic cancer is fraught with difficulty. Unfortunately, the initial symptoms are often quite nonspecific and subtle in onset.

Patients typically report the gradual onset of nonspecific symptoms such as anorexia, malaise, nausea, fatigue, and midepigastric or back pain, and significant weight loss Pain is the most common presenting symptom in patients with pancreatic cancer. Typically, it is midepigastric in location, with radiation of the pain sometimes occurring to the mid- or lower-back region. Back radiation of the pain is a worrisome sign indicating retroperitoneal invasion of the splanchnic nerve plexus by the tumor. The most characteristic sign of pancreatic carcinoma of the head of the pancreas is painless obstructive jaundice. Depression is reported to be more common in patients with pancreatic cancer than in patients with other abdominal tumors.

Migratory thrombophlebitis (i.e., Trousseau sign) and venous thrombosis also occur with higher frequency in patients with pancreatic cancer. Lab Studies:

General laboratory studies

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The laboratory findings in patients with pancreatic cancer are usually nonspecific. As with many chronic diseases, a mild normochromic anemia as well asThrombocytosis Patients presenting with obstructive jaundice show significant elevations in bilirubin and obstructive enzymes. Interestingly, amylase and lipase are infrequently elevated in pancreatic carcinoma unless the patient is presenting with acute pancreatitis secondary to the pancreatic cancer. Only 5% of patients with pancreatic cancer initially present with an episode of pancreatitis. Liver metastases alone do not usually cause jaundice and usually result in relatively low-grade elevations of alkaline phosphatase and transaminase levels.

Tumor markers
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The major useful tumor marker for pancreatic carcinoma is carbohydrate antigen 19-9 (CA 19-9). The reference range of CA 19-9 is less than 33-37 U/mL. , a CA 19-9 value greater than 100 U/mL is highly specific for malignancy, usually pancreatic. Elevation of CA 19-9 levels has been used as an adjunct to imaging studies for helping determine the resectability potential of pancreatic carcinoma. Fewer than 4% of patients with a CA 19-9 level of more than 300 U/mL have been found to have resectable tumors. imaging

Considerations in the choice of diagnostic modality include the accuracy of the imaging procedure for providing staging information, its ability to simultaneously obtain tissue for a biopsy, and its capacity to facilitate therapeutic procedures such as biliary stent placement or celiac neurolysis.

CT scanning
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CT scanning is usually the mainstay of initial diagnostic modalities used for assessing patients suspected to have pancreatic carcinoma.

Newer models using spiral (ie, helical) CT scanning with multiple detectors and dual-phase contrast enhancement have significantly improved the sensitivity and specificity of abdominal CT findings in patients with pancreatic carcinoma. Dual-phase spiral CT findings are approximately 80% accurate for helping determine the resectability potential of pancreatic carcinoma. However, small tumors can still be missed even with the most advanced CT scanning currently available. CT scanning can be used to direct fine-needle aspiration of pancreatic masses.

Caption: Picture 4. Pancreatic cancer. Computerized tomographic scan showing a pancreatic adenocarcinoma of the pancreatic head. The gallbladder (gb) is distended because of biliary obstruction. The superior mesenteric artery (sma) is surrounded by tumor, making this an unresectable T4 lesion.

Ultrasonography Sonar has less utility in pancreatic carcinoma than CT scanning because the pancreas is often obscured by overlying gas.
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Sonar is very useful as an initial screening test in evaluating patients who present with possible obstructive jaundice.

Endoscopic ultrasonography
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EUS has proven to be the most sensitive and specific diagnostic test for pancreatic cancer. In numerous series, EUS has detection rates of 99-100% for all pancreatic carcinomas, including those smaller than 3 cm. EUS is as accurate as ERCP or MRCP for assessing the etiology of obstructive jaundice. An diagnostic advantage is EUS-guided fine-needle aspiration, which allows for the simultaneous cytologic confirmation of pancreatic carcinoma at the time of EUS diagnosis. EUS appears to be equivalent to dual-phase spiral CT scanning for assessing tumor resectability potential.

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EUS showing 2.2cmpancreatic cancerobstructing the CBD and not invading the SMV or portal vein.CT scan failed to detect this lesion.

Endoscopic retrograde cholangiopancreatography

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Of patients with pancreatic adenocarcinoma, 90-95% have abnormalities on ERCP findings. However, the changes observed on ERCP are not always highly specific for pancreatic carcinoma and can be difficult to differentiate from changes observed in patients with chronic pancreatitis. ERCP is highly invasive with 5-10% risk of significant complications with the procedure. Brush cytology and forceps biopsy at the time of ERCP have been used to diagnose pancreatic carcinoma histologically; however, in most series, the yield has been less than 50%. ERCP findings provide only limited staging information, but ERCP does have the advantage of allowing for therapeutic palliation of obstructive jaundice with either a plastic or metal biliary stent.

Magnetic resonance imaging

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The role of MRI in pancreatic cancer has been less well studied than the role of CT scanning. It does not appear to be superior to spiral CT scanning.

Positron emission tomography scanning

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PET scanning can be especially useful in looking for occult metastatic disease. Its role in pancreatic cancer evaluation management is still under investigation. False-positive PET scans have been reported in pancreatitis.

Other Tests:

Needle aspiration

The necessity of obtaining a cytologic or tissue diagnosis of pancreatic cancer prior to operation remains controversial. Some centres advocate the practice of aggressively operating on all patients thought to have pancreatic cancer and argue against a preoperative tissue diagnosis. The contention in these centres is that negative findings after preoperative fine-needle aspiration may just be sampling error and, thus, should not stop a pancreaticoduodenectomy if a potentially resectable pancreatic neoplasm is strongly suggested based on preoperative testing. Additionally, preoperative attempts at fine-needle aspiration or biopsy of the pancreas might contaminate the peritoneum with tumor cells. Other surgeons are hesitant to operate on patients without a positive tissue or cytologic diagnosis of cancer. Additionally, tissue diagnosis is almost always required prior to initiation of chemotherapy, radiation therapy (whether palliative or neoadjuvant), or nonoperative palliation of obstructive jaundice using permanent metallic stents. Studies of the risk of peritoneal contamination with CT-guided biopsy have suggested that this risk is actually very low. Additionally, the histology of a pancreatic tumor can change the surgical approach to the tumor. For example, a pancreatic lymphoma should be treated medically rather than with operative resection. Using EUS-guided fine-needle aspirations, a cytologic diagnosis can be made in 85-95% of patients. A recent study has also suggested that transcutaneous aspiration may be associated with a higher risk of peritoneal tumor spread than aspiration with EUS. Thus, for potentially resectable tumors, EUS-guided fine-needle aspiration is the preferred biopsy technique, if it is available and if a biopsy needs to be obtained. The yield of CT-guided fine-needle aspiration or biopsy findings is approximately 50-85% in the lesions that are visible on CT scanning.

Staging laparoscopy or laparotomy

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Some centers advocate performing a staging laparoscopy or laparotomy before proceeding to attempted resection. A few centers also advocate performing intraoperative laparoscopic ultrasonography to help further assess the tumor stage and to look for occult metastases. Using this approach, a significant number of patients are found to have previously unsuspected peritoneal or liver metastases. The operations avoided by staging laparoscopy largely depend on how aggressively and accurately the patient was staged preoperatively.

Staging: Once an imaging modality has helped establish a probable diagnosis of pancreatic cancer, the next issue is whether the lesion is amenable to surgical resection.

Only 20% of all patients presenting with pancreatic cancer are ultimately found to have easily resectable tumors with no evidence of local advancement. No survival benefit is achieved for patients undergoing noncurative resections for pancreatic carcinoma. Thus, to avoid operating on patients who cannot benefit from the operation, accurate preoperative staging is essential. Pancreatic ca is classified by the (TNM) staging system. This staging has recently been modified by the American Joint Committee on Cancer (AJCC).

Staging of pancreatic tumors is as follows (AJCC, 2002):

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Tumor (T) TX - Primary tumor cannot be assessed T0 - No evidence of primary tumor Tis - Carcinoma in situ T1 - Tumor limited to the pancreas, 2 cm or smaller in greatest dimension T2 - Tumor limited to the pancreas, larger than 2 cm in greatest dimension T3 - Tumor extension beyond the pancreas (eg, duodenum, bile duct, portal or superior mesenteric vein) but not involving the celiac axis or superior mesenteric artery T4 - Tumor involves the celiac axis or superior mesenteric arteries Regional lymph nodes (N) NX - Regional lymph nodes cannot be assessed N0 - No regional lymph node metastasis N1 - Regional lymph node metastasis Distant metastasis (M) MX - Distant metastasis cannot be assessed M0 - No distant metastasis M1 - Distant metastasis

Stage grouping for pancreatic cancer is as follows:

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Stage 0 - Tis, N0, M0 Stage IA - T1, N0, M0 Stage IB - T2, N0, M0 Stage IIA - T3, N0, M0 Stage IIB - T1-3, N1, M0 Stage III - T4, Any N, M0 Stage IV - Any T, Any N, M1

At initial presentation, only 20% of patients present with stage I disease, 40% present with locally advanced disease, and 40% present with disease metastatic to nodes or distant sites.

To date, studies show that EUS is approximately 70-80% accurate for correctly staging pancreatic carcinoma. EUS appears to better assess involvement of the portal vein/superior mesenteric vein. Spiral CT scanning with dual-phase contrast probably has similar or better overall accuracy and is especially good at assessing major arterial involvement.

Surgical Care: The vast majority of patients ultimately found to have resectable disease have tumors of the head of the pancreas. Unfortunately, patients presenting with cancer of the body or tail of the pancreas have almost uniformly unresectable disease at the time of presentation and rarely survive over the long term, even if they undergo resection. Pancreatic body and tail lesions often manifest later in the disease, with larger lesions that have invaded deeply into the retroperitoneum or spread distantly into the peritoneum or liver. The major determinant of resectability is the local invasion of the tumor into the vascular structures surrounding the pancreatic head. In cancers of the pancreatic head, the relationships among the cancer and the portal vein, superior mesenteric vein, and the celiac or superior mesenteric artery are critical. If the cancer has invaded into the portal or superior mesenteric vein, then a potentially curative resection may require either excision of part of the vessels or venous grafting. In expert hands, this can be accomplished with minimal additional morbidity; however, it may require the assistance of a vascular surgeon. Not all pancreatic surgeons advocate attempts at venous resection. In high-volume centers, curative resections with or without venous resection carry similar prognoses. Invasion or encasement of the superior mesenteric or celiac arteries makes an attempt at curative resection impossible. In most series, documented metastases to peripancreatic lymph nodes are considered a poor prognostic finding and may be a relative contraindication to attempting a curative resection. Preresection laparoscopy or exploratory laparotomy and intraoperative ultrasonography have also been advocated to determine which patients will fare best with attempts at curative resection. The role of pacreatico-dudenectomy for palliative intent remains controversial.

Palliative therapy Regardless of the dismal survival in most cases, every attempt, whether operative or non-operative, should be made to improve the quality of life for patients with unresectable cancer of the pancreas. pain

Pain is the most debilitating symptom that quickly leads to the deterioration of the quality of life. Although only 30% to 40% of patients report pain at diagnosis, more than 80% with advanced cancer experience severe pain before death. Pain relief is crucial in these patients. Narcotic analgesics should be used early and in adequate dosages. Combining narcotic analgesics with tricyclic antidepressants or antiemetics can sometimes potentiate their analgesic effects. In some patients, narcotics are insufficient and other approaches must be considered.
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Neurolysis of the celiac ganglia may provide significant long-term pain relief in patients with refractory abdominal pain. Early implementation of celiac block before the onset of incapacitating pain has been shown to be more effective in maintaining overall quality of life. This can be performed either

1. Thoracoscopic splanchnicectomy 2. Transabdominally under CT guidance. 3. Transgastrically using EUS-guided fine-needle injection 4. Intraoperative chemical splanchnicectomy when assessing the patient's potential for resection. Chemical splanchnicectomy involves the injection of 20 ml of 50% alcohol on each side of the aorta at the level of celiac axis. This can achieve acute pain relieve in 80% of patients and prevent onset of pain for up to 6 months postoperatively.
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Radiation therapy for pancreatic cancer can palliate pain but does not affect the patient's survival. Some patients may be experiencing pain from the obstruction of the pancreatic or biliary ducts, especially if the pain significantly worsens after eating. These patients may benefit from endoscopic decompression with stents.

Jaundice
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Obstructive jaundice warrants palliation if the patient has pruritus or right upper quadrant pain or has developed cholangitis. Some patient's anorexia, malabsorptive diarrhea and progressive malnutrition also seem to improve after relief of biliary obstruction. Biliary obstruction from pancreatic cancer is usually best palliated by the endoscopic placement of plastic or metal stents. The more expensive and permanent metallic stents appear to have a longer period of patency and are preferable in patients with an estimated lifespan of more than 3 months. Plastic stents usually need to be replaced every 3-4 months and therefore are better used in pts with larger tumours and those with metastatic liver disease.

Endoscopic Biliary drainage using 10-F stent is successful in 90% of cases. 10% fail due to tumour infiltration of the duodenal wall preventing access to the ampula. In these cases PTC should be used as a method of drainage. Patients can also undergo operative biliary decompression at the time of an operation for resectability assessment. either by choledochojejunostomy or cholecystojejunostomy. The use of laparotomy and gastric and Biliary bypass as routine palliative measures is no longer justified in most patients. Laparotomy for palliation carries a mortality rate of 2% to 5%, a morbidity rate of 20% to 30%, and a median hospital stay of 10 days in most series. A number of randomized trials have compared operative bypass with Biliary stenting and shown that complications such as cholangitis and Biliary leak, are more common with bypass procedures, whereas recurrent jaundice is feature of stenting because of stent occlusion or migration. A recent study from Amsterdam medical centre randomly allocated patients to either endoscopic or surgical palliation. They suggested that patients who are free from major comorbidities have better palliation by surgery than endoscopy. Laparoscpic bilairy and gastric bypass is also a safe and effective technique.

Duodenal obstruction:

Approximately 5% of patients develop duodenal obstruction secondary to pancreatic carcinoma. These patients can be palliated operatively with a gastrojejunostomy or an endoscopic procedure. Endoscopic stenting of duodenal obstruction is usually reserved for patients who are poor operative candidates. Some surgeons empirically palliate patients with a gastrojejunostomy at the time of an unsuccessful attempt at pancreatic resection in an effort to prevent the later need for this operation. The John Hopkins group randomized 87 patients with irresectable disease to prophylactic gastrojejunostomy with Biliary bypass(44 pts), or Biliary bypass only(43pts), the two groups had same survival of 8.3 months, but 8 of the second group developed gastric outlet obstruction. similar findings were reported by the Amsterdam group.

The role of pancreaticodudenectomy in palliation The John Hopkins group retrospectively compared the outcomes of 64 pts who had pancreaticodudenectomy with evidence of disease at the resections margins, with 62 pts with locally advanced disease who had undergone surgical bypass. Morbidity and mortality rates were similar. The actuarial survival in the first group was improved ( 12 versus 8 months) but the groups were not comparable. Chemotherapeutic agents have shown meaningful alleviation of cancer related symptoms and survival. Gemcitabine a nucleoside analogue has shown good clinical benefit response (pain,Karnofsky performance status,daily analgesic usage, and weight)

Clinical benefit response is defined as a significant reduction in 1 or more of these features lasting for at least 4 weeks without deterioration in another parameter. 24% of Pts received gemcitabine showed clinical benefit response compared to 5% of those who were treated with 5-fluo-uracil. Various phase 3 trials are examining different combinations of chemotherapeutic agents and radiation regimens.

The approach to which palliative modality to use depends on how uresectability is determined. Palliative therapy for pancreatic cancer should be planned using a multidisciplinary approach, including input from the surgeon, gastroenterologist, radiologist, and medical and radiation oncologist. More focus need to be placed on the support structures: medical (eg patient support groups), social (job support, health leave), and financial support. As surgeons we need to learn how to reach out more effectively to those who are in need at the end of life.

References: 1. Dunn GP. Surgical palliative care: an enduring framework for surgical care.suRg clin N Am 85(2005) 169-190 2. Michael G. House, Michael A. Choti: palliative therapy for pancreatic/Biliary cancer. Surg clin N Am 85(2005) 359-371.

3. Alexakis C. Halloran et al. current standards of surgery for pancreatic cancer. Br J surg 2004;91:1410-1427 4. Curtis j. Wray et al. surgery for pantreatic cancer: recent controversies and current practice, Gastroenterol 2005;128:16261641. 5. Lokhart A. Craiget al.treatment for pancreatic cancer: current therapy and continued progress.Gastroenterol 2005;128:16421654. 6. Richard G. Erickson. Pancreatic cancer. www.emedicine.com last updated 15December2005.