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Palliative options in advanced pancreatic cancerE. OsmanModerator Dr. A. De Beer

Palliative cares goal is to relieve suffering and improve quality of life in the context of anindividuals family and society.

The Three pillars of palliative care are:1. Pain and non-pain symptoms management2. 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 morphineadministration.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 yearsof 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 institutionThe 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 withdeath; it is an outcome that might be equated with defeat. Many surgeons are also uncomfortablewith 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 isour patient. this shared responsibility for surgical patient has positive application in theinterdisciplinary 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 thefifth leading cause of cancer-related mortality. The disease is difficult to diagnose in its earlystages, and most patients have incurable disease by the time they present with symptoms. Theoverall 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


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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 peryear in black males in the United States. While the incidence in India is less than2 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. Only5-10% is hereditary in nature. Fewer than 5% of all pancreatic cancers are related tounderlying chronic pancreatitis.

Mortality/Morbidity:

Pancreatic carcinoma is usually a fatal disease. Most patients eventuallysuccumb to the consequences of local invasion and metastatic cancer, and truelong-term cures are rare. Overall, fewer than 5% of all patients are still alive 5years after initial diagnosis. The collective median survival time of all patients is4-6 months.

In patients able to undergo a successful curative resection (only 20% of patients), mediansurvival 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 asanorexia, malaise, nausea, fatigue, and midepigastric or back pain, andsignificant 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 aworrisome sign indicating retroperitoneal invasion of the splanchnic nerve plexusby the tumor.

The most characteristic sign of pancreatic carcinoma of the head of the pancreasis painless obstructive jaundice.

Depression is reported to be more common in patients with pancreatic cancerthan in patients with other abdominal tumors.


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

Lab Studies:

General laboratory studies

o The laboratory findings in patients with pancreatic cancer are usuallynonspecific. As with many chronic diseases, a mild normochromic anemiaas well asThrombocytosis

o Patients presenting with obstructive jaundice show significant elevationsin bilirubin and obstructive enzymes.

o Interestingly, amylase and lipase are infrequently elevated in pancreaticcarcinoma unless the patient is presenting with acute pancreatitissecondary to the pancreatic cancer.

o Only 5% of patients with pancreatic cancer initially present with anepisode of pancreatitis.

o Liver metastases alone do not usually cause jaundice and usually resultin relatively low-grade elevations of alkaline phosphatase andtransaminase levels.

Tumor markers

o The major useful tumor marker for pancreatic carcinoma is carbohydrateantigen 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 formalignancy, usually pancreatic.

Elevation of CA 19-9 levels has been used as an adjunct toimaging studies for helping determine the resectability potential ofpancreatic carcinoma. Fewer than 4% of patients with a CA 19-9level of more than 300 U/mL have been found to have resectabletumors.

imaging

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

CT scanning

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


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o Newer models using spiral (ie, helical) CT scanning with multipledetectors and dual-phase contrast enhancement have significantlyimproved the sensitivity and specificity of abdominal CT findings in

patients with pancreatic carcinoma. Dual-phase spiral CT findings areapproximately 80% accurate for helping determine the resectabilitypotential of pancreatic carcinoma. However, small tumors can still bemissed even with the most advanced CT scanning currently available.

o CT scanning can be used to direct fine-needle aspiration of pancreaticmasses.

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

o

Ultrasonography

Sonar has less utility in pancreatic carcinoma than CT scanning becausethe pancreas is often obscured by overlying gas.

o Sonar is very useful as an initial screening test in evaluating patients whopresent with possible obstructive jaundice.

Endoscopic ultrasonography

o EUS has proven to be the most sensitive and specific diagnostic test for

pancreatic cancer.o In numerous series, EUS has detection rates of 99-100% for all

pancreatic carcinomas, including those smaller than 3 cm. EUS is asaccurate as ERCP or MRCP for assessing the etiology of obstructive

jaundice.o An diagnostic advantage is EUS-guided fine-needle aspiration, which

allows for the simultaneous cytologic confirmation of pancreaticcarcinoma at the time of EUS diagnosis.

o EUS appears to be equivalent to dual-phase spiral CT scanning forassessing 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

o Of patients with pancreatic adenocarcinoma, 90-95% have abnormalitieson ERCP findings. However, the changes observed on ERCP are notalways highly specific for pancreatic carcinoma and can be difficult todifferentiate from changes observed in patients with chronic pancreatitis.

o ERCP is highly invasive with 5-10% risk of significant complications withthe procedure.

o 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%.

o ERCP findings provide only limited staging information, but ERCP doeshave the advantage of allowing for therapeutic palliation of obstructive

jaundice with either a plastic or metal biliary stent.

Magnetic resonance imaging

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

Positron emission tomography scanning

o PET scanning can be especially useful in looking for occult metastaticdisease. Its role in pancreatic cancer evaluation management is still underinvestigation. False-positive PET scans have been reported inpancreatitis.

Other Tests:

Needle aspiration

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o The necessity of obtaining a cytologic or tissue diagnosis of pancreaticcancer prior to operation remains controversial.

Some centres advocate the practice of aggressively operating on

all patients thought to have pancreatic cancer and argue against apreoperative tissue diagnosis.

The contention in these centres is that negative findings afterpreoperative fine-needle aspiration may just be sampling errorand, thus, should not stop a pancreaticoduodenectomy if apotentially resectable pancreatic neoplasm is strongly suggestedbased on preoperative testing.

Additionally, preoperative attempts at fine-needle aspiration orbiopsy of the pancreas might contaminate the peritoneum withtumor cells.

o Other surgeons are hesitant to operate on patients without a positive

tissue or cytologic diagnosis of cancer. Additionally, tissue diagnosis isalmost always required prior to initiation of chemotherapy, radiationtherapy (whether palliative or neoadjuvant), or nonoperative palliation ofobstructive jaundice using permanent metallic stents.

Studies of the risk of peritoneal contamination with CT-guidedbiopsy have suggested that this risk is actually very low.

Additionally, the histology of a pancreatic tumor can change thesurgical approach to the tumor. For example, a pancreaticlymphoma should be treated medically rather than with operativeresection.

o Using EUS-guided fine-needle aspirations, a cytologic diagnosis can be

made in 85-95% of patients. A recent study has also suggested thattranscutaneous aspiration may be associated with a higher risk ofperitoneal tumor spread than aspiration with EUS. Thus, for potentiallyresectable tumors, EUS-guided fine-needle aspiration is the preferredbiopsy technique, if it is available and if a biopsy needs to be obtained.

o The yield of CT-guided fine-needle aspiration or biopsy findings isapproximately 50-85% in the lesions that are visible on CT scanning.

Staging laparoscopy or laparotomy

o Some centers advocate performing a staging laparoscopy or laparotomybefore proceeding to attempted resection. A few centers also advocateperforming intraoperative laparoscopic ultrasonography to help furtherassess the tumor stage and to look for occult metastases.

o Using this approach, a significant number of patients are found to havepreviously unsuspected peritoneal or liver metastases. The operationsavoided by staging laparoscopy largely depend on how aggressively andaccurately the patient was staged preoperatively.

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


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Only 20% of all patients presenting with pancreatic cancer are ultimately found to haveeasily resectable tumors with no evidence of local advancement.

No survival benefit is achieved for patients undergoing noncurative resections forpancreatic carcinoma. Thus, to avoid operating on patients who cannot benefit from theoperation, accurate preoperative staging is essential.

Pancreatic ca is classified by the (TNM) staging system. This staging has recently beenmodified by the American Joint Committee on Cancer (AJCC).

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

o 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 theceliac axis or superior mesenteric artery

T4 - Tumor involves the celiac axis or superior mesenteric arteries

o Regional lymph nodes (N) NX - Regional lymph nodes cannot be assessed N0 - No regional lymph node metastasis N1 - Regional lymph node metastasis

o Distant metastasis (M) MX - Distant metastasis cannot be assessed M0 - No distant metastasis M1 - Distant metastasis

Stage grouping for pancreatic cancer is as follows:

o Stage 0 - Tis, N0, M0

o Stage IA - T1, N0, M0o Stage IB - T2, N0, M0o Stage IIA - T3, N0, M0o Stage IIB - T1-3, N1, M0o Stage III - T4, Any N, M0o 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 metastaticto nodes or distant sites.


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To date, studies show that EUS is approximately 70-80% accurate for correctlystaging 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 betteroverall 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 ofthe head of the pancreas. Unfortunately, patients presenting with cancer of the body ortail of the pancreas have almost uniformly unresectable disease at the time ofpresentation 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 lesionsthat have invaded deeply into the retroperitoneum or spread distantly into theperitoneum or liver.

The major determinant of resectability is the local invasion of the tumor into the vascularstructures surrounding the pancreatic head. In cancers of the pancreatic head, therelationships among the cancer and the portal vein, superior mesenteric vein, and theceliac or superior mesenteric artery are critical. If the cancer has invaded into the portalor superior mesenteric vein, then a potentially curative resection may require eitherexcision of part of the vessels or venous grafting. In expert hands, this can beaccomplished with minimal additional morbidity; however, it may require the assistanceof a vascular surgeon. Not all pancreatic surgeons advocate attempts at venousresection.

In high-volume centers, curative resections with or without venous resection carrysimilar prognoses. Invasion or encasement of the superior mesenteric or celiac arteriesmakes an attempt at curative resection impossible.

In most series, documented metastases to peripancreatic lymph nodes are considered apoor prognostic finding and may be a relative contraindication to attempting a curativeresection. Preresection laparoscopy or exploratory laparotomy and intraoperativeultrasonography have also been advocated to determine which patients will fare bestwith 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 ornon-operative, should be made to improve the quality of life for patients withunresectable cancer of the pancreas.

pain


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Pain is the most debilitating symptom that quickly leads to the deterioration of thequality 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 usedearly and in adequate dosages.

Combining narcotic analgesics with tricyclic antidepressants or antiemeticscan sometimes potentiate their analgesic effects. In some patients, narcoticsare insufficient and other approaches must be considered.

o Neurolysis of the celiac ganglia may provide significant long-term painrelief in patients with refractory abdominal pain. Early implementation ofceliac block before the onset of incapacitating pain has been shown to bemore effective in maintaining overall quality of life.

o 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'spotential 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 painrelieve in 80% of patients and prevent onset of pain for up to 6 monthspostoperatively.

o Radiation therapy for pancreatic cancer can palliate pain but does notaffect the patient's survival.

o Some patients may be experiencing pain from the obstruction of thepancreatic or biliary ducts, especially if the pain significantly worsens aftereating. These patients may benefit from endoscopic decompression withstents.

Jaundice

o Obstructive jaundice warrants palliation if the patient has pruritus or rightupper quadrant pain or has developed cholangitis.

o Some patient's anorexia, malabsorptive diarrhea and progressivemalnutrition also seem to improve after relief of biliary obstruction.

o Biliary obstruction from pancreatic cancer is usually best palliated by theendoscopic placement of plastic or metal stents.

o The more expensive and permanent metallic stents appear to have alonger period of patency and are preferable in patients with an estimatedlifespan of more than 3 months. Plastic stents usually need to be replacedevery 3-4 months and therefore are better used in pts with larger tumoursand those with metastatic liver disease.


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o Endoscopic Biliary drainage using 10-F stent is successful in 90% ofcases. 10% fail due to tumour infiltration of the duodenal wall preventingaccess to the ampula. In these cases PTC should be used as a method of

drainage.o Patients can also undergo operative biliary decompression at the time of

an operation for resectability assessment. either bycholedochojejunostomy or cholecystojejunostomy.

o The use of laparotomy and gastric and Biliary bypass as routine palliativemeasures is no longer justified in most patients. Laparotomy for palliationcarries a mortality rate of 2% to 5%, a morbidity rate of 20% to 30%, anda median hospital stay of 10 days in most series.

o A number of randomized trials have compared operative bypass withBiliary stenting and shown that complications such as cholangitis andBiliary leak, are more common with bypass procedures, whereasrecurrent jaundice is feature of stenting because of stent occlusion or

migration.o A recent study from Amsterdam medical centre randomly allocated

patients to either endoscopic or surgical palliation. They suggested thatpatients who are free from major comorbidities have better palliation bysurgery than endoscopy.

o Laparoscpic bilairy and gastric bypass is also a safe and effectivetechnique.

Duodenal obstruction:

Approximately 5% of patients develop duodenal obstruction secondary topancreatic carcinoma. These patients can be palliated operatively with a

gastrojejunostomy or an endoscopic procedure. Endoscopic stenting of duodenalobstruction is usually reserved for patients who are poor operative candidates.

Some surgeons empirically palliate patients with a gastrojejunostomy at the timeof an unsuccessful attempt at pancreatic resection in an effort to prevent the laterneed for this operation.

The John Hopkins group randomized 87 patients with irresectable disease toprophylactic gastrojejunostomy with Biliary bypass(44 pts), or Biliary bypassonly(43pts), the two groups had same survival of 8.3 months, but 8 of the secondgroup 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 hadpancreaticodudenectomy with evidence of disease at the resections margins, with 62pts with locally advanced disease who had undergone surgical bypass. Morbidity andmortality rates were similar. The actuarial survival in the first group was improved ( 12versus 8 months) but the groups were not comparable.

Chemotherapeutic agents have shown meaningful alleviation of cancer relatedsymptoms and survival. Gemcitabine a nucleoside analogue has shown good clinicalbenefit response (pain,Karnofsky performance status,daily analgesic usage, and weight)


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Clinical benefit response is defined as a significant reduction in 1 or more of thesefeatures lasting for at least 4 weeks without deterioration in another parameter. 24% ofPts 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 agentsand radiation regimens.

The approach to which palliative modality to use depends on how uresectability isdetermined.

Palliative therapy for pancreatic cancer should be planned using a multidisciplinaryapproach, including input from the surgeon, gastroenterologist, radiologist, andmedical and radiation oncologist.

More focus need to be placed on the support structures: medical (eg patient supportgroups), social (job support, health leave), and financial support.

As surgeons we need to learn how to reach out more effectively to those who are inneed at the end of life.

References:

1. Dunn GP. Surgical palliative care: an enduring framework forsurgical care.suRg clin N Am 85(2005) 169-190

2. Michael G. House, Michael A. Choti: palliative therapy forpancreatic/Biliary cancer. Surg clin N Am 85(2005) 359-371.


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3. Alexakis C. Halloran et al. current standards of surgery forpancreatic 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;128:1626-1641.

5. Lokhart A. Craiget al.treatment for pancreatic cancer: currenttherapy and continued progress.Gastroenterol 2005;128:1642-1654.

6. Richard G. Erickson. Pancreatic cancer.www.emedicine.com lastupdated 15December2005.

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