Advanced unresectable pancreatic cancer: Choose therapy with care

From Pancreatic Cancer, Oncology

Advanced unresectable pancreatic cancer: Choose therapy with care

Erlotinib is FDA-approved for use with gemcitabine in advanced unresectable pancreatic cancer; however, the combination is associated with significant patient toxicity. Regimens should be chosen with care.

Medical Care

There is consensus on the fact that surgery is the primary mode of treatment for pancreatic cancer. However, an important role exists for the use of chemotherapy and/or radiation therapy in an adjuvant setting, neoadjuvant setting, and in the treatment of patients with unresectable disease.

Chemotherapy
The 2 most active agents have been 5-fluorouracil (5-FU) and, more recently, gemcitabine. The addition of targeted therapy in the form of epidermal growth factor receptor antagonists (ie, erlotinib) has had a synergistic effect.
In patients with metastatic disease, the combination of gemcitabine and erlotinib has led to a significantly higher median survival and 1-year survival than the use of gemcitabine alone.25 This has led to FDA approval of erlotinib to be used in combination with gemcitabine in advanced unresectable pancreatic cancer. The recommendation that this combination should now constitute standard therapy for metastatic or unresectable local disease is premature and problematic. The improvements in response rates seen, although significant, were not great and were obtained with no small amount of patient toxicity.
The combination should be used with considerable care, and the use of gemcitabine alone should still be considered as appropriate therapy for patients with metastatic disease. Gemcitabine alone should also be considered as appropriate therapy for patients with unresectable disease; there is no meaningful significant benefit obtained to adding radiotherapy in this situation. Such an addition simply increases toxicity.26
The addition of bevacizumab to the combination of gemcitabine and erlotinib does not improve the response rate of the combination alone.27 The combination of gemcitabine and capecitabine has previously been investigated to determine whether their use together improves overall survival. Unfortunately, recent clinical trials have not shown that combining these 2 agents produces any change in clinical response or quality of life.28, 29
Capecitabine alone or capecitabine plus erlotinib may provide second-line therapy benefit in patients refractory to gemcitabine.30 There is no advantage to giving gemcitabine in any dose or time of infusion other than 1000 mg/m ² over one half hour intravenously.
Combinations of gemcitabine with any of cisplatin, oxaliplatin, irinotecan, or docetaxel have in phase III trials not been of superior benefit to gemcitabine alone.
In the adjuvant setting, several studies (including the GITSG, ESPAC, CONKO) had suggested the possibility that chemotherapy with or without radiation therapy would significantly improve median survivals following surgical resection of operable disease.31, 32 These studies were not definitive and not widely accepted as justification for offering either modality for adjuvant therapy. Gemcitabine alone has now been shown to significantly affect survival following resection for operable disease. It prolongs survival in the adjuvant setting when compared to surgery alone.33
The 3-year survival rates were 36.5% and 19.5% for the gemcitabine and surgery only arms respectively (p<0.001). The 5-year survival rates were 21% and 9% for the gemcitabine and surgery only arms respectively (p<0.001). Postsurgical adjuvant treatment with gemcitabine doubled the 5-year survival rate when compared to surgery and observation alone.
This trial is definitive and transformative. Adjuvant therapy with gemcitabine is now accepted as standard therapy for surgically resected pancreatic cancer.34
The use of chemotherapy and/or radiation therapy in the neoadjuvant setting has been a source of controversy. The rationale for neoadjuvant therapy includes the following:
Pancreatic cancer is a systemic disease and should be treated systemically from the start.
Patients will be able to tolerate the toxic effects of chemotherapy more readily before undergoing major pancreatic resection than after.
The tumor will shrink and the resection will be less cumbersome, leading to an improved overall survival.
Several trials conducted at M.D. Anderson Cancer Center have shown median survival as high as 25 months.35, 36 No form of neoadjuvant therapy in pancreatic carcinoma should be regarded as a standard form of therapy; this remains an area for clinical trial study.

Palliative therapy
Pain
Patients not undergoing resection for pancreatic cancer should have therapy focused on palliating their major symptoms. 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.
Neurolysis of the celiac ganglia may provide significant long-term pain relief in patients with refractory abdominal pain. This can be performed either transthoracically or transabdominally by invasive radiology or anesthesiology, transgastrically using EUS-guided fine-needle injection, or intraoperatively when assessing the patient's potential for resection.
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
Obstructive jaundice warrants palliation if the patient has pruritus or right upper quadrant pain or has developed cholangitis. Some patient's anorexia also seems 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.
Patients can also undergo operative biliary decompression, either by choledochojejunostomy or cholecystojejunostomy, at the time of an operation for resectability assessment.
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.

Surgical Care

Prior to any surgical procedures, the resectability of malignant pancreatic tumors needs to be established. Pancreatic masses are characterized as resectable, unresectable, or borderline resectable. The latter is usually based on both the experience and technical skill of the surgeon involved in treatment as well as the overall health of the patient and his or her wishes. Typically, extrapancreatic disease precludes curative resection, and surgical treatment may be palliative at best.

Historically, vascular involvement has been considered a contraindication to resective cure. The invasion of the superior mesenteric or portal vein is no longer an absolute contraindication.37 These veins can be resected partially with as much as 50% narrowing of the lumen. Also, complete reconstruction is possible especially using native veins as replacement (ie, internal jugular, greater saphenous, or splenic). Nonetheless, invasion of the superior mesenteric, celiac, and hepatic arteries still presents a barrier to resection. No evidence indicates that a vascular reconstruction which permits an attempt at surgical resection improves or contributes to survival.

After a thorough preoperative workup, the surgical approach can be tailored to the location, size, and locally invasive characteristics of the tumor. Curative resection options include pancreaticoduodenectomy, with or without sparing of the pylorus, total pancreatectomy, or distal pancreatectomy. Each procedure is associated with its own set of perioperative complications and risks, and these points should be taken into consideration by the surgical team and discussed with the patient when considering the goal of resection.

Pancreaticoduodenectomy (Whipple procedure)

Patients who will most likely benefit from this procedure have a tumor located in the head of the pancreas or the periampullary region. The Whipple procedure is not strictly the surgical approach for pancreatic head tumors. Pancreatic ductal tumors, cholangiocarcinoma (bile duct cancer), and duodenal masses will all require this resection. The operation traditionally involves the following: removal of the pancreatic head, duodenum, gallbladder, and the antrum of the stomach with surgical drainage of the distal pancreatic duct and biliary system, usually accomplished through anastomosis to the jejunum. The primary reason for removing such a large quantity of intraabdominal structures is that they all share a common blood supply.

Pancreaticoduodenectomy has been shown to have an overall mortality rate of 6.6%.38 Many forms of morbidity are associated with the operation. One of these is delayed gastric emptying. This occurs in approximately 25% of patients. This condition may require nasogastric decompression and will lead to a longer hospital stay.39 Other morbidities include pancreatic anastomotic leak. This can be treated with adequate drainage. Postoperative abscesses are not uncommon. It is unclear whether preoperative biliary drainage leads to increased rates of postoperative infection.40

The standard Whipple operation may be altered in order to include a pylorus-sparing procedure. This modification was previously incorporated to increased nutritional strength in these patients as the increased-gastric emptying associated with antrectomy caused nutritional deficiencies. Although many believe that delayed gastric emptying is worsened by this modification, studies have proven both resections to be equivalent in that regard. Another source of controversy is the extent of lymphadenectomy that is necessary in a Whipple operation. In an elegant study, Pawlik et al found the ratio of positive nodes to total nodes removed was an important prognostic factor.41 This was even more significant than margin positivity.42

Distal pancreatectomy

This procedure possesses a lower mortality rate than the standard Whipple procedure at 3.5%, but its use in curative resection remain limited.38 Essentially, a distal pancreatectomy may be an effective procedure for tumors located in the body and tail of the pancreas. Unfortunately, masses located in this area present later than the periampullary tumors and hence have a higher unresectability rate. The procedure involves isolation of the distal portion of the pancreas containing the tumor followed by resection of that segment, with oversewing of the distal pancreatic duct. The main complications for distal pancreatectomy involve pancreatic stump leak, hemorrhage, or endocrine insufficiency.43 Once again, the best treatment for the pancreatic leak is adequate drainage.

Total pancreatectomy

Although this procedure is the least commonly done with the highest associated mortality at 8.3%, it may still remain a valuable instrument in the surgical cure of pancreatic cancer.38 The indication is cases in which the tumor involves the neck of the pancreas. This can either be a situation in which the tumor originates from the neck or is growing into the neck. These patients obviously get insulin-dependent diabetes. In some cases, the diabetes can be hard to control. Despite this, the morbidity of a total pancreatectomy is comparable to that of a Whipple procedure.44

Consultations

The management of pancreatic carcinoma is a multidisciplinary process. Most patients initially present to their primary care practitioner with general symptoms such as abdominal pain, weight loss, or fatigue. Patients may also be seen initially by a gastroenterologist if they present with obstructive jaundice. Typically, the management of pancreatic cancer would entail consultations with a gastroenterologist, medical oncologist, general surgeon or surgical oncologist, and possibly a radiation oncologist.

A gastroenterologist would usually be involved either for evaluation of the cause of the patient's presenting symptoms (eg, abdominal pain, nausea, weight loss, diarrhea) or for definitive diagnosis of the cause of jaundice by EUS and/or ERCP. Consultation with a gastroenterologist is needed if an endoscopically placed stent is needed for palliation of obstructive jaundice. If a gastroenterologist is able to provide EUS-guided fine-needle aspiration, then this is the preferred biopsy technique for pancreatic neoplasms, especially if resection is considered an option. Consultation with a gastroenterologist may also be required to place an enteral stent for palliation of duodenal obstruction by tumor.
Consultation with a medical oncologist is often needed to select and administer neoadjuvant, adjuvant, or primary chemotherapy for the disease. Consultation with a medical oncologist is also useful for management of other common cancer symptoms such as pain and nausea.
Consultation with a surgeon is needed when the patient's imaging studies suggest that operative resection may be feasible. The surgeon may perform diagnostic laparoscopy or even laparoscopic ultrasonography prior to an attempt at definitive resection. If curative resection is not possible, consultation with a surgeon may still be useful to consider operative palliation of biliary and/or duodenal obstruction. Consult with a surgeon or surgical oncologist who is very experienced in performing pancreaticoduodenectomies.
Consultation with a radiologist may be needed for special issues such as obstructive jaundice that is difficult to manage where percutaneous transhepatic cholangiography may be needed.
Consultation with a radiation oncologist is usually considered at the discretion of a medical oncologist when combined chemoradiation may be beneficial. This approach is only indicated when this combination therapy is the subject of a clinical trial.
Diet
As with most patients with advanced cancer, patients with pancreatic carcinoma are often anorexic. Usually, pharmacologic stimulation of appetite is not successful, but it may be tried.
Patients may have some degree of malabsorption secondary to exocrine pancreatic insufficiency caused by the cancer obstructing the pancreatic duct. Patients with malabsorption diarrhea and weight loss may benefit from pancreatic enzyme supplementation. Their diarrhea may also be improved with avoidance of high-fat or high-protein diets.