Pancreatic Cancer Treatment & Management

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 or neoadjuvant setting, and in the treatment of patients with unresectable disease.

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. However, the invasion of the superior mesenteric or portal vein is no longer an absolute contraindication.^[47] These veins can be resected partially with as much as 50% narrowing of the lumen. In addition, 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; and 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.

The NCCN's 2011 guidelines recommend that decisions about treatment and resectability involve input from a multidisciplinary group of specialists. The panel also agreed that selecting patients for surgery should be based on the probability of cure as determined by resection margins. Other factors include comorbidities, overall performance, and age.^[8]

In patients with metastatic disease, the combination of gemcitabine and erlotinib has led to a significantly higher median survival and 1-year survival than has the use of gemcitabine alone.^[48] This has led to US Food and Drug Administration (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.^[49]

The combination of gemcitabine and capecitabine in advanced pancreatic cancer has been investigated by several groups.

A randomized, multicenter, phase III clinical trial in 319 patients by the Central European Cooperative Oncology Group found that clinical response or quality of life was no better with the combination than with gemcitabine alone.^[50]

This finding contrasts with the results of the phase III United Kingdom National Cancer Research Institute GEMCAP trial, an open-label, randomized study of gemcitabine alone versus gemcitabine combined with capecitabine in 533 patients. Compared with gemcitabine alone, treatment with the gemcitabine-capecitabine combination produced a significantly higher objective response rate (12.4% vs 19.1%, respectively) and progression-free survival and was associated with a trend toward improved overall survival.

In addition, a meta-analysis of two additional studies involving 935 patients showed a significant survival benefit in favor of the gemcitabine-capecitabine combination. Accordingly, these researchers recommended considering gemcitabine-capecitabine as one of the standard first-line options in locally advanced and metastatic pancreatic cancer.^[51]

In 2011, the NCCN recommended gemcitabine monotherapy for symptomatic patients with metastatic or locally advanced unresectable disease with poor performance status. Additional recommendations for metastatic disease were also added, including the GTX regimen (gemcitabine, docetaxel and capecitabine) and combination therapy with gemcitabine and nab-paclitaxel.^[8]

More recently, the results of a European phase III trial (ACCORD/PRODIGE) that compared the nongemcitabine regimen FOLFIRINOX (LV5-FU plus oxaliplatin plus irinotecan) to gemcitabine were reported.^[52] The median survival on the FOLFIRINOX arm was 11.1 months, versus 6.8 months on the gemcitabine arm. Of note, the incidence of adverse events and febrile neutropenia was significantly higher on the FOLFIRINOX arm, despite the fact that only patients with ECOG performance status of 0-1 were included in this trial. It remains to be seen how well this regimen will be integrated into the care of patients with pancreatic cancer and good performance status worldwide. In 2011, the NCCN recommended FOLFIRINOX as a first-line treatment for patients with metastatic or locally advanced unresectable disease with good performance status.^[8]

Capecitabine alone or capecitabine plus erlotinib may provide second-line therapy benefit in patient's refractory to gemcitabine.^[53] There is no advantage to giving gemcitabine in any dose or time of infusion other than 1000 mg/m² over 1 half hour intravenously.

Combinations of gemcitabine with cisplatin, oxaliplatin, irinotecan, or docetaxel have in phase III trials not been of superior benefit to gemcitabine alone.

A review of 8 trials by Rothwell et al indicated that the use of aspirin daily over a period of 5 years reduces death caused by several cancers, including pancreatic cancer.^[54]

A study by Bekaii-Saab et al found that selumetinib has interesting activity and acceptable tolerability in patients with metastatic biliary cancer. Further studies are warranted.^[55]

Several studies (including the GITSG, ESPAC, CONKO) suggested the possibility that chemotherapy, with or without radiation therapy, would significantly improve median survivals following surgical resection of operable disease.^{[56, 57]} These studies were not definitive and not widely accepted as justification for offering either modality for adjuvant therapy.

However, a large, retrospective study supported the use of adjuvant chemoradiotherapy. Yang et al analyzed a registry of 2,877 patients who underwent surgical resection with curative intent for pancreatic adenocarcinoma; approximately half received no adjuvant therapy, and approximately a quarter received postoperative chemoradiotherapy. A significant survival benefit was found for the chemoradiotherapy patients.^[58] In 2011, the NCCN panel recommended the measurement of serum CA 19-9 levels after surgery and before adjuvant therapy.^[8]

A study by Neuhaus et al in 368 patients with resected pancreatic cancer found that adjuvant gemcitabine prolongs survival when compared with surgery alone.^[59] The 3-year survival rates were 36.5% and 19.5% for the gemcitabine and surgery-only arms of the study, respectively. The 5-year survival rates were 21% and 9% for the gemcitabine and surgery-only arms, respectively.

This trial was definitive and transformative. Adjuvant therapy with gemcitabine is now accepted as standard therapy for surgically resected pancreatic cancer.^[60]

Neoadjuvant therapy

The use of chemotherapy and/or radiation therapy in the neoadjuvant setting has been a source of controversy. The rationale for using neoadjuvant therapy includes the assertions that (1) pancreatic cancer is a systemic disease and should be treated systemically from the start, (2) patients will be able to tolerate the toxic effects of chemotherapy more readily before undergoing major pancreatic resection than after, and (3) the tumor will shrink with neoadjuvant therapy, 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.^{[61, 62]} 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. The NCCN agrees with this recommendation.^[8]

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 so much of the intraabdominal structures is that they all share a common blood supply.

Pancreaticoduodenectomy has been shown to have an overall mortality rate of 6.6%.^[63] 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.^[64] Other morbidities include pancreatic anastomotic leak. This can be treated with adequate drainage. Postoperative abscesses are not uncommon.

Although preoperative biliary drainage was introduced to improve the postoperative outcome in patients with obstructive jaundice caused by tumors of the pancreatic head, van der Gaag et al found that routine use of this maneuver increases the rate of complications. In a multicenter, randomized trial, 202 patients with obstructive jaundice and a bilirubin level of 40–250 mmol/L (2.3-4.6 mg/dL) were assigned to undergo either preoperative biliary drainage for 4-6 weeks, followed by surgery, or surgery alone within 1 week after diagnosis. The rate of serious complications was higher in the biliary drainage group than in the early surgery group (74% vs 39%, respectively). No significant difference was noted in mortality or length of hospital stay between the 2 groups.^[65]

Similarly, Limongelli et al found that preoperative biliary drainage predisposes patients to a positive intraoperative biliary culture, which in turn is associated with an increased risk of postoperative infectious complications and wound infection.^[66]

The standard Whipple operation may be altered in order to include a pylorus-sparing procedure. This modification was previously incorporated to increase nutritional strength in these patients, because 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.^[67] This was even more significant than margin positivity.^[68]

This procedure possesses a lower mortality rate than the standard Whipple procedure does, at 3.5%, but its use in curative resection remains limited.^[63] 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, and endocrine insufficiency.^[69] Once again, the best treatment for the pancreatic leak is adequate drainage.

Although this procedure is the least commonly performed and has the highest associated mortality rate (8.3%), it may still be a valuable instrument in the surgical cure of pancreatic cancer.^[63]

The indication for the use of total pancreatectomy is in 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.^[70]

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 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 experience 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 patients’ 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.

As with most patients with advanced cancer, patients with pancreatic carcinoma are often anorexic. Pharmacologic stimulation of appetite is usually unsuccessful, 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 by avoidance of high-fat or high-protein diets.

The management of pancreatic carcinoma is a multidisciplinary process. Typically, the management of pancreatic cancer entails consultations with a gastroenterologist, medical oncologist, general surgeon or surgical oncologist, and, possibly, a radiation oncologist.

A gastroenterologist is usually involved either for evaluation of the cause of the patient's presenting symptoms (eg, abdominal pain, nausea, weight loss, diarrhea) or for a definitive diagnosis of the cause of jaundice by EUS and/or ERCP. Consultation with a gastroenterologist is also needed if an endoscopically placed stent is needed for palliation of obstructive jaundice.

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 the 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.