Pancreatic Cancer Treatment & Management

Updated: Jun 13, 2022
  • Author: Tomislav Dragovich, MD, PhD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Treatment

Approach Considerations

There is consensus that surgery is the primary mode of treatment for pancreatic cancer. However, an important role exists for 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, tumor invasion of the superior mesenteric or portal vein is no longer an absolute contraindication. [74] 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. In qualified high-volume centers, pancreatic surgery (especially distal pancreatectomy, but including pancreaticoduodenectomy) can often be performed laparoscopically. [75]

Guidelines from the National Comprehensive Cancer Network (NCCN) recommend that decisions about resectability involve input from a multidisciplinary group of specialists at a high-volume center. The NCCN 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. [30]

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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 following assertions:

  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.
  3. The tumor will shrink with neoadjuvant therapy so resection will be less cumbersome, leading to improved overall survival.

Trials of preoperative chemoradiotherapy conducted at M.D. Anderson Cancer Center have shown median survival as high as 25 months. [76, 77] However, 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 finds there is limited evidence to recommend specific neoadjuvant regimens off-study for patients with resectable or borderline resectable tumor, and practices vary with regard to the use of chemotherapy and radiation. The guidelines prefer consultation at a high-volume center when considering neoadjuvant therapy. If recommended, treatment should be at or coordinated through a high-volume center when possible. Participation in a clinical trial is encouraged. [30]

Possible neoadjuvant regimens include the following [30] :

  • FOLFIRINOX (folinic acid [leucovorin], 5-fluorouracil, irinotecan, oxaliplatin)/modified FOLFIRINOX, with or without subsequent chemoradiation
  • Gemcitabine + albumin-bound paclitaxel, with or without subsequent chemoradiation
  • Gemcitabine + cisplatin (≥2–6 cycles) followed by chemoradiation (only for known  BRCA1/2 or PALB2 mutations)

A study by Dhir et al in 193 patients with resectable or borderline resectable pancreatic ductal carcinoma concluded that FOLFIRINOX and gemcitabine plus albumin-bound paclitaxel are viable options for neoadjuvant treatment. After adusting for covariates, however, overall survival was found to be 4.9 months longer with FOLFIRINOX than with gemcitabine-paclitaxel. [78]

In a retrospective study of 49 stage III locally advanced/borderline resectable patients who were initially unresectable, were downstaged through chemotherapy, and subsequently underwent surgical resection, prolonged preoperative chemotherapy was associated with excellent overall survival and high rates of lymph node–negative disease. [79, 80] A study by Loeherer et al found an improvement in overall survival from 9.2 months to 11.4 months with the addition of concurrent external beam radiation therapy to gemcitabine alone. [81]

A phase 2 randomized clinical trial of preoperative and postoperative chemotherapy with modified FOLFIRINOX or gemcitabine/albumin-bound paclitaxel in patients with resectable pancreatic cancer found that 2-year overall survival was not significantly improved with either regimen, compared with historical data from trials of adjuvant therapy in resectable pancreatic cancer. [82]

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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 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 intra-abdominal structures is that they all share a common blood supply.

Pancreaticoduodenectomy has been shown to have an overall mortality rate of 6.6%. [83] 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. [84] 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. [85]

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. [86]

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 that the ratio of positive nodes to total nodes removed was an important prognostic factor. [87] This was even more significant than margin positivity. [88]

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Distal Pancreatectomy

This procedure possesses a lower mortality rate than the standard Whipple procedure does, at 3.5%, but its use in curative resection remains limited. [83] 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. [89] Once again, the best treatment for pancreatic leak is adequate drainage.

 

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Total Pancreatectomy

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. [83]

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. [90]

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Adjuvant Therapy

Several studies suggested the possibility that postoperative chemotherapy, with or without radiation therapy, would significantly improve median survivals following surgical resection of operable disease. These included the Gastrointestinal Tumor Study Group (GITSG), European Study Group for Pancreatic Cancer (ESPAC), and Charité Onkologie (CONKO) trials. [91, 92, 93, 94, 95]

The first well-powered study to establish the role of adjuvant chemotherapy in pancreatic cancer, conducted by Neuhaus et al in 368 patients with resected pancreatic cancer, found that adjuvant gemcitabine prolongs survival when compared with surgery alone. 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. [95]

Based on encouraging efficacy shown in the metastatic setting, the PRODIGE Group tested FOLFIRINOX in the adjuvant setting, in 493 patients who had undergone curative resection of the pancreas. Median overall survival was 54.4 months in the FOLFIRINOX arm, compared with 35 months in patients randomized to gemcitabine (the control arm). [96] This study established modified FOLFIRINOX as a main choice for adjuvant chemotherapy in patients with resected pancreatic cancer.  

Another landmark trial, conducted by ESPAC, compared adjuvant therapy with gemcitabine only and gemcitabine plus capecitabine (GemCap) in 732 patients who had undergone R0 or R1 resection for pancreatic ductal adenocarcinoma (PDAC). Median overall survival was  28 months in the gemcitabine plus capecitabine arm versus 25.5 months for gemcitabine arm, suggesting a benefit from adding capecitabine to gemcitabine in the postoperative setting. [97]

Although GemCap has never been compared with modified FOLFIRINOX in a randomized trial, GemCap can be still considered as an option for patients too old or too frail to receive FOLFIRINOX (see Chemotherapy for Unresectable and Metastatic Pancreatic Cancer). [98, 30]

Combining gemcitabine with nab-paclitaxel for adjuvant therapy was explored in the phase 3 APACT trial, which included 8666 patients who had undergone complete resection of pancreatic cancer. While there was a suggestion of benefit from gemcitabine plus nab-paclitaxel compared with gemcitabine alone, the study did not meet its primary endpoint of longer disease-free survival or its secondary endpoint of improved overall survival. [99] Consequently, this combination cannot be currently recommended in the adjuvant setting.

Current European Society for Medical Oncology (ESMO) guidelines include the following recommendations for adjuvant therapy [100] :

  • mFOLFIRINOX should be the first adjuvant therapeutic option after resection of pancreatic cancer in selected and fit patients, in view of survival outcomes and associated toxicity profile.
  • In more frail patients (age > 70, Eastern Cooperative Oncology Group performance status 2, or patients who have any contraindication to the drugs used in FOLFIRINOX), GemCap could be an option.
  • Gemcitabine alone should be used only in frail patients.

A systematic review and meta-analysis by Wan et al found that adjuvant therapy with metformin signficantly reduced the risk of death in Asian patients with pancreatic cancer, but not in Whites. Mortality risk was reduced in Asian patients with stage I-II disease treated with metformin (hazard ratio [HR]=0.76, 95% CI=0.68-0.86) as well as in those with stage I-IV disease (HR=0.88, 95% CI=0.79-0.99), but not in those with stage III-IV disease. [101]

Acinar cell adenocarcinoma

The existing literature on treatment of acinar cell adenocarcinoma (ACC) consists largely of retrospective cohorts and case reviews; there are almost no prospective randomized trials to provide high-level evidence to treat ACC differently than PDAC. As first-line therapy in fit patients, there appears to be a slight preference for using fluoropyrimidine-based combinations (FOLFIRINOX or FOLFOX) versus gemcitabine plus nab-paclitaxel. Regardless of regimen, the disease control rate in ACC seems to be higher than is seen in PDAC. Also based on some small studies, ACC appears to be more radiosensitive than PDAC, thus warranting consideration of radiotherapy or stereotactic brachytherapy in the neoadjuvant or palliative setting. Overall, the stage-based treatment paradigm is similar to the one for PDAC.

Adenosquamous carcinoma of the pancreas

Due to the rarity of adenosquamous carcinoma of the pancreas (ASCP), no randomized trials have addressed treatment strategy for it. Based on small case cohorts and the molecular profile of ASCP,  there is a sense that ASCP may have sensitivity to regimens comprising a fluoropyrimidine plus platinum (eg, FOLFIRINOX, XELOX). As expected for a squamous variant, ASCPs tend to be radiosensitive. Although ASCP tends to have higher expression of PDL-1 than PDAC, the efficacy of immune checkpoint inhibitors in these patients has not been studied.

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Venous Thromboembolism Prophylaxis

Venous thromboembolism (VTE) is a common and sometimes fatal complication in patients with pancreatic cancer. [53] Primary prophylaxis with low molecular weight heparin (LMWH) or direct oral anticoagulants (DOAC) has been shown to significantly reduce the rate of VTE, without increasing the risk of major bleeding. Consequently, most clinical practice guidelines recommend thromboprophylaxis for ambulatory cancer patients at high risk of VTE, in the absence of contraindications. [102]

Risk for VTE can be determined by calculating the Khorana score (see the Khorana risk score calculator). However, the Khorana score assigns +2 points for pancreatic cancer and so classifies all patients with pancreatic cancer at at least intermediate risk of VTE; thus, some guidelines recommend considering primary VTE prophylaxis in all patients with pancreatic cancer who are undergoing chemotherapy. [102]

 

 

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Systemic Therapy for Unresectable and Metastatic Pancreatic Cancer

In the phase 3 Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), the addition of nanoparticle albumin–bound (nab)-paclitaxel to gemcitabine significantly improved overall survival in treatment-naive patients with metastatic pancreatic cancer compared with gemcitabine alone. Overall survival was approximately 2 months longer in patients treated with combination therapy (8.5 vs 6.7 months). One-year and 2-year survival rates were also higher in the combination therapy group (35% vs 22% and 9% vs 4%, respectively). [3]

FOLFIRINOX demonstrated a survival advantage compared with gemcitabine, but increased toxicity, in the European phase III ACCORD/PRODIGE trial, conducted in 342 patients with metastatic pancreatic cancer. Median survival in the FOLFIRINOX arm was 11.1 months, versus 6.8 months on the gemcitabine arm, but 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. [103]

The NCCN currently recommends FOLFIRINOX or modified FOLFIRINOX as a preferred first-line treatment for patients with metastatic or locally advanced unresectable disease who have good performance status. The alternative first-line option is gemcitabine plus nab-paclitaxel. For patients with poor performance status, the NCCN recommends gemcitabine monotherapy. [30] Capecitabine alone may provide second-line therapy benefit in patients whose cancer is refractory to gemcitabine. [104]

Another recommended second-line regimen in patients with metastatic pancreatic cancer that has failed to respond to gemcitabine-based therapy is liposomal irinotecan (Onivyde) in combination with fluorouracil and leucovorin. US Food and Drug Administration (FDA) approval for this was based on a 3-arm, randomized, open-label study (NAPOLI-1 trial) in which median overall survival with liposomal irinotecan/fluorouracil/leucovorin was 6.1 months, compared with 4.2 months for patients treated with fluorouracil/leucovorin or liposomal irinotecan alone. Improvement in progression-free survival was also observed, to a median of 3.1 months with irinotecan liposomal plus fluorouracil/leucovorin compared with 1.5 months for fluorouracil/leucovorin alone. [105]

In the 5-9% of pancreatic cancer patients with BRCA1/2 or PALB2 germline mutations, or those rare patients with somatic (tumor) BRCA mutations, platinum-based chemotherapy combinations such as FOLFIRINOX or gemcitabine plus cisplatin should be considered as first-line options for  unresectable or metastatic disease. [106, 107] For patients with borderline performance status, carboplatin can be considered as an alternative to cisplatin. Mitomycin C is another DNA intercalating agent that has shown activity in BRCA2-associated pancreatic cancer. [108]

Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, is indicated for first-line maintenance treatment of adults with deleterious or suspected deleterious germline BRCA1/2 mutations whose metastatic pancreatic adenocarcinoma has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. FDA approval for this indication was based on the POLO trial, in which patients on olaparib maintenance arm had superior progression-free survival (7.4 months, vs 3.8 months in the placebo arm). [8]

Rucaparib, another selective PARP inhibitor, also demonstrated efficacy in a phase 2 trial, with overall response rate of 25% and disease control rate of 32%. [109] Unfortunately, adding the PARP inhibitor veliparib to gemcitabine plus cisplatin chemotherapy, or to modified FOLFIRI, did not demonstrate additive benefit. [110, 111]

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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 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.

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Diet

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.

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Consultations

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.

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