Pancreatic Adenocarcinoma: Management of Advanced Unresectable and Metastatic Disease
Targeted Therapies
A variety of targeted therapies have failed to demonstrate major activity in metastatic pancreatic cancer, including bevacizumab targeting vascular endothelial growth factor, cetuximab targeting epidermal growth factor receptor, ruxolitinib targeting JAK pathway signaling, saridegib targeting the hedgehog pathway, and MK-0646 targeting insulin-like growth factor 1 receptor (IGFR). Other novel agents against targetable pathways that had promising early-phase results are currently being studied in ongoing clinical trials; these include JAK-2, PI3K, MEK, and BRAF inhibitors and immunotherapy.
Recent research efforts have focused on targeted testing of advanced pancreatic cancers for mismatch repair deficiency (dMMR) and high microsatellite instability (MSI-H) and for the germline and somatic BRCA1/2 or PALB2 mutations to determine potential eligibility for immunotherapy. Patients with these tumor characteristics and/or mutations might also be more sensitive to platinum-based chemotherapy agents or poly (ADP-ribose) polymerase (PARP) inhibitors. Germline mutations in BRCA 1/2 are present in 5% to 8% of patients with pancreatic cancer (up to 10%–15% in Ashkenazi Jewish population).28 A superior median OS was retrospectively observed for patients with advanced stage BRCA 1/2-associated pancreatic adenocarcinoma who were treated with platinum-based chemotherapy agents versus those treated with non-platinum-based agents (22 versus 9 months; P = 0.039).22 PARP inhibitors have shown activity in germline BRCA1/2-associated breast (off label) and ovarian cancers (approved by the FDA). The efficacy and safety of PARP inhibitors were evaluated in a phase 2 study of a spectrum of BRCA1/2-associated cancers, including pancreatic cancer. The results revealed a tumor response rate of 21.7% (5 of 23 patients with pancreatic cancer [95% CI 7.5 to 43.7]), and 35% of patients had stable disease for a duration of 8 weeks or more (95% CI 16.4 to 57.3) with good tolerability.29 Three novel PARP inhibitors are currently under clinical trial investigation in patients with germline BRCA 1/2- and PALB2-mutated metastatic pancreatic cancer: maintenance olaparib (NCT02184195) and rucaparib (NCT03140670) are both being studied as monotherapy in patients whose disease has not progressed on first-line platinum-based chemotherapy, and veliparib is being evaluated in a 3-arm study that includes gemcitabine and cisplatin with or without veliparib and single-agent maintenance veliparib (NCT01585805).
In 2017, the FDA granted accelerated approval to pembrolizumab for treatment of patients with unresectable or metastatic MSI-H or dMMR solid tumors whose disease progressed on prior treatments, making it the first oncology drug to be approved based on the genetic features of the tumor rather than its location in the body. This first tissue/site-agnostic approval was based on results from 5 single-arm trials involving 149 patients, including 5 patients with pancreatic cancer.30 The objective response rate with pembrolizumab was 39.6% (95% CI 31.7 to 47.9), including a 7.4% complete response rate and a 32.2% partial response rate. The median duration of response was not reached at the time of publication (range, 1.6+ months to 22.7+ months).
Palliative and Supportive Care
Case Continued
The patient opts to participate in a novel immunotherapy clinical trial and is currently on his second cycle. He continues to have right upper quadrant pain despite opioid analgesia, has not gained any weight, and noticed new right lower extremity swelling after a recent holiday vacation to Florida.
- What supportive measures should be in place for patients with metastatic adenocarcinoma?
Most patients with advanced pancreatic adenocarcinoma will require a palliative intervention. All new unresectable pancreatic cancer patients should have an early psychosocial evaluation; identification of symptoms and implementation of preventive interventions that would improve quality of life and reduce suffering are paramount. A multidisciplinary team including physician/nursing staff, nutritionist/dietitian, palliative service, a social worker, and a case manager should be involved in patient care. More than two-thirds of patients can develop symptomatic biliary obstruction.31 Bile duct obstruction due to locally advanced pancreatic adenocarcinoma causes hyperbilirubinemia, which requires endoscopic placement of a metallic or plastic stent; plastic stents have a higher rate of re-occlusion.32 Appropriate bile flow allows treatment with irinotecan-based regimens. Percutaneous biliary drainage may be necessary if endoscopic intervention is not feasible.
Approximately one quarter of patients may present with gastric outlet obstruction due to duodenal obstruction.31 Endoscopic placement of an enteral expandable metal stent is preferred. Alternatively, percutaneous endoscopic gastrostomy tube placement may give symptomatic relief. Palliative surgical interventions are reserved for patients with greater life expectancy and in whom all other interventions have failed or are not feasible.
Almost all patients with pancreatic adenocarcinoma will experience cancer-associated pain. Intractable pain should be treated with a celiac plexus block. Radiation therapy may be considered as an adjunct therapy for pain, bleeding, and/or local obstruction. The National Comprehensive Cancer Network guidelines recommend that patients who undergo a laparotomy for potentially resectable disease but are found to have unresectable disease at the time of surgery should undergo stenting, open biliary-enteric bypass with or without gastrojejunostomy, and/or celiac plexus neurolysis.33
Pancreatic exocrine enzyme insufficiency due to tumor extension, duct blockage, or surgical removal may cause malabsoprtive steatorrhea, contributing to cancer cachexia syndrome. Nutritional evaluation and daily oral pancreatic enzyme supplementation are recommended.34
Patients diagnosed with pancreatic adenocarcinoma have a venous thromboembolism (VTE) incidence of 20 per 100 person-years (5%–60% of patients) and are considered at very high risk for VTE based on the Khorana score.35 The preferred VTE treatment is low-molecular-weight heparin rather than warfarin based on the results of the CLOT study.36 There is no current evidence for routine prophylactic therapy or the use of direct oral anticoagulants.
Finally, a cancer diagnosis, particularly pancreatic cancer, causes a significant amount of psychosocial stress and requires active support and counseling from a professional.
