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Current Treatment Landscape and Emerging Therapies for Pancreatic Cancer
Nelly Adel, PharmD, BCOP, BCPS
Participating Faculty
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Current Treatment Landscape and Emerging Therapies for Pancreatic Cancer

Nelly Adel, PharmD, BCOP, BCPS
Pancreatic cancer remains a disease that is difficult to treat due to a typically late presentation, relatively high resistance to chemotherapy, and lack of effective targeted therapies. The standard of care relies on cytotoxic chemotherapy, primarily FOLFIRINOX and gemcitabine-based regimens. Dose modifications and/or the use of alternative combinations can reduce adverse effects, but these regimens remain highly toxic. As a result, long-term survival is low for patients with advanced or metastatic disease. There is a great need for novel anticancer agents that provide efficacy with minimal toxicity. Currently, inhibitors of immune tolerance and immune checkpoint inhibitors; PARP inhibitors; novel cytotoxic chemotherapies, such as trifluridine/tipiracil; and modifiers of the tumor microenvironment, such as pegylated hyaluronidase, are in clinical trials for the treatment of pancreatic cancer. This activity will review the current treatment landscape and preview emerging therapies for the treatment of advanced pancreatic cancer.
Am J Manag Care. 2019;25:-S0
Pancreatic cancer is a major challenge to patients, the public, and oncologists. In general, it is difficult to detect, most often presents at an advanced stage, and is resistant to therapy. Unfortunately, the treatment of pancreatic cancer has not benefited from recent gains in the molecular understanding of cancer seen with other types, such as non–small cell lung cancer. However, there has been considerable research and clinical trial activity in recent years. This article will evaluate the clinical data for current and emerging treatment strategies for patients with pancreatic adenocarcinoma.

Epidemiology and Prevalence

Approximately 1.6% of all people will develop pancreatic cancer at some point in their lives.1 In 2018 in the United States, it was estimated that there would be 55,440 new cases of pancreatic cancer and 44,330 deaths, making pancreatic cancer the tenth most common cancer diagnosis, and the fourth most common cause of cancer-related death in both genders.2 The 5-year survival for all patients diagnosed with pancreatic cancer is just 8.5%, but it varies tremendously by the stage at diagnosis (Figure 1).1 These data include all pancreatic cancer subtypes, including the relatively uncommon pancreatic neuroendocrine tumors (PNETs), which have a much better prognosis.3

The number of new cases of pancreatic cancer is slightly higher for men and for blacks compared with whites and Asians/Pacific Islanders (16.9, 14.4, and 11.0 per 100,000 men and 14.3, 11.1, and 9.2 per 100,000 women, respectively).1 It is typically diagnosed in older people, with a median age of onset of 70 years and median age of death of 72 years. The incidences of new disease and deaths have remained relatively constant since the National Cancer Institute started keeping records in 1975. However, beginning in the mid-2000s, the 5-year survival began to climb upward and is now 8.5% overall, as compared with less than 5% in 2000.1

Standard of Care

The pancreas is a mixed glandular organ located behind the stomach, making palpation of this organ difficult, and detection not easy (see Figure 24).5 It is mostly an exocrine gland that produces a mixture of bicarbonate and enzymes to aid in the digestion of complex molecules. The endocrine gland portion consists of discrete units, known as Islets of Langerhans, that secrete several important hormones, including insulin, glucagon, somatostatin, and pancreatic polypeptide. Structurally, the pancreas has a head and a tail, like a tadpole. The exocrine secretions drain through the main and accessory pancreatic ducts into the duodenum, and the endocrine hormones are released directly into the blood. The location of the tumor will dictate surgical options, which, unfortunately, are available to just 15% to 20% of patients at the time of diagnosis.6

Diagnosis

Risk factors associated with developing pancreatic cancer include a family history, smoking, obesity, sudden onset of diabetes, and chronic pancreatitis.3,7 Pancreatic cancer is a notoriously silent- growing tumor. Its retroperitoneal location and generalized symptoms make identification difficult. Symptoms typically do not manifest at an early stage. Rather, the cancer reveals itself when there is anatomical obstruction of an organ function, and symptoms may include jaundice, light-colored stools or dark urine, pain in the upper or middle abdomen and back, weight loss for no known reason, loss of appetite, and fatigue.

There are various imaging tests that are performed on patients to help in the diagnosis of the disease and guide in surgical evaluation; these tests include computed tomographic (CT) scan, magnetic resonance imaging scan, and minimally invasive, laparoscopic techniques.3,7 There are no tumor-specific markers for pancreatic cancer, and other markers, such as serum cancer antigen (CA) 19-9, have low specificity (80%-90%).

The overwhelming majority (90%) of pancreatic cancers are referred to as pancreatic ductal adenocarcinoma (PDAC).3,7 PNETs account for 3% to 5% of pancreatic tumors, with the remainder being a variety of histologic types. Precancerous and small cancerous lesions are occasionally found incidental to another imaging procedure. These include high-grade pancreatic intraepithelial neoplasia (PanIn-3), intraductal papillary mucinous tumor, and mucinous cystic tumor.

Staging of Pancreatic Neoplasms

The American Joint Committee on Cancer (AJCC) has designated staging by tumor size, involvement of the lymph nodes, and metastasis to other organs throughout the body, referred to as TNM classification (Table 1).8 N1 represents the presence of 1 to 3 regional nodes, and N2 represents the involvement of 4 or more regional lymph nodes; M1 represents the presence of distance metastasis. Changes to the seventh edition of the AJCC manual incorporated into the current (eighth) edition aid primarily in stratifying patients for surgery because the impact of pancreatic tumor stage on treatment is minimal.

Treatment Options

Although there are significant roles for radiation and chemoradiation, these are reserved for the resectable and adjuvant settings, where incorporation may decrease the potential for recurrence. Cytotoxic chemotherapy continues to form the backbone for the treatment of advanced pancreatic cancer. The FDA-approved treatment options for pancreatic cancer are limited to a small group of these agents9:
  • Fluorinated pyrimidine antimetabolites: fluorouracil, gemcitabine (GEM)
  • Topoisomerase I inhibition: irinotecan (metabolized to the active agent SN-38), liposomal irinotecan
  • DNA crosslinking agents: oxaliplatin, cisplatin
  • Tubulin inhibitors: paclitaxel, nab-paclitaxel (albumin-bound paclitaxel)


Guidelines

The main guidelines for the treatment of pancreatic cancer are published by the National Comprehensive Cancer Network (NCCN), American Society for Clinical Oncology (ASCO), and European Society for Medical Oncology (ESMO).7,10,11

First-Line Therapy for Advanced-Stage Disease

Because most patients present with advanced disease, many of them also have deteriorating performance status due to the loss of appetite and weight. Performance status is a key component in determining which therapy can be tolerated by the patient. All 3 organizations recommend 5-fluorouracil (5FU), leucovorin (folinic acid; LV), irinotecan, and oxaliplatin (FOLFIRINOX) or nab-

paclitaxel/GEM in patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (Table 2).7,10,11 For patients with PS 2, single-agent GEM remains the preferred option by all 3 groups. Single-agent GEM is additionally listed by ESMO as an option for patients with bilirubin levels greater than 1.5 times the upper limit of normal (ULN).10 At PS 3-4, all groups recommend palliative care, although the NCCN and ASCO recommend single-agent GEM for select patients.

Subsequent Lines of Therapy

The preferred regimen for the next line of therapy is whichever regimen was not administered in the first-line setting (ie, FOLFIRINOX if nab-paclitaxel/GEM was administered first, and nab-paclitaxel/GEM if FOLFIRINOX was administered first).7,10,11 After this, the options are severely limited; choice of therapy is mainly dependent on the adverse effect profile of the regimen and the current status of the patient. Single-agent 5FU or capecitabine, 5FU/LV/irinotecan (FOLFIRI), 5FU/LV/liposomal irinotecan, and 5FU/LV/oxaliplatin (FOLFOX) are possibilities. Pembrolizumab is suggested for microsatellite instability–high (MSI-H) tumors, or those tumors with deficiencies in mismatch repair mechanisms (dMMR). Single-agent chemotherapy is usually a last option after exhausting this relatively short list. Beyond this, patients typically receive best supportive care.

Other Treatment Options

Although the standard of care for stage III/IV pancreatic cancer includes regimens of FOLFIRINOX and nab-paclitaxel/GEM, other treatment options are available to patients, particularly, GEM-based regimens. These include GEM/docetaxel/capecitabine (GTX), GEM/oxaliplatin, and GEM/capecitabine.12-16 GEM/erlotinib is used often for patients with endothelial growth factor receptor–positive (EGFR+) tumors, whereas GEM/cisplatin is used for patients with BRCA1/2-mutated tumors.7

Drug Resistance

Pancreatic cancer is characterized by a high resistance to traditional chemotherapies.17,18 Resistance can be intrinsic (de novo) and/or acquired in response to challenge with therapy. The most commonly used agents and regimens have modest clinical benefit and questionable impact on survival. Mechanisms of drug resistance in pancreatic cancer include aberrant gene expression, mutations, deregulation of key signaling pathways, support of stroma cells, presence of dense stroma, and presence of highly resistant stem cells. The effect of these mechanisms is to produce an environment that hinders drug penetration, expels the drug from tumor cells, and overcomes the toxic effects of chemotherapy.

Current Pharmacologic Treatment Options

 
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