Pharmacotherapeutic options for pancreatic ductal adenocarcinoma

ABSTRACT

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy projected to be the 2^nd leading cause of cancer related death in the USA by 2030. This manuscript discusses current and evolving treatment approaches in patients with pancreatic cancer.

Areas covered

PDAC is classified as: a) resectable, b) borderline resectable, c) unresectable (locally advanced and metastatic). The standard of care for patients who present with resectable pancreatic adenocarcinoma is six months of adjuvant modified (m) FOLFIRINOX, gemcitabine plus capecitabine, or single agent gemcitabine. For many reasons, there has been a paradigm shift to employing neoadjuvant chemotherapy. For resectable and borderline resectable patients, we generally start with systemic therapy and reevaluate resectability with subsequent scans specifically when the tumor is located in the head or body of the pancreas. Combined chemoradiation therapy can be employed in select patients. The standard of care for metastatic PDAC is FOLFIRINOX or gemcitabine and nab-paclitaxel. Germline and somatic genomic profiling should be obtained in all patients. Patients with a germline BRCA mutation can receive upfront gemcitabine and cisplatin.

Expert opinion

Thorough understanding of molecular pathogenesis in PDAC has opened various therapeutic avenues. We remain optimistic that future treatment modalities such as targeted therapies, cellular therapies and immunotherapy will further improve survival in PDAC.

KEYWORDS:

• Pancreatic cancer
• pharmacotherapeutics
• future approaches
• clinical trials

Article highlights

• PDAC is a fatal malignancy projected to be the 2^nd most common cause of cancer related mortality in the United States by 2030.

• Clinically, PDAC patients are classified into a) resectable, b) borderline resectable, c) unresectable which includes locally advanced and metastatic disease.

• Surgical resection remains the only curative option in pancreatic cancer with a 5-year overall survival rate (OS) of 10% for node positive disease and 30% for node negative disease. Standard of care is to offer 6 cycles of FOLFIRINOX to patients with good performance status. Gemcitabine alone or combined with capecitabine are also good options for adjuvant therapy. Chemotherapy can also be considered in the neoadjuvant setting in select patients.

• Borderline resectable patients are treated initially with systemic therapy and revaluated in multidisciplinary tumor boards for potential resectability. Patients who are downstaged to resectable status should proceed to curative intent surgery preferably at a high-volume center. Patients who either progress or remain unresectable should continue systemic therapy. Combined modality chemo-radiation therapy is also an option that has demonstrated improvement in progression free survival in select patients.

• Unresectable pancreatic cancer patients include locally advanced and metastatic disease, and patients are treated with FOLFIRINOX or gemcitabine plus nab-paclitaxel. Addition of cisplatin to gemcitabine plus nab-paclitaxel is an active combination with impressive median progression free survival and median overall survival in a phase 1b/2 study. This active combination can be considered in patients with BRCA1/2 mutations. Patients with germline BRCA1/2 mutations can also be considered for olaparib if they have not progressed after 16 weeks or more on a platinum-based therapy (FOLFIRINOX or gemcitabine plus cisplatin) specifically if chemotherapy toxicity is a concern. There is no prospective data comparing gemcitabine plus nab-paclitaxel to FOLFIRINOX. However, we recommend offering the latter to fit patients as first line based on retrospective comparison.

• Patients who received gemcitabine plus nab-paclitaxel can be treated with nano-liposomal irinotecan and 5-FU/leucovorin according to the NAPOLI-1 trial. All patients who have relapsed after first line chemotherapy should be considered for clinical trial.

• Supportive and palliative care should be an integral component for all patients with pancreatic cancer.

• Clinical trials with novel targeted, cytotoxic and immune therapies are warranted.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

H Babiker is a Paul Calabresi Scholar at the Mayo Clinic Cancer Center and acknowledges K-12 Grant Program, K12CA090628.