Pancreatic ductal adenocarcinoma is a challenging disease with a poor prognosis, with 5-year survival rates in the single digits (~8%).1 Survival rates in pancreatic cancer are low in part because most patients have advanced disease at the time of diagnosis and early development of systemic metastatic disease is common, with approximately 52% of patients with newly diagnosed pancreatic cancer having metastatic disease at diagnosis.1 Surgical resection with negative margins is the cornerstone of potentially curative therapy for localized disease, but only 15% to 20% of patients are eligible for resection at the time of initial diagnosis. Patients with unresectable and metastatic disease are offered palliative chemotherapy. Unfortunately, early recurrence is common in patients with resectable tumors who achieve a complete resection and are treated with adjuvant therapy (5-year recurrence rate ~80%).2,3 This article reviews the management of patients with unresectable and/or metastatic pancreatic cancer. A previous article reviewed the diagnosis and staging of pancreatic cancer and the approach to neoadjuvant and adjuvant therapy in patients with resectable and borderline-resectable disease.4
First-Line Systemic Treatment
A 72-year-old man who underwent treatment for pancreatic adenocarcinoma 18 months ago presents to the emergency department after developing poor appetite, weight loss, and abdominal discomfort and fullness without diarrhea, which has been constant for the past 2 weeks even though he has been taking analgesics and pancreatic enzymes.
The patient was diagnosed with pancreatic cancer 18 months ago after presenting with yellowish skin and sclera color; abdominal and pelvis computed tomography (CT) with intravenous contrast showed a pancreatic head mass measuring 2.6 × 2.3 cm minimally abutting the anterior surface of the superior mesenteric vein. Endoscopic ultrasound confirmed an irregular mass at the head of the pancreas and sonographic evidence suggested invasion into the portal vein. Examination of a tissue sample obtained during the procedure showed that the mass was consistent with pancreatic adenocarcinoma. Magnetic resonance imaging (MRI) performed to define venous vasculature involvement revealed a pancreatic head mass measuring 3.0 × 2.7 cm without arterial or venous vasculature invasion. The mass was abutting the portal vein and superior mesenteric veins, and a nonspecific 8-mm aortocaval lymph node was noted. The tumor was deemed to be borderline resectable, and the patient received neoadjuvant therapy with gemcitabine and nab-paclitaxel. After 4 cycles, his carbohydrate antigen (CA) 19-9 level decreased, and MRI revealed a smaller head mass (1.3 × 1.4 cm) with stable effacement of the superior mesenteric vein and no portal vein involvement; the aortocaval lymph node remained stable. He was treated with gemcitabine chemoradiotherapy prior to undergoing an uncomplicated partial pancreaticoduodenectomy. Analysis of a surgical pathology specimen revealed T3N0 disease with a closest margin of 0.1 cm. Postsurgery, the patient completed 4 cycles of adjuvant chemotherapy with gemcitabine plus capecitabine.
At his current presentation, MRI of the abdomen and pelvis reveals a new liver mass and peritoneal thickness. Serology testing reveals a CA 19-9 level of 240 U/mL, and other liver function tests are within normal limits. Biopsy of the mass confirms recurrence.
- What systemic chemotherapy would you recommend for this patient with metastatic pancreatic adenocarcinoma?
Most cases of pancreatic cancer are unresectable and/or metastatic at the time of diagnosis. Identifying treatment endpoints and the patient’s goals of care is a critical step in management. Systemic chemotherapy can provide significant survival benefit in first-line and second-line treatment compared to best supportive care. Palliative interventions also include systemic therapy, which often improves pain control and other cancer related–symptoms and hence quality of life. Participation in clinical trials should be offered to all patients. Therapy selection depends on the patient’s performance status, comorbidities, and liver profile and the results of biomarker testing and mutation analysis.
Several single-agents, including fluoropyrimidines, gemcitabine, irinotecan, platinum compounds, and taxanes, have minor objective response rates (< 10%) and a minimal survival benefit (~2 weeks) in metastatic pancreatic adenocarcinoma. Conversely, multi-agent therapies provide higher response rates and can extend overall survival (OS). Two combinations, nab-paclitaxel plus gemcitabine and FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and flourouracil), have significantly prolonged survival compared to best single-agent gemcitabine, as demonstrated in the MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) and PRODIGE 4/ACCORD 11 trials.5,6 Because both multi-agent regimens are also associated with a more toxic adverse effect profile, gemcitabine monotherapy continues to be a front-line therapy for patients with multiple comorbidities, elderly frail patients (> 80 years of age), or patients who cannot tolerate other combinations.7
Gemcitabine became a standard of care treatment for pancreatic cancer in the mid-1990s, and was tested as a second-line therapy in a multicenter phase 2 clinical trial that accrued 74 patients with metastatic pancreatic cancer who had progressed on fluorouracil therapy. In this trial, 27% of patients treated with gemcitabine achieved a clinical benefit response and the median OS was 3.85 months.8 The agent was generally well-tolerated with a low incidence of grade 3 or 4 toxicities. Subsequently, a randomized clinical trial compared gemcitabine to fluorouracil in the front-line setting in 126 patients with newly diagnosed advanced pancreatic cancer.9 Patients were randomly assigned to receive single-agent intravenous fluorouracil administered without leucovorin as a short-term infusion (600 mg/m2 once weekly) or gemcitabine (1000 mg/m2 weekly for up to 7 weeks followed by 1 week of rest, and then weekly for 3 out of every 4 weeks thereafter). A higher proportion of patients treated with gemcitabine had a clinical benefit response (23.8% versus 4.8%), with an improvement in a composite measure of pain (pain intensity and analgesic consumption) and performance status. Clinical responses assessed by a secondary measure, weight gain, were below 10% in both arms, but the median OS was significantly longer for the gemcitabine arm (5.65 months versus 4.4 months, P = 0.0025) and the 1-year OS rate also favored the gemcitabine arm (18% versus 2%). Grade 3/4 neutropenia was reported more frequently in the gemcitabine arm (23% versus 5%). There is no evidence that increasing the dose intensity of the fixed-dose rate of gemcitabine (1000 mg/m2 per week administered as a 30-minute infusion) leads to improved antitumor activity.