US Pharm. 2012;37(12):HS-12-HS-15.

ABSTRACT: Estimates point to 43,920 new cases of, and 37,390 deaths from, pancreatic cancer (PC) in the United States in 2012. The absence of early symptoms and lack of diagnostic testing contribute to late-stage diagnosis, leading to poor survival rates and highlighting the need for early detection and improved treatment. Surgical resection remains the only potentially curative option. Chemotherapy (ChT) and radiotherapy are adjuvant treatments that may provide some benefit; however, poor outcomes persist. Investigational options should be considered in all phases of disease management. There is currently no standard ChT regimen for the adjuvant treatment of PC. The pharmacist plays a key role in educating patients about the importance of regular health care visits, healthy lifestyle, medication adherence, safe administration of oral ChT agents, and management of adverse effects associated with ChT.

Pancreatic cancer (PC) is a devastating and lethal disease affecting one in 68 Americans.¹ The incidence rate of PC has increased by 1.5% per year since 2004, and an estimated 43,920 new cases and 37,390 deaths from PC in the United States were expected to occur in 2012.² The median age at diagnosis from 2005 to 2009 was 71 years; the median age at death was 73 years. One-year and 5-year relative survival rates are 26% and 6%, respectively. These statistics highlight an urgent need for early detection and improved treatment of PC.

Along with the rise in incidence, the mortality rate has been increasing by 0.4% per year since 2004.² The absence of early symptoms and lack of diagnostic testing contribute to late-stage diagnosis and the high mortality associated with PC. Symptoms, if present, include weight loss, upper abdominal pain that may radiate to the back, glucose intolerance, and jaundice (from common bile duct obstruction).² Tobacco use (cigarettes, smokeless tobacco) is a known risk factor for PC, and cigarette smokers have twice the risk of developing PC compared with nonsmokers. Other risk factors include a family history of PC or a personal history of pancreatitis, diabetes, or obesity. Dietary consumption of red meat and alcohol has been proposed (but not proven) in epidemiologic studies as a possible cause of PC. Other potential factors, such as Lynch syndrome (in which the patient has a higher-than-normal risk of developing certain types of cancer, often before age 50 years) and other genetic disorders, may be associated with PC.^2,3

TREATMENT OPTIONS

Nonpharmacologic

Surgery is the only potentially curative option for PC. Unfortunately, only 15% to 20% of patients are candidates for surgical resection at diagnosis.⁴ Age, comorbidities, performance status, frailty, and tumor location and size should be considered when deciding whether a patient is eligible for surgery. Tumors are classified as resectable, borderline resectable, or unresectable (locally advanced or metastatic).⁵ Patients are selected for surgery based on their likelihood of achieving an R0 resection (negative surgical margin), the key criterion for eligibility.^6,7 Borderline-resectable patients may undergo neoadjuvant chemotherapy (ChT) or chemoradiotherapy (CRT) to improve the odds of an R0 resection, or they may have surgery immediately.⁸

Neoadjuvant therapy is given before the primary treatment in order to shrink the tumor or improve primary (surgical) treatment effects.³ Adjuvant therapy, administered after the primary treatment, is intended to reduce the risk of recurrence. The role of adjuvant radiotherapy (RT) is not yet defined, but RT is usually given before or after systemic ChT.⁹ RT should be administered at a dose of 45 to 46 Gy, with high-energy photons to the tumor bed, surgical anastomoses, and adjacent lymph node regions, followed by 5 to 15 Gy to the tumor bed (with careful attention to small-bowel exposure).⁸ No studies have demonstrated the superiority of CRT administered before versus after ChT. However, if a patient has a margin-positive resection, initial CRT followed by systemic ChT is appropriate.^9-11

Pharmacologic

ChT has a modest effect against PC. However, there is an extremely high likelihood of a poor outcome, so investigational options should be considered in all phases of disease management.⁸ There is currently no standard combination ChT regimen for adjuvant treatment of PC, although several agents may be used. Pharmacology, dosing, and common adverse events (AEs) of ChT agents are given in TABLE 1. Outcomes of clinical trials involving ChT agents for PC appear in TABLE 2.

Gemcitabine (GEM): In 1997, GEM became the standard ChT regimen for advanced PC. In a randomized trial of GEM versus 5-fluorouracil (5-FU), GEM significantly improved median overall survival (OS) and clinical utility.¹² GEM may be used as monotherapy in patients with metastatic disease and in patients with unresectable locoregional disease and good performance status, and for symptomatic relief in patients with metastatic or locally advanced unresectable disease and poor performance status.⁸ GEM should be given 1,000 mg/m² over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing/holding a dose), followed by a week of rest from treatment (TABLE 1).¹³

Fixed-Dose Rate GEM (FDR-GEM): Evidence supports the use of FDR-GEM for PC.¹⁴ One study found that patients given FDR-GEM had improved survival but more severe AEs, specifically hematologic toxicities.¹⁵ A subsequent trial demonstrated an increase in median OS with FDR-GEM versus standard infusion, although this did not satisfy protocol-specified criteria for superiority.¹⁶ FDR-GEM may be given at 10 mg/m²/min as an alternative to standard infusion over 30 minutes (TABLE 1).

GEM Combinations: Efforts to improve PC treatment have led to the investigation of GEM given together with various other ChT agents, but none of these combinations has demonstrated superiority over GEM monotherapy. To date, two phase III trials have compared GEM monotherapy with GEM in combination with 5-FU, but neither regimen increased OS.^17,18 However, one of these trials showed improvement in progression-free survival (PFS) in patients with primarily metastatic disease.¹⁷ The combination of GEM and 5-FU may be used in patients with good performance status.

Capecitabine (CAP), an orally administered prodrug of 5-FU, mimics the continuous infusion of 5-FU.¹⁹ As with 5-FU, CAP given with GEM has not significantly improved OS compared with GEM alone.^20,21 However, in one trial, the combination did improve PFS and response rate (RR) versus GEM alone.²⁰ The combination of GEM and CAP is a viable option for patients with locally advanced or metastatic disease.⁸

GEM has also been investigated in combination with alkylating agents, with conflicting results. The combination of GEM and cisplatin (CIS) has not demonstrated an improvement in OS. Two phase III trials of GEM plus CIS showed a significant improvement in RR^22,23; a different, larger study found no benefit in RR or PFS.²⁴ GEM plus CIS may be a good choice for PC patients with certain family histories, such as BRCA mutation.^25-27 Similarly, oxaliplatin (OX) in conjunction with GEM did not improve OS^16,28; however, in one study, the combination improved PFS, RR, and clinical benefit.²⁸ Improved OS has not been demonstrated for GEM combined with pemetrexed or irinotecan (IRI).^29,30 Paclitaxel (protein-bound) plus GEM has shown activity against PC in a phase I-II trial and may be considered for patients with advanced disease and good performance status.³¹

GEM With Tyrosine Kinase Inhibitors (TKIs) and/or Monoclonal Antibodies (Mabs): GEM has been studied in combination with newer targeted ChT agents, such as TKIs and Mabs. GEM plus erlotinib (ERL) is the only combination that has shown an improvement in OS.^32-36 In one study, GEM plus ERL significantly improved OS and PFS compared with GEM alone.³² Median survival favored the combination group (6.24 months in study group vs. 5.91 months in controls), and a higher percentage of patients survived at 1 year (23% in study group vs. 17% in control group).³² This combination is recommended for patients with locally advanced or metastatic disease and good performance status.⁸

Bevacizumab (BEV) combined with GEM plus ERL was studied, but this regimen did not improve OS.³³ However, PFS was significantly improved compared with GEM plus ERL alone. The addition of BEV, axitinib, or cetuximab to GEM did not improve OS or PFS.^34-36

Non-GEM Regimens: In the PRODIGE trial, FOLFIRINOX (folinic acid [LV], FU, IRI, OX) improved median PFS and median OS versus GEM.³⁷ FOLFIRINOX has been made a category 1 recommendation for first-line treatment of good-performance-status patients with metastatic PC, and a category 2A recommendation for patients with locally advanced unresectable disease. AE incidence increased with the combination regimen, but these AEs did not significantly affect quality of life.³⁷ CAP, 5-FU/LV/OX, and CAP plus OX are acceptable second-line options for metastatic PC.^38-40

LV: There is currently an LV shortage in the U.S. Alternatives are to use levoleucovorin (TABLE 1); lower the LV dosage for all doses in all patients, which is likely to be just as efficacious; or increase the 5-FU dosage (10% range).⁸

TREATMENT GUIDELINES

Treatment of PC is determined by cancer staging of the cancer as resectable, borderline resectable, or unresectable or metastatic. TABLE 3 provides an overview of current treatment recommendations for pancreatic adenocarcinoma.

THE PHARMACIST’S ROLE

The pharmacist can play a vital role in educating patients about the necessity of routine visits to their health care provider, along with the importance of maintaining a healthy lifestyle. Smoking cessation is one of the most critical changes patients can make to improve their overall health and prevent the development of cancer and many other life-threatening diseases. Oral ChT agents such as CAP and ERL are becoming more prevalent in the management of cancer. Educating patients about medication adherence, safe administration of oral ChT agents, and AE management is fundamental to optimization of therapy. Finally, supportive care in patients receiving ChT is paramount. For more information regarding the National Comprehensive Cancer Network’s Guidelines for Supportive Care, visit www.nccn.org/professionals/physician_gls/f_guidelines.asp.

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