Pancreatic Cancer: Pharmacologic Management

Pancreatic ductal adenocarcinoma (PDAC), which arises from the exocrine compartment of the pancreas, is the most prevalent pancreatic malignancy.¹ This condition represents approximately 3% of all cancers in the United States and approximately 7% of all cancer deaths.² 

An estimated 64,050 cases of pancreatic cancer are anticipated to be diagnosed in 2023.³ The median age at the time of diagnosis of pancreatic cancer is 70, with individuals aged 65 to 74 being most frequently affected. Although the disease burden of PDAC has remained fairly stable over the past decade, the 5-year survival rate has improved by just 2% in that time — from 9.8% to 12%.^2-3 

Pancreatic Ductal Adenocarcinoma Treatment

Surgery, chemotherapy, and radiation are therapeutic approaches for pancreatic cancer management. Surgical resection combined with systemic multiagent chemotherapy is the only known cure for PDAC.⁴ Patients with disease confined to the pancreas are eligible for this regimen, but fewer than 1 in 5 patients are diagnosed at this early stage. 

Chemoradiation is the most common modality used in the treatment of PDAC.⁴ This article will focus on the pharmacotherapeutic options for this disease. Determining the appropriate treatment for PDAC begins with staging.² 

Staging of Pancreatic Cancer 

The American Joint Committee on Cancer (AJCC) TNM system is the primary staging system used to characterize pancreatic cancer.² TNM refers to the 3 components of the staging system: extent of the tumor (T), spread to nearby lymph nodes (N), and metastasis to distant sites (M). This information is combined to categorize stages into groups and to determine the overall cancer stage.  

TNM stages range from 0 through 4, with the lower number representing less spread and the higher number signifying more advanced cancer.² Two broad categories exist when staging a tumor: the surgical stage and the clinical stage. The surgical stage, as the name suggests, is determined by examining the tumor and its extent of spread during surgery. 

A clinical stage will be assigned if a cancer is determined to be too advanced for surgery during the initial patient evaluation including examination, laboratory evaluation, and imagine studies.² The clinical stage is used to identify the best treatment options for unresectable PDAC. 

Table 1. AJCC Stages of Pancreatic Ductal Adenocarcinoma

AJCC Stage	Stage Grouping	Description
0	Tis, N0, M0	Cancer is confined to the top layers of pancreatic duct cells, without deep tissue invasion (Tis); there is no spread beyond the pancreas, no spread to nearby lymph nodes (N0), and no spread to distant sites (M0)
IA	T1, N0, M0	Cancer is confined to the pancreas and measures no larger than 2 cm across (T1); there is no spread to nearby lymph nodes (N0) and no spread to distant sites (M0)
IB	T2, N0, M0	Cancer is confined to the pancreas and measures larger than 2 cm but no greater than 4 cm across (T2); there is no spread to nearby lymph nodes (N0) and no spread to distant sites (M0)
IIA	T3, N0, M0	Cancer is confined to the pancreas and measures larger than 4 cm across (T3); there is no spread to nearby lymph nodes (N0) and no spread to distant sites (M0)
IIB	T1, N1, M0	Cancer is confined to the pancreas and measures no larger than 2 cm across (T1); there is spread to no more than 3 nearby lymph nodes (N1) and no spread to distant sites (M0)
T2, N1, M0	Cancer is confined to the pancreas and size is T2; there is N1 lymph node involvement and no spread to distant sites (M0)
T3, N1, M0	Cancer is confined to the pancreas and size is T3; there is N1 lymph node involvement and no spread to distant sites (M0)
III	T1, N2, M0	Cancer is confined to the pancreas and size is T1; there is spread to 4 or more nearby lymph nodes (N2) and no spread to distant sites (M0)
T2, N2, M0	Cancer is confined to the pancreas and size is T2; there is N2 lymph node involvement and no spread to distant sites (M0)
T3, N2, M0	Cancer is confined to the pancreas and size is T3; there is N2 lymph node involvement and no spread to distant sites (M0)
T4, Any N, M0	Cancer is extending outside the pancreas and into nearby large blood vessels (T4), with or without lymph node involvement (any N) and no spread to distant sites (M0)
IV	Any T, Any N, M1	Cancer has spread to distant sites such as the liver, peritoneum, lungs, or bones (M1), the tumor can be of any size (Any T), and the cancer may or may not have spread to nearby lymph nodes (Any N)

Tis = carcinoma in situ

From American Cancer Society staging information.²

Pancreatic Cancer Surgery Eligibility

Planning treatment for PDAC requires stratifying the tumor based on resectability.² The TNM staging system allows to physicians categorize PDAC as resectable, borderline resectable, or unresectable. 

PDAC is considered resectable if the tumor is confined to the pancreas with no spread to surrounding lymph nodes or major blood vessels.² PDAC is considered borderline resectable when the tumor has only just contacted nearby blood vessels. 

Of note, the category of the tumor can change during surgery if the surgical team finds that the disease has spread further than previously identified.² Should this occur, the surgeon will perform a biopsy of the tumor and discontinue the surgical procedure. 

PDAC is considered locally advanced when it extends into or surrounds nearby blood vessels but has not spread to distant organs.²  Stage IV or metastatic PDAC has undergone spread to distant organs. Surgical eligibility in advanced PDAC depends on each individual presentation, but most commonly these tumors are unresectable and treated with chemoradiation.⁵

At the time of diagnosis, approximately 50% to 60% of patients have metastatic disease, 25% to 30% have locally advanced disease, and 10% to 15% have local (resectable or borderline resectable) disease.⁶ The remainder of this article will focus on the recommended pharmacotherapy in each of these clinical situations. 

Neoadjuvant Chemotherapy

Neoadjuvant chemotherapy can be offered to patients with resectable or borderline resectable PDAC prior to surgery.² Neoadjuvant chemotherapy can shrink tumors that appear to be resectable but are too large for surgical removal at the time of diagnosis. 

Another potential benefit of neoadjuvant therapy is that it offers better target tissue access than adjuvant therapy as the primary tumor remains intact.⁷ Based on guidelines established by the National Comprehensive Cancer Network (NCCN), the use of neoadjuvant therapy is determined on an individual basis.⁸ Although some studies have shown a modest survival increase with neoadjuvant chemotherapy, larger randomized clinical trials are needed to better characterize its utility.⁷ 

The first-line treatment recommendation for PDAC is FOLFIRINOX, a 4-drug regimen containing fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin.^7-8 However, guidelines only recommend the use of FOLFIRINOX in patients with good performance status (ability to complete daily tasks) due to the significant side effects associated with the regimen. In patients who cannot tolerate FOLFIRINOX, gemcitabine plus albumin-bound paclitaxel (nab-paclitaxel) is recommended as alternative neoadjuvant therapy. 

Adjuvant Chemotherapy 

Adjuvant chemotherapy is considered the standard of care after PDAC surgical resection.⁶ However, due to high rates of postsurgical complications, many patients end up not receiving it. PRODIGE 24 (ClinicalTrials.gov Identifier: NCT01526135) and ESPAC-4 (ClinicalTrials.gov Identifier: NCT00058201) are 2 recent clinical trials that inform current PDAC treatment guidelines.⁷

The PRODIGE 24 trial compared modified FOLFIRINOX (mFOLFIRINOX; reduced irinotecan and no 5-FU bolus) and gemcitabine monotherapy in 493 patients with resected PDAC.⁹ As prior research found that mFOLFIRINOX had similar treatment efficacy to FOLFIRINOX in patients with advanced PDAC, this study used the modified regimen to reduce side effects. 

Overall survival of patients in PRODIGE 24 was 19.4 months longer in patients receiving mFOLFIRINOX compared with those receiving gemcitabine (54.4 months vs 35 months, respectively).⁹ The NCCN guidelines now recommend mFOLFIRINOX in patients with good performance status as first-line adjuvant chemotherapy. 

The ESPAC-4 trial found that gemcitabine with capecitabine was associated with an increase in overall survival of 28 months compared with 25 months in patients who received gemcitabine monotherapy.⁷ Based on this modest survival benefit, guidelines recommend gemcitabine with capecitabine as alternative adjuvant therapy for patients with PDAC.⁸ 

Management of Advanced PDAC 

Although surgery is possible in a small number of patients with advanced PDAC, this section will focus on their pharmacologic management. Chemotherapy is the most common treatment modality used in locally advanced and metastatic PDAC.² 

Systemic Chemotherapy 

A variety of systemic chemotherapeutic drugs have been approved by the US Food and Drug Administration (FDA) for the management of advanced PDAC.¹⁰ Of note, chemotherapy given in advanced PDAC is typically palliative, intended only to improve overall survival and not to cure the disease.⁷

NCCN guidelines recommend FOLFIRINOX as first-line systemic therapy for both locally advanced and metastatic PDAC in patients with good performance status.^2,7-8 These recommendations are based on several randomized trials demonstrating that treatment with FOLFIRINOX improved overall survival compared with gemcitabine. 

As patients with lower performance status and comorbidities cannot tolerate FOLFIRINOX’s side effect profile, the NCCN offers additional treatment recommendations for these populations.⁸ The FDA-approved chemotherapy agents available to treat PDAC are reviewed here. 

Table 2. Management Guidelines for Systemic Chemotherapy for Pancreatic Ductal Adenocarcinoma

Drug	Dose	Administration	Treatment Duration	Patient Population
Albumin-bound paclitaxel (nab-paclitaxel)	125 mg/m2	IV infusion over 30-40 min	Days 1, 8, and 15 of each 28-d cycle; given with gemcitabine	Metastatic (stage IV) disease
Capecitabine	See gemcitabine-capecitabine in Table 3	See gemcitabine-capecitabine in Table 3	See gemcitabine-capecitabine in Table 3	Adjuvant treatment for resectable disease (stages I-II), given only with gemcitabine
Fluorouracil (5-FU)	400 mg/m2 bolus on day 1, then 2400 mg/m2 as a continuous infusion over 46 h every 2 wk	IV infusion	Given in a multidrug chemotherapy regimen (see Table 3) or with leucovorin only	Adjuvant or neoadjuvant treatment for resectable disease
Gemcitabine	1000 mg/m2	IV infusion over 30 min; for weeks 1-8, weekly dosing for first 7 wk, followed by 1-wk rest; after week 8, weekly dosing on days 1,8, and 15 of each 28-d cycle	Indicated after treatment with 5-FU, administered with albumin-bound paclitaxel	Nonresectable stages II-III and metastatic disease
Irinotecan	70 mg/m2	IV infusion over 90 min every 2 wk	Given in combination with 5-FU and leucovorin after disease progression following gemcitabine treatment	Metastatic disease

IV = intravenous.

From FDA-approved prescribing information.^11-15

In addition to the agents reviewed above, mitomycin is also approved for use in PDAC.^16-17 Mitomycin is an antibiotic with antitumor properties. It is typically used in combination with other chemotherapeutic agents to treat locally advanced or metastatic PDAC that has been unresponsive to previous treatments.^16,17 Mitomycin is given in a 20 mg/m² dose on day 1 of 6- to 8-week cycles.¹⁷

Several studies have demonstrated that multidrug chemotherapy regimens have better survival outcomes than single-drug chemotherapy in PDAC.⁷ As a result, the FDA has approved several multidrug treatment options for the management of PDAC. The guidelines for dosing, administration, and target patient population are discussed here.

Table 3. Management Guidelines for Multidrug Chemotherapy Regimens for Pancreatic Ductal Adenocarcinoma

Drug	Dose	Administration	Treatment Duration	Patient Population8
FOLFIRINOX18	Oxaliplatin 85 mg/m2 over 2 h, then leucovorin 400 mg/m2 as 2-h infusion; after 30 min, add irinotecan 180 mg/m2 over 90 min, then immediately 5-FU 400 mg/m2 bolus followed by 2400 mg/m2 over 46 h	IV infusion	14-d cycles for 24 wk (12 cycles)	Neoadjuvant therapy for resectable and borderline resectable disease (stages I and II); locally advanced and metastatic disease
Gemcitabine-capecitabine19	Gemcitabine 1000 mg/m2 over 30 min; capecitabine 650 mg/m2 twice daily	IV infusion for gemcitabine; orally for capecitabine	Gemcitabine on days 1 and 8 and capecitabine on days 1-14 of 21-d cycle	Neoadjuvant and adjuvant therapy for resectable and borderline resectable disease (stages I and II); locally advanced and metastatic disease
Gemcitabine-cisplatin20	Gemcitabine 1000 mg/m2 over 30 min; cisplatin 50 mg/m2 over 1h	IV infusion	Administered on days 1 and 15 of 4-wk cycle	Locally advanced or metastatic disease
Gemcitabine-nab-paclitaxel21	Nab-paclitaxel 125 mg/m2 over 30-40 min, followed by gemcitabine 1000 mg/m2	IV infusion	Administered weekly for 7 of 8 wk (cycle 1), then administered on days 1, 8, and 15 every 4 wk	Neoadjuvant therapy for resectable and borderline resectable disease (stages I and II); locally advanced and metastatic disease
mFOLFIRINOX9	Oxaliplatin 85 mg/m2 over 2 h, then leucovorin 400 mg/m2 as 2-h infusion; after 30 min, add irinotecan 150 mg/m2 over 90 min, then immediately 5-FU 2400 mg/m2 over 46 h	IV infusion; administered in 14-d cycles	14-d cycles for 24 wk (12 cycles)	Neoadjuvant and adjuvant therapy for resectable and borderline resectable disease (stages I and II); locally advanced and metastatic disease
OFF22	Oxaliplatin 50 mg/m2 over 2h, followed by leucovorin 50 mg/m2  bolus and 5-FU 500 mg/m2 over 1 h	IV infusion of oxaliplatin, IV bolus of leucovorin and 5-FU	Administered weekly until toxicity or disease progression	Advanced disease after progression following gemcitabine treatment

FOLFIRINOX = fluorouracil, leucovorin, irinotecan, and oxaliplatin; IV = intravenous; mFOLFIRINOX = FOLFIRINOX with reduced irinotecan and no 5-FU bolus; OFF = fluorouracil, leucovorin, and oxaliplatin.

Targeted Therapy

With developments in tumor genomics and molecular understanding of tumor properties, targeted therapies have become more widely available to treat a variety of tumors. The goal of targeted treatment is to target only cancer cells, sparing normal cells and reducing side effects.²³ Currently, targeted therapy is used as second-line or maintenance treatment in patients with metastatic PDAC that has progressed after first-line chemotherapy.²⁴

Erlotinib is an epidermal growth factor receptor (EGFR) blocker that was the first targeted therapy to be approved by the FDA for the treatment of PDAC.²⁵ EGFR is a cell-membrane protein on some cells that binds EGF.²⁶ The EGF pathway is involved in controlling cell survival. In the presence of an EGFR mutation, cell division can proceed unchecked, leading to cancer development.

Genomic testing over the past decade has identified several mutational targets in PDAC that have altered the scope of treatment options for the condition.⁷ Approximately 25% of patients with PDAC have mutations in their DNA damage repair (DDR; BRCA1 and BRCA2) and homologous recombination (HR) repair genes. 

Patients with metastatic PDAC with DDR mutations that has not responded to first-line chemotherapy may benefit from treatment with a poly(adp-ribose) polymerase (PARP) inhibitor (ie, olaparib). PARP inhibitors block DNA repair in cancer cells, promoting cell death.²⁷  

Another mutation in some PDAC tumors occurs in the neurotrophin tyrosine receptor kinase (NTRK) fusion gene. This mutation occurs when a piece of the chromosome containing the NTRK gene separates and attaches to a different chromosome, producing a TRK fusion protein that may help cancer cells to grow.²⁸ This mutation is rare in patients with pancreatic cancer; however, those patients with the NTRK fusion gene whose disease has progressed on first-line chemotherapy are eligible for treatment with larotrectinib or entrectinib.²⁴ 

The KRAS gene is a new target of interest in PDAC treatment, as most patients with PDAC have this gene mutation.⁷ There are currently no FDA-approved treatments for PDAC that target KRAS. Still, several recent clinical trials have shown promising survival and safety benefits with KRAS-targeting agents.⁷ More research is needed to better characterize these treatment options.

Table 4. Management Guidelines for Targeted Chemotherapy for Pancreatic Adenocarcinoma 

Drug	Dose	Administration	Treatment Duration	Patient Population
Entrectinib	600 mg	Orally, with or without food	Daily until disease progression or unacceptable toxicity	Locally advanced, unresectable, and metastatic disease
Erlotinib	100 mg	Orally, on an empty stomach (1 h before or 2 h after eating)	Daily with gemcitabine, given until disease progression or unacceptable toxicity	Locally advanced, unresectable, and metastatic disease
Larotrectinib	100 mg	Orally	Twice daily until disease progression or unacceptable toxicity	Locally advanced, unresectable, and metastatic disease
Olaparib	300 mg	Orally, twice daily, with or without food	Maintenance therapy if no disease progression after ≥16 wk of platinum-based chemotherapy regimen	Metastatic disease in patients with BRCA1 and BRCA2 germline mutations

From FDA-approved prescribing information.^29-32

Immunotherapy 

Immunotherapy has not been effective in treating PDAC due to the disease’s immunosuppressive characteristics.⁷ However, one immunomodulating drug — pembrolizumab — has shown modest benefit as a second-line treatment in patients with a mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H).^7,24 Approximately 2% of PDAC patients have these mutations. 

Pembrolizumab targets programmed death-1 (PD-1), a protein that keeps T cells from attacking normal cells in the body. Blocking this checkpoint allows T cells to attack cells that have become cancerous.³³ Pembrolizumab dosing, administration, and target population are reviewed here.

Table 5. Management Guidelines for Immunotherapy for Pancreatic Adenocarcinoma

Drug	Dose	Administration	Treatment Duration	Patient Population
Pembrolizumab	200 mg over 30 min	IV infusion	Every 3 wk until disease progression or unacceptable side effects, or up to 24 mo without disease progression	Metastatic disease with dMMR or MSI-H

dMMR = mismatch repair deficiency; IV = intravenous; MSI-H = high microsatellite instability.

From FDA-approved prescribing information.³⁴

Monitoring Treatment for Pancreatic Adenocarcinoma 

As with any cancer treatment, monitoring for side effects, adverse events, drug interactions, and needs for special populations is essential. This information is collected during clinical trials and is available for all FDA-approved treatments.

Systemic Chemotherapy 

The systemic chemotherapeutic agents used to treat PDAC require close monitoring. These agents are typically nonspecific in action and target both rapidly growing cancer cells and normal cells.²⁴ This nonspecific action contributes to the extensive side effect profiles associated with chemotherapy. Common side effects among these agents are nausea, vomiting, loss of appetite, hair loss, rash, mouth sores, and diarrhea or constipation.³⁶ Side effects are generally experienced more frequently in patients older than 65 years.^11-15

Table 6. Side Effect Profiles for Systemic Chemotherapy for Pancreatic Adenocarcinoma

Drug	Common Adverse Events	Side Effects Necessitating Treatment Discontinuation	Drug-Drug Interactions	Special Populations
Albumin-bound paclitaxel (nab-paclitaxel)	In combination with gemcitabine: neutropenia, fatigue, peripheral neuropathy, nausea/vomiting, decreased appetite, alopecia, peripheral edema, pyrexia, vomiting, rash, dehydration	Peripheral neuropathy, severe myelosuppression (<500 cells/mm3 for 7 d or more or platelets <50,000 cells/mm3; treatment initiation should be delayed if ANC <1500 cells/mm3 or platelet count <100,000 cells/mm3 on day 1 of cycle), febrile neutropenia, sepsis, pneumonitis, severe hypersensitivity (anaphylaxis)	Use caution when prescribing nab-paclitaxel with medicines known to inhibit or induce either CYP2C8 or CYP3A4 (paclitaxel is metabolized by CYP2C8 and CYP3A4)	Contraindicated in patients with baseline neutrophil counts <1500 cells/mm3; history of hypersensitivity to nab-paclitaxel; close monitoring is required for patients with hepatic impairment; avoid in pregnancy*; avoid breastfeeding
Capecitabine	Coagulopathy, hand-and-foot syndrome (palmar-plantar erythrodysesthesia), dehydration, diarrhea, vomiting, hyperbilirubinemia	Severe diarrhea (grade 3 or 4), DPD deficiency (increases risk of severe, life-threatening capecitabine toxicity), severe mucocutaneous and dermatologic toxicity (Stevens-Johnson syndrome and toxic epidermal necrolysis), grade 2 or 3 hand-and-foot syndrome, severe neutropenia or thrombocytopenia, severe dehydration, cardiotoxicity, severe hyperbilirubinemia	Concomitant warfarin therapy requires frequent INR monitoring to adjust anticoagulant as needed (capecitabine increases PT and INR, increasing bleeding risk); careful phenytoin level monitoring with concomitant use (phenytoin dose may need reduction); avoid allopurinol	Contraindicated in patients with severe renal impairment (CrCl <30 mL/min), close monitoring is required for patients with mild to moderate renal impairment; contraindicated if known hypersensitivity to capecitabine or 5-FU; avoid in pregnancy*; avoid breastfeeding; contraindicated in patients with baseline neutrophil counts <1500 cells/mm3; close monitoring is needed for patients with mild to moderate hepatic dysfunction
Fluorouracil	Diarrhea, hand-and-foot syndrome, neutropenia, thrombocytopenia, anemia, mucositis	Acute early-onset or unusually severe toxicity (may indicate low DPD activity), cardiotoxicity, hyperammonemic encephalopathy, neurologic toxicity including acute cerebellar syndrome, severe diarrhea, grade 2 or 3 hand-and-foot syndrome, severe myelosuppression, severe mucositis	Concomitant warfarin therapy requires frequent INR monitoring to adjust anticoagulant as needed; CYP2C9 substrates	Avoid in pregnancy*; unknown if metabolites are in human milk, but necessitates risk/benefit assessment; no identified safety differences in geriatric population
Gemcitabine	Neutropenia, thrombocytopenia, anemia, nausea/vomiting, increased ALT and AST, proteinuria, rash, fever, edema	Severe myelosuppression, pulmonary toxicity including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema and ARDS, HUS or severe renal impairment, severe hepatic toxicity, capillary leak syndrome, PRES	None identified	Contraindicated if known hypersensitivity; check renal and liver function prior to treatment; avoid in pregnancy*; avoid breastfeeding; not recommended in combination with radiation; increased risk of severe thrombocytopenia in geriatric population; gemcitabine clearance is decreased in women
Irinotecan	Early diarrhea (occurring shortly after infusion) and cholinergic symptoms (treated with atropine), neutropenia (especially with reduced UGT1A1 activity), abdominal pain, anorexia, abnormal bilirubin	Late (severe, occurring >24 h after infusion)  diarrhea (with ileus, colitis, bleeding, infection), renal failure, severe myelosuppression (neutrophils <1000 cells/mm3), sepsis, interstitial pulmonary disease	Strong CYP3A4 inducers and inhibitors	Contraindicated if known hypersensitivity; avoid in patients with low performance status; avoid pregnancy*; avoid breastfeeding; close monitoring is needed for patients with hepatic or renal impairment; increased risk of early and late diarrhea in geriatric population

ALT = alanine transaminase; ANC = absolute neutrophil count; ARDS = acute respiratory distress syndrome; AST = aspartate aminotransferase; CrCl = creatinine clearance; DPD = dihydropyrimidine dehydrogenase; HUS = hemolytic uremic syndrome; INR = international normalized ratio for blood clotting assessment; myelosuppression = neutropenia, thrombocytopenia, and anemia; PRES = posterior reversible encephalopathy syndrome; PT = prothrombin time.

*Safety in pregnancy is mostly assessed in animal models; therefore, benefit/risk analysis should be conducted individually between patient and physician. 

From FDA-approved prescribing information.^11-15

Targeted Therapy 

Although targeted therapies have side effect profiles that are different from those associated with systemic chemotherapy, their use still requires close monitoring.⁴ Common side effects among these agents are nausea, vomiting, fatigue, rash, and diarrhea. 

Table 7. Effect Profiles for Targeted Therapy for Pancreatic Adenocarcinoma

Drug	Common Adverse Events	Side Effects Necessitating Treatment Discontinuation	Drug-Drug Interactions	Special Populations
Entrectinib	Cognitive impairment, mood disorders, confusion, memory impairment, increased ALT and AST, elevated uric acid, QT prolongation, skeletal fractures, blurred vision, photophobia, diplopia, nausea/vomiting, constipation, fatigue, pyrexia, edema	New onset or worsening CHF, severe cognitive or mood changes, severe ALT/AST changes, severe hyperuricemia, severe QT prolongation, vision changes interfering with daily function	Strong or moderate CYP3A inhibitors, grapefruit products, QT-prolonging drugs	Assess LVEF prior to initiation in patients with symptoms or known CHF risk factors; avoid driving and hazardous machinery; avoid in pregnancy*; avoid breastfeeding
Erlotinib	Increased ALT, AST, and bilirubin; microangiopathic hemolytic anemia with thrombocytopenia; ocular disorders; rash; diarrhea; decreased weight	ILD (new-onset dyspnea, cough, and fever), renal failure, hepatic failure, hepatorenal syndrome, GI perforation, Stevens-Johnson syndrome, toxic epidermal necrolysis, stroke, acute or severe ocular changes	Concomitant warfarin therapy requires close INR monitoring; CYP3A4 inhibitors and inducers, CYP1A2 inducers, cigarette smoking, PPIs	Check liver function periodically during treatment; avoid in patients with pre-existing hepatic impairment or significant hyperbilirubinemia; avoid in pregnancy*; avoid breastfeeding
Larotrectinib	Cognitive and memory impairment, confusion, attention disturbance, skeletal fractures, increased ALT and AST, fatigue, anemia, musculoskeletal pain, cough, neutropenia, constipation, diarrhea, nausea, vomiting, abdominal pain, pyrexia, pneumonia, edema	Severe cognitive or mood changes, severe hepatotoxicity, severe pyrexia, pneumonia	Strong and moderate CYP3A4 inhibitors and inducers, sensitive CYP3A4 substrates	Check liver function every 2 wk during first month of treatment, then monthly after; avoid in pregnancy*; avoid breastfeeding
Olaparib	Nausea, fatigue, anemia, vomiting, diarrhea, decreased appetite, headache, cough, neutropenia, leukopenia, thrombocytopenia	MDS/AML, pneumonitis, VTE/PE	Increased myelosuppressive toxicity when combined with other myelosuppressive anticancer agents; strong and moderate CYP3A inducers	Do not start until recovery from hematologic toxicity from previous chemotherapy; monitor CBC closely; avoid in pregnancy*; avoid breastfeeding

ALT = alanine transaminase; AML = acute myeloid leukemia; AST = aspartate aminotransferase; CBC = complete blood count; CHF = congestive heart failure; GI = gastrointestinal; ILD interstitial lung disease; INR = international normalized ratio for blood clotting assessment; LVEF = left ventricular ejection fraction; MDS = myelodysplastic syndrome; PPI = proton pump inhibitor; PE = pulmonary embolism; VTE = venous thromboembolism. 

*Safety in pregnancy is mostly assessed in animal models, benefit/risk analysis should be conducted on an individual basis between patient and physician. 

From FDA-approved prescribing information.^29-32

Immunotherapy 

Common side effects associated with immunotherapy include nausea, decreased appetite, constipation, and rash.⁴ Immunotherapy can cause more severe side effects and adverse events as a result of the immune system attacking healthy cells.

Table 8. Side Effect Profiles for Immunotherapy for Pancreatic Adenocarcinoma

Drug	Common Adverse Events	Side Effects Necessitating Treatment Discontinuation	Drug-Drug Interactions	Special Populations
Pembrolizumab	Pruritus, rash, nausea, vomiting, diarrhea, decreased appetite, constipation, diarrhea, abdominal pain, cough, anemia, pyrexia, hyperglycemia, hypoalbuminemia, hypertriglyceridemia	Severe immune-mediated adverse reactions including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and dermatologic reactions; hypersensitivity and anaphylaxis	None identified	Avoid in pregnancy*; avoid breastfeeding

*Safety in pregnancy is mostly assessed in animal models, benefit/risk analysis should be conducted on an individual basis between patient and physician. 

From FDA-approved prescribing information.³⁴ 

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Author Bio

Chelsea Alvarado, MD, earned her BS in Biochemistry from Temple University in Philadelphia, Pennsylvania, and her MD from the University of Maryland School of Medicine in Baltimore. She currently works as a freelance medical writer and is passionate about making medical science accessible to all.