Management of adverse reactions to targeted therapy and immunotherapy for pancreatic cancer: A literature review

Abstract

Conventional therapies for pancreatic cancer involve limitations. Targeted therapy and immunotherapy are partially effective; however, they often cause adverse reactions and toxic side effects, sometimes necessitating treatment discontinuation. Early identification, diagnosis, and management of these treatment-related complications are crucial for ensuring patient safety while maintaining optimal therapeutic efficacy. This narrative review summarizes common adverse reactions to targeted therapy and immunotherapy for pancreatic cancer as well as corresponding management strategies.

Keywords

Pancreatic cancer targeted therapy immunotherapy adverse reaction management

This review is guided by the Scale for the Assessment of Narrative Review Articles (SANRA). The global annual number of pancreatic cancer (PC) cases has risen steadily, with varying incidence rates across countries and regions.¹ North America, Europe, and Argentina report the highest rates, followed by East Asia and Australia.^2–4 Developed Chinese regions show rising trends, while low-income countries such as Africa and Central and South Asia exhibit extremely low rates owing to insufficient imaging and pathological evaluation expertise.^4,5 PC, a highly invasive malignancy, has a 5-year survival rate of 2%–9% owing to aggressive progression and late diagnosis.^2,3 Conventional therapies face limitations such as late diagnosis and poor patient conditions.^6,7 Targeted therapy and immunotherapy have brought new hope; however, adverse reactions may lead to treatment discontinuation owing to issues such as reduced tolerability and compliance. Therefore, vigilant monitoring is necessary to mitigate the side effects of these therapies.⁸

Targeted therapy and immunotherapy and their possible mechanism in PC

In recent years, targeted therapy has brought new hope by precisely targeting genetic mutations, minimizing damage to normal cells, reducing adverse effects compared with chemotherapy, and enabling personalized treatment via genetic testing.

Angiogenesis supports PC cell growth and metastasis by providing nutrition, making it a promising target for treatment with anti-angiogenic drugs. The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway primarily regulates the formation of new blood vessels, and targeted therapies either block the VEGF–VEGFR interaction or directly inhibit VEGFR to treat PC.⁹

Erlotinib, a tyrosine kinase inhibitor (TKI) targeting VEGFRs, competes with adenosine triphosphate (ATP) to inhibit epidermal growth factor receptor (EGFR) phosphorylation, blocking intranuclear signaling, thereby suppressing tumor growth and metastasis.¹⁰ In PC, nuclear factor kappa B (NF-κB) is highly expressed and active;¹⁰ erlotinib inhibits epidermal growth factor–mediated NF-κB activation, significantly reducing pancreatic cancer cell-1 (PANC-1) proliferation and NF-κB activity to suppress PC cell proliferation and invasion.^9,10

Nimotuzumab, a highly humanized anti-EGFR monoclonal antibody, binds specifically to the extracellular domain of EGFR.^10,11 It competitively blocks EGFR downstream signaling; reduces PC cell proliferation; enhances apoptosis; and exhibits strong selectivity, prolonged action, and lower adverse reactions.^10,11

Previous studies have shown that most PCs originate from pancreatic intraepithelial neoplasia and progress through genetic mutations, with approximately 90% involving KRAS mutations that drive pancreatic carcinogenesis.¹² Mutant KRAS activates various downstream pathways, such as RAS–MEK–MAPK and PI3K–AKT–mTOR, promoting cell proliferation, transformation, and apoptosis resistance.^12,13 Targeted therapies can suppress the oncogenic effects of KRAS by locking it in an inactive state.^12,13 Preclinical studies have indicated that sotorasib directly targets KRAS mutants through covalent binding to the G12C mutant’s cysteine residue, blocking abnormal KRAS activation and inhibiting PC cell proliferation.¹⁴

Larotrectinib is a targeted therapeutic agent for tumors with neurotrophic tyrosine receptor kinase (NTRK) gene fusions and is found in various cancers, including rare PCs.¹⁵ It acts by inhibiting abnormal NTRK protein activation, thereby blocking the enhanced signaling to suppress cancer cell proliferation, survival, and metastasis.¹⁵

Entrectinib, an oral small-molecule inhibitor, competitively binds to the ATP site of multiple kinases. Data from a multicenter, prospective, interventional clinical study demonstrated that as a broad-spectrum anti-tumor agent, entrectinib shows significant activity against NTRK fusion–positive solid tumors and effectively crosses the blood–brain barrier, inhibiting kinase-mediated signaling pathways to exert anti-tumor effects.^15,16

Olaparib, a poly-adenosine diphosphate ribose polymerase (PARP) inhibitor, is used for treating metastatic PC patients with germline breast cancer gene mutations who have not progressed after >16 weeks of first-line platinum-based chemotherapy.¹⁷ The phase III POLO clinical trial revealed that PARP disrupted DNA repair in cancer cells, enhancing DNA damage sensitivity and blocking repair pathways to promote apoptosis.¹⁷

Immunotherapy and its possible mechanism in the treatment of PC

Immunotherapy offers several advantages, including good efficacy, mild toxicity, and high tolerability. Adoptive cell therapy, particularly chimeric antigen receptor–modified T (CAR-T) cell therapy, is increasingly being used in PC treatment.¹⁸ CAR-T therapy genetically engineers patient T cells to express chimeric antigen receptors, achieving precise identification of tumor cells and enhanced T cell activation and proliferation.¹⁸

A large, multicenter, global, phase II trial (NCT02628067) reported that PC is a nonimmunogenic tumor with poor immunotherapeutic response, characterized by low programmed death (PD) ligand 1 (L1) expression and genomic instability in <1% of patients.¹⁹ Pembrolizumab, a humanized immunoglobulin G4 monoclonal antibody targeting microsatellite instability–high/deficient mismatch repair cancers, blocks PD-1/PD-L1/L2 interactions to restore T cell–mediated cancer cell destruction and enhance immune response.²⁰

Pancreatic ductal adenocarcinoma (PDAC) is an immune-cold tumor with a tumor microenvironment–suppressing immune cell activity. The PD-1/PD-L1 axis suppresses T cell activation, causing insufficient T cell numbers and impaired function in PDAC. Nivolumab, a PD-1 inhibitor, blocks PD-1/PD-L1 interaction, promoting tumor-specific T cell activation/proliferation, offering a novel PDAC treatment.²¹

Incidence of adverse reactions to targeted therapy and immunotherapy in PC

Targeted therapy and immunotherapy exhibit limitations such as treatment-associated adverse reactions. These reactions may involve one or more body systems or organs and can be mild, severe, or life-threatening; they affect treatment continuity and cause serious physical and psychological harm to patients.

Incidence of skin-related adverse reactions

Skin-related adverse reactions are known as adverse cutaneous reactions (ACRs). ACRs not only significantly lower the patients’ quality of life but may also lower treatment compliance, potentially leading to treatment discontinuation or increased infection risk.²² EGFR inhibitors (EGFRIs), VEGF inhibitors, and immune checkpoint inhibitors (ICIs) are strongly associated with ACRs, which occur most frequently during treatment with EGFRIs and ICIs.^22,23

A retrospective study reported xerosis as the most common ACR in Asian patients using EGFRIs; approximately 52.5% of EGFRI-treated patients developed xerosis, potentially linked to EGFRI-induced plasma hepatocyte growth factor concentrations.^22,23 Another study reported that 60%–80% of patients manifested ACRs as a papulopustular rash in sebaceous areas, typically emerging 1–2 weeks post-treatment, occasionally affecting lower extremities in a dose-dependent manner.²² ACRs due to targeted therapy and immunotherapy are usually mild, self-limiting, and manageable; fatal ACRs such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis are relatively rare.^22–24

Incidence of gastrointestinal tract (GIT)–related adverse reactions

Approximately 35% of PC patients taking cytotoxic T‐lymphocyte antigen‐4 (CTLA-4) or PD-1 inhibitors develop GIT toxicity.²¹ Anti-PD-1 users experience fewer GIT-related adverse reactions than anti-CTLA-4 users, with dose-dependent adverse reactions observed in both patient populations.^21,25

The adverse reactions to combination immunotherapy are reportedly more severe than those to single-agent therapy.¹¹ ICI-mediated GIT reactions typically present with increased defecation frequency, alongside water–electrolyte imbalance symptoms, such as colitis, abdominal pain, nausea, vomiting, and bloody stools; in severe cases, bowel obstruction or even gastrointestinal perforation may occur.^21,25 These reactions may be related to ICI-induced chronic active inflammation involving neutrophil infiltration, crypt abscesses, and crypt epithelial cell upregulation.^21,24,25

Incidence of liver-related adverse reactions

Among immune-related adverse events (irAEs) associated with targeted therapy and immunotherapy, liver-related reactions typically occur after 7 weeks of treatment in approximately <15% of patients; the incidence of hepatotoxicity increases with the use of combination medications.²⁶

The main liver-related adverse reaction is liver inflammation, which primarily manifests as elevated transaminase levels. Laboratory blood examination may reveal increased bilirubin levels and eosinophil counts, sometimes accompanied with weakness, pyrexia, and decreased appetite.²⁶ As inflammation progresses, patients may exhibit fatigue, jaundice, hyperbilirubinemia, and hypergammaglobulinemia. Fulminant hepatitis may occur in a small number of cases, which causes death upon rapid progression to liver failure.²⁷ The mechanisms underlying the occurrence of liver-related adverse reactions in patients receiving targeted therapy and immunotherapy remain unclear; however, they are generally believed to involve immune checkpoint mechanisms that maintain immune homeostasis.^26–28

Incidence of lung-related adverse reactions

The median time of occurrence of lung-related adverse reactions is approximately 2.8 months, and the incidence of pneumonia caused by PD-L1 inhibitors is higher than that caused by CTLA-4 inhibitor monotherapy. Interstitial pneumonia is reportedly more likely to occur with combination therapy.^24,26,27

The main clinical symptoms of targeted therapy– and immunotherapy-related pneumonia include upper respiratory tract infection, pyrexia, chest pain, persistent dry cough, and dyspnea; moreover, rapid disease progression may lead to respiratory failure, which may elicit severe complications or even result in death.^27,28

Incidence of cardiovascular system–related adverse reactions

Hypertension is the most common cardiovascular system–related adverse reaction to targeted therapy. Other adverse reactions include arrhythmias, heart failure, pulmonary hypertension, and bleeding.

Hypertension is a common adverse reaction, with an overall incidence of 22.4% and severe hypertension incidence of approximately 11%. It is mainly caused by the effects of medications on vascular endothelial cell synthesis and proliferation, reducing nitric oxide generation and increasing endothelin-1 production.²⁹ The use of the TKI erlotinib inhibits human ether-à-go-go-related gene channels, thereby prolonging the ventricular action potential duration and the corrected QT interval, resulting in arrhythmias.²⁹ Erlotinib affects circulation in the terminal vessels of the pulmonary vascular bed, which causes vascular obstruction and results in the development of pulmonary hypertension; this may be related to pulmonary artery endothelial cell damage.^9,29 Relevant literature has revealed that the use of ICIs may lead to the development of fatal myocarditis, and it has also been reported that myocarditis associated with anti-CTLA-4 ICIs is more severe than that associated with anti-PD-1 and anti-PD-L1 ICIs, but the underlying mechanism of this phenomenon has not yet been elucidated.^29,30

Incidence of endocrine system–related adverse reactions

Endocrine system–related adverse reactions induced by the use of ICIs are relatively rare. Previous research has shown that approximately 5% of patients with malignant tumors who receive ICI therapy may exhibit varying degrees of endocrine disorders, which may be life-threatening in severe cases.³⁰

The main endocrine system–related adverse reactions are anti-CTLA-4 therapy–associated hypophysitis and anti-PD-1 therapy–associated thyroid dysfunction; adverse reactions also include primary adrenal insufficiency, hypogonadism, hypercalcemia, and type I diabetes mellitus.³¹

Incidence of cytokine release syndrome (CRS) and immune-effector cell–associated neurotoxicity syndrome (ICANS)

CAR-T cell therapy–related adverse reactions, particularly CRS and ICANS, are more common in patients with PC.³² The clinical manifestations of CRS include pyrexia, fatigue, headache, arthralgia, and myalgia; high fever and hypotension may occur upon disease progression.^26,32

The pathogenesis of CAR-T cell therapy–related CRS may be related to strong immune responses elicited by the release of large numbers of cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α, by activated CAR-T cells and lysed tumor cells.^32,33 ICANS, a form of neurotoxicity, is the second most common adverse effect of CAR-T cell therapy.³² It may occur concurrently with CRS or after CRS and mainly manifests as toxic encephalopathy. Early presentations include decreased concentration, speech and language impairment, dysgraphia, obnubilation, drowsiness, and tremor; in severe cases, it may cause epileptic seizures, motor weakness, increased intracranial pressure, and hydrocephalus.^32,33 The pathogenesis of ICANS may be related to increases in the levels of IL-1, IL-6, IL-15, TNF-α, and interferon-gamma (IFN-γ), which promote the development of ICANS.^32,33

Manifestations of adverse reactions to targeted therapy and immunotherapy for PC are detailed in Table 1.³⁴ The incidences of adverse reactions to targeted therapy and immunotherapy are shown in Table 2.^35–40

Table 1.

Clinical manifestations of adverse reactions to targeted therapy and immunotherapy for pancreatic cancer.

Adverse reactions	Typical clinical manifestations
Skin	Xerosis, acneiform eruptions, maculopapules, mucositis, paronychia, papulopustular rash in sebaceous areas, Stevens–Johnson syndrome, and toxic epidermal necrolysis^22–24
Gastrointestinal tract	Increase in defecation frequency, colitis, abdominal pain, nausea, vomiting, bloody stools, bowel obstruction, and gastrointestinal perforation^21,25
Liver	Elevated transaminase levels, increased bilirubin levels, increased eosinophil counts, weakness, pyrexia, decreased appetite, fatigue, jaundice, hyperbilirubinemia, hypergammaglobulinemia, and fulminant hepatitis^26,27
Lung	Interstitial pneumonia, upper respiratory tract infection, pyrexia, chest pain, persistent dry cough, dyspnea, respiratory failure, and death^24,26–28
Cardiovascular	Hypertension, arrhythmia, heart failure, pulmonary hypertension, bleeding, pulmonary hypertension, and fatal myocarditis^9,29,30
Endocrine	Hypophysitis, thyroid dysfunction, primary adrenal insufficiency, hypogonadism, hypercalcemia, and type I diabetes mellitus³¹
CRS	Pyrexia, fatigue, headache, arthralgia, myalgia, hypotension, shock, vascular leakage, disseminated intravascular coagulation, and multiple organ dysfunction syndrome^26,32,34
ICANS	Toxic encephalopathy, decreased concentration, speech and language impairment, dysgraphia, obnubilation, drowsiness, tremor, epileptic seizures, motor weakness, increased intracranial pressure, and hydrocephalus^32,33

CRS: cytokine release syndrome; ICANS: immune-effector cell–associated neurotoxicity syndrome.

Table 2.

Incidence of common adverse reactions and immune-related adverse events (irAEs) in targeted therapy and immunotherapy.

Drug	Adverse reactions or irAEs		Incidence rate
Erlotinib	Skin	Acneiform eruptions, xerosis, itchiness, paronychia^22,23	>10%
	Gastrointestinal tract	Diarrhea, nausea, vomiting, anepithymia^{21,25,34–36}	>10%
	Systemic reaction	Fatigue, fever^26,32,34,37	1%–10%
	Liver	Liver function abnormalities^38,39	1%–10%
	Hematological reactions	Anemia, leukopenia, thrombocytopenia^9,10	1%–10%
	Respiratory	Cough, dyspnea^9,10,27,28	1%–10%
Nimotuzumab	Infusion-related reactions	Fever, chills, headache, nausea^26–28	>10%
	Alimentary tract	Nausea, vomiting, diarrhea, abdominal pain^21,25–28	1%–10%
	Skin	Rash, itchiness, dry skin^21,24,35	1%–10%
	Systemic reaction	Fatigue, fever^26,27,32	1%–10%
	Hematological reactions	Leukopenia, thrombocytopenia, anemia^10,11	1%–10%
Sotorasib	Gastrointestinal tract	Diarrhea, nausea, vomiting, abdominal pain, constipation^34,37	>10%
	Hepatic reactions	Liver function abnormalities, jaundice^27,38,39	1%–10%
	Systemic reactions	Fatigue, fever^26,32,34,37	1%–10%
	Musculoskeletal reactions	Muscle pain, joint pain^12,14	1%–10%
	Respiratory	Cough, dyspnea^27,28	1%–10%
	Skin	Rash, itching^21,22	1%–10%
Larotrectinib	Neurological reactions	Dizziness, ataxia¹⁵	>10%
	Gastrointestinal tract	Nausea, vomiting, diarrhea, constipation^21,25,34	>10%
	Systemic reactions	Fatigue, fever^26,32,34,37	1%–10%
	Liver	Liver function abnormalities^38,39	1%–10%
	Musculoskeletal reactions	Muscle and joint pain^12,14	1%–10%
Entrectinib	Neurological reactions	Dizziness, ataxia, dysgeusia^15,16	>10%
	Gastrointestinal tract	Nausea, vomiting, diarrhea, constipation, abdominal pain^{16,21,25,34,37}	>10%
	Systemic reactions	Fatigue, fever^26,32,34,37	1%–10%
	Musculoskeletal reactions	Muscle and joint pain^12,14,16	1%–10%
	Liver	Liver function abnormalities^16,37,39	1%–10%
	Respiratory	Cough, dyspnea^16,27,28	1%–10%
Olaparib	Gastrointestinal tract	Nausea, vomiting, diarrhea, abdominal pain, anepithymia^{17,21,25,34,37}	>10%
	Systemic reactions	Fatigue, fever^{17,26,32,34,37}	>10%
	Hematologic reactions	Anemia, leukopenia, thrombocytopenia, neutropenia¹⁷	>10%
	Respiratory	Cough, dyspnea^17,27,28	1%–10%
	Musculoskeletal reactions	Muscle and joint pain^12,14,17	1%–10%
	Neurological reactions	Headache, dizziness^17,26,32	1%–10%
	Skin	Rash, itching^17,21,22	1%–10%
CAR-T	CRS	High fever, hypotension, dyspnea, tachycardia^32,33	>10%
	Neurological toxicity	Headache, confusion, seizures, speech impairment^32–34,40	>10%
	Hematologic reactions	Leukopenia, thrombocytopenia, anemia, neutropenia^9–11,17	>10%
	Systemic reactions	Fatigue, fever, chills^{26–28,32,34,37}	1%–10%
	Gastrointestinal tract	Nausea, vomiting, diarrhea, abdominal pain^21,25	1%–10%
	Liver	Liver function abnormalities^38,39	1%–10%
Pembrolizumab	Systemic reactions	Fatigue, fever, chills^{19,26,32,34,37}	>10%
	Gastrointestinal tract	Nausea, vomiting, diarrhea, abdominal pain^{19–21,24,25}	1%–10%
	Skin reactions	Rash, itching, vitiligo^19–22	1%–10%
	Endocrine	Thyroid dysfunction, adrenal insufficiency^19,20,31	1%–10%
	Liver	Liver function abnormalities^19,20,38,39	1%–10%
Nivolumab	Systemic reactions	Fatigue, fever, chills^21,26,32	>10%
	Gastrointestinal tract	Nausea, vomiting, diarrhea, abdominal pain^21,25	1%–10%
	Skin	Rash, itching, vitiligo^21,22	1%–10%
	Endocrine	Thyroid dysfunction, adrenal insufficiency^21,31	1%–10%
	Liver	Liver function abnormalities^21,38,39	1%–10%

CAR-T: chimeric antigen receptor–modified T; CRS: cytokine release syndrome.

Management of adverse reactions to targeted therapy and immunotherapy in PC

There are several limitations associated with targeted therapy and immunotherapy, including strong genetic dependency, limited applicability to specific patient populations, and challenges such as specific adverse reactions and irAEs. Therefore, management of adverse events is crucial. In general, the primary aim of adverse event management is effective prevention of possible adverse reactions and their sequelae without affecting the intended beneficial therapeutic effects.⁴¹

Management of skin-related adverse reactions

Skin-related adverse reactions to targeted therapy and immunotherapy are usually self-limiting.^24,35 Appropriate treatment methods may be employed based on the patient’s clinical presentations and grades as follows. Grades 1–2 ACRs typically only require symptomatic treatment, such as local application of a skin lotion or local application of an intermediate-acting corticosteroid combined with oral administration of antipruritic medications. In most cases, discontinuation of the targeted therapy or immunotherapy is not necessary. For grade 3–4 ACRs, such as systemic exfoliative dermatitis, high-potency corticosteroids should be actively used for systemic treatment; in addition, a skin biopsy should be performed, and the targeted therapy or immunotherapy should be discontinued if necessary.^24,35

Patients who develop SJS are highly prone to bacterial and fungal infections owing to the loss of the physical barrier and may die from sepsis; the severe nature of this adverse reaction necessitates the early use of high-dose glucocorticoids and human immunoglobulins in accordance with the doctor’s prescriptions.^24,35

Management of GIT-related adverse reactions

When GIT-related adverse reactions occur, physical, laboratory, and endoscopic examinations should be performed to exclude intestinal discomfort unrelated to the targeted therapy or immunotherapy.

Patients who develop mild-to-moderate colitis with diarrhea (frequency of <6 times per day) should be closely monitored and administered antimotility drugs for diarrhea treatment; if symptoms persist for >3 days and other infection-related factors have been excluded, corticosteroids can be administered orally or intravenously.²⁵ For patients exhibiting grades 2–3 or higher colitis, it is advisable to temporarily discontinue ICIs and initiate steroid therapy as the primary treatment; if symptoms persist without improvement, infliximab administration should be considered.^25,36 The steroid dosage should be gradually tapered, beginning at 48 h after symptom relief and continuing for 4–6 weeks.³⁶ For patients with grade 2 or higher diarrhea, immunotherapy should be temporarily suspended, and intermediate-acting glucocorticoids should be administered orally.^25,36 When the diarrhea severity is reduced to grade 1 or lower, the glucocorticoid dose can be gradually reduced at a rate of 5 mg/week.^25,35,36 For patients with persistent grade 2 symptoms and those who exhibit symptoms of higher-grade diarrhea, intravenous injection of hydrocortisone should be considered, and targeted therapy or immunotherapy drugs should be discontinued.^35,36 If severe symptoms of colitis occur, intravenous methylprednisolone administration should be initiated immediately. If corticosteroid treatment proves ineffective or diarrhea symptoms remain pronounced, targeted therapy or immunotherapy should be discontinued, and infliximab should be administered for symptom alleviation. Moroever, a colonoscopy should be performed to guide appropriate adjustment of the infliximab dose and duration.^25,35,36

Management of liver-related adverse reactions

When liver-related adverse reactions occur during targeted therapy or immunotherapy, relevant imaging and biopsy examinations can help determine the patient’s condition.^38,39 In most patients, liver-related adverse reactions resolve spontaneously after treatment cessation. However, liver failure may occur in a small number of patients.³⁸ When grade 1 adverse reactions occur, targeted therapy or immunotherapy can be continued; however, liver function must be assessed weekly; when grade 2 adverse reactions arise, targeted therapy and immunotherapy must be suspended temporarily, 0.5 mg/kg/day prednisone should be administered, and liver function must be monitored. In case of grade 3 or higher adverse reactions, immunotherapy should be discontinued permanently, markers of liver function should be monitored periodically, and 1–2 mg/kg/day methylprednisolone should be administered intravenously. In addition, alternative treatment methods such as the administration of mycophenolate mofetil and plasma exchange can be considered.^38,39

It is imperative to perform hepatitis screening before initiating ICI therapy and prior to each subsequent administration. This screening typically involves monitoring the patient’s transaminase and bilirubin levels to detect any potential liver abnormalities.⁴² If abnormal liver enzyme levels are detected, further testing is warranted to exclude viral or disease-induced liver dysfunction. In cases where doctors detect an unexplained increase in serum alanine aminotransferase or aspartate aminotransferase levels, immune-related hepatitis should be strongly suspected, although most patients exhibit no overt symptoms other than abnormal laboratory findings.^39,42 A definitive diagnosis of autoimmune hepatitis generally necessitates a liver biopsy, and upon confirmation, patients should be administered corticosteroid treatment.^38,39,42

Management of lung-related adverse reactions

Only a few severe lung-related adverse reactions are associated with targeted therapy and immunotherapy; however, they may be life-threatening.⁴³ For patients experiencing grade 1 pneumonia, it is advisable to temporarily suspend the use of ICIs and perform close follow-up monitoring. In over 85% of cases, cessation of medication along with immunosuppressive therapy is reported to provide relief and recovery.⁴⁴ If the condition fails to improve, corticosteroid treatment should be initiated; for patients with grade 2 or higher pneumonia, immediate discontinuation of the medication is crucial, and corticosteroids should be administered. In refractory cases, infliximab and/or cyclophosphamide treatment may be an option; however, their effectiveness is limited and may pose a heightened risk of infection.^36,44 Throughout the treatment process, doctors must continuously assess and monitor the patient’s condition. Broad-spectrum antibiotic treatment, intravenous infusion of high-dose methylprednisolone, and permanent discontinuation of targeted therapy and immunotherapy should be considered; mechanical ventilation can be performed if necessary. In addition, preventive treatment for opportunistic infections should be administered when the duration of hormonal or immunosuppressive therapy exceeds 4–6 weeks.^43–45

Management of cardiovascular system–related adverse reactions

Cardiovascular system–related adverse reactions rarely arise during treatment with ICIs; the most common adverse reaction is myocarditis. ICI therapy must be suspended temporarily when adverse reactions cause life-threatening malignant arrhythmias or fulminant myocarditis concomitant with heart failure.⁴⁶

Prednisone or methylprednisolone should be administered in patients with mild adverse reactions. When grade 2 or higher adverse reactions arise, ICI therapy should be discontinued immediately, and high-dose glucocorticoids should be used. For patients in whom glucocorticoid therapy for 24 h proves ineffective, the use of immunosuppressants such as infliximab and tacrolimus should be considered as soon as possible.^46,47 However, infliximab must be avoided in patients with concomitant severe heart failure.⁴⁷

Management of endocrine system–related adverse reactions

Endocrine system–related adverse reactions are also common in targeted therapy or immunotherapy. In cases of endocrine system–related adverse reactions caused by targeted immunotherapy, prompt and decisive intervention is required.

In case of hypophysitis, targeted therapy or immunotherapy should be suspended immediately; magnetic resonance imaging (MRI) should be performed to confirm the diagnosis, and methylprednisolone, prednisone, or corresponding hormone replacement therapy should be administered concurrently.²⁵ Hypophysitis may cause irreversible impairment of adrenal function, potentially necessitating long-term or lifetime glucocorticoid replacement therapy.^34,37 Furthermore, if patients exhibit symptoms such as fatigue, weakness, headaches, vision disturbances, hypotension, and nausea or if these symptoms intensify, the possibility of pituitary inflammation should be considered and pituitary function should be promptly evaluated.³⁴ Early-stage pituitary MRI is recommended to rule out pituitary metastasis and assess the extent of pituitary enlargement and any potential compression on the optic chiasm; notably, symptoms associated with pituitary stalk compression typically alleviate within approximately 6 weeks.^34,37 For patients with thyroid dysfunction, continuation of targeted therapy or immunotherapy with periodic monitoring of thyroid function should be considered in the absence of obvious symptoms; however, if symptoms of impaired thyroid function such as fatigue and constipation are observed, antithyroid antibody testing and thyroid nuclear scanning should be performed, serum thyroid-stimulating hormone levels should be monitored, and low-dose thyroid hormone replacement therapy should be employed as the first-line treatment; the use of the β-blocker propranolol can be considered in patients who exhibit hyperthyroidism.^34,37 If thyroiditis occurs and is accompanied with pain, targeted therapy or immunotherapy must be discontinued, and appropriate corticosteroid hormone therapy should be administered. In clinical settings, to limit further thyroid cell damage caused by ICIs, medication is often discontinued.^34,37,48 Furthermore, hormone therapy with methylprednisolone or prednisone is prescribed to mitigate thyroid-associated adverse reactions. Concurrently, symptomatic treatment is provided based on the patient’s specific manifestations.^34,37,48

Management of adverse reactions to CRS and ICANS

The unwanted effects of adoptive therapy using genetically modified T cells can be divided into three main classes: on-target toxicity, off-target toxicity, and conditioning toxicity. Moreover, the excessive release of various cytokines, such as IFN-γ, granulocyte-macrophage colony-stimulating factor, TNF-α, IL-6, and IL-1β, by T cells may trigger a cytokine storm.^44,49,50

CAR-T cell–induced on-target toxicity can be alleviated using immunoglobulin replacement therapy; however, off-target toxicity cannot be easily controlled using drug therapy. CAR-T cell optimization may be performed by introducing a suicide gene into the modified T cells as a safety switch to assure the safety of CAR-T cell therapy and reduce the risk of off-target toxicity.^49,50

CRS is a form of limiting toxicity. Currently, two main types of medications are used for the treatment of CAR-T cell therapy–induced CRS, namely, corticosteroids and cytokine antagonists. The former provides significant therapeutic benefit for the mitigation of adverse reactions and inflammatory responses associated with activated T cells, while the latter reduces the cytokine levels in the body, which weakens the T cell–induced CRS effects.⁵⁰ When corticosteroids become ineffective, cyclosporin A can be used as a second-line drug.⁴⁰

Patients diagnosed with ICANS should undergo neurological function scoring to categorize the syndrome into grades 1–4, as outlined in previous studies.^40,50 For those with grades 2–3 or higher, corticosteroid therapy, preferably dexamethasone or methylprednisolone, is recommended, and the dosage should be promptly adjusted based on clinical improvements.⁴⁰ Supportive therapy, antiepileptic treatment, and treatment with IL-6 receptor antibodies, such as tocilizumab, are essential in case of CRS co-occurence.⁴⁰ Throughout the management process, close monitoring of neurological function, consciousness levels, seizures, motor ability, and intracranial pressure is crucial to ensure treatment effectiveness and allow timely therapeutic adjustments.⁴⁰

Management of adverse reactions in targeted therapy and immunotherapy for PC are described in Table 3.

Table 3.

Management of adverse reactions to targeted therapy and immunotherapy for pancreatic cancer.

Adverse reactions	Management strategies
Skin	Skin lotion, intermediate-acting corticosteroids, oral administration of antipruritic medications, high-potency corticosteroids, high-dose glucocorticoids, human immunoglobulins, and discontinuation of the targeted therapy or immunotherapy^24,35
Gastrointestinal tract	Physical examinations, laboratory examinations, endoscopic examinations, antimotility drugs, oral or intravenous corticosteroids, infliximab, oral intermediate-acting glucocorticoids, hydrocortisone, methylprednisolone, and discontinuation of the targeted therapy or immunotherapy^11,21,24,25
Liver	Hepatitis screening before initiating ICI therapy and prior to each subsequent administration, monitoring of transaminase levels and bilirubin levels, imaging and biopsy examinations, monitoring of liver function, prednisone, methylprednisolone, mycophenolate mofetil, plasma exchange, and discontinuation of the targeted therapy or immunotherapy^38,39,42
Lung	Corticosteroids, infliximab, cyclophosphamide, broad-spectrum antibiotics, high-dose methylprednisolone, temporary suspension of ICI use, mechanical ventilation, and permanent discontinuation of targeted therapy and immunotherapy^24,26–28
Cardiovascular	Prednisone, methylprednisolone, high-dose glucocorticoids, infliximab, tacrolimus, and discontinuation of targeted therapy and immunotherapy^9,29–31,34
Endocrine	Magnetic resonance imaging examination, methylprednisolone, prednisone, hormone replacement therapy, glucocorticoid replacement therapy, pituitary function evaluation, antithyroid antibody testing, thyroid nuclear scanning, monitoring of thyroid-stimulating hormone, thyroid hormone replacement therapy, β-blocker propranolol, corticosteroid hormone therapy, and discontinuation of targeted therapy and immunotherapy^25,34,37,48
CRS	Immunoglobulin replacement therapy, corticosteroids, cytokine antagonists, and cyclosporin A^26,32,33
ICANS	Scoring of neurological function, corticosteroid therapy, dexamethasone, methylprednisolone, supportive therapy, antiepileptic treatment, IL-6 receptor antibody, and monitoring of neurological function, consciousness levels, seizures, motor ability, and intracranial pressure^32,33

Conclusion

This review is limited by the lack of real-world guidelines and long-term toxicity data. Active efforts should be made to prevent these adverse reactions to targeted therapy and immunotherapy treatments in PC treatment, identify pertinent symptoms of adverse reactions as soon as possible, manage adverse reactions in a timely manner, and strengthen patient management during the treatment process.

Footnotes

Acknowledgements

We would like to thank Yu-Kui Huang and Li-Xuan Huang for their assistance in this review.

Author contributions

Fang Huang conceptualized the study and wrote the original draft. Zhen-Peng Huang was in charge of illustration, literature, review, and editing. All authors have read and approved the final version of the manuscript.

Data availability statement

This review is based on previously published studies. All data analyzed or discussed in this manuscript are available from the references cited.

Declaration of conflicting interest

The authors declare no competing interests.

Funding

None.

ORCID iD

Zhen-Peng Huang

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