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New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management

View Article: PubMed Central - PubMed

ABSTRACT

Pharmacological and cellular treatment of cancer is changing dramatically with benefits for patient outcome and comfort, but also with new toxicity profiles. The majority of adverse events can be classified as mild or moderate, but severe and life-threatening complications requiring ICU admission also occur. This review will focus on pathophysiology, symptoms, and management of these events based on the available literature.

While standard antineoplastic therapy is associated with immunosuppression and infections, some of the recent approaches induce overwhelming inflammation and autoimmunity. Cytokine-release syndrome (CRS) describes a complex of symptoms including fever, hypotension, and skin reactions as well as lab abnormalities. CRS may occur after the infusion of monoclonal or bispecific antibodies (MABs, BABs) targeting immune effectors and tumor cells and is a major concern in recipients of chimeric antigen receptor (CAR) modified T lymphocytes as well. BAB and CAR T-cell treatment may also be compromised by central nervous system (CNS) toxicities such as encephalopathy, cerebellar alteration, disturbed consciousness, or seizures. While CRS is known to be induced by exceedingly high levels of inflammatory cytokines, the pathophysiology of CNS events is still unclear. Treatment with antibodies against inhibiting immune checkpoints can lead to immune-related adverse events (IRAEs); colitis, diarrhea, and endocrine disorders are often the cause for ICU admissions.

Respiratory distress is the main reason for ICU treatment in cancer patients and is attributable to infectious agents in most cases. In addition, some of the new drugs are reported to cause non-infectious lung complications. While drug-induced interstitial pneumonitis was observed in a substantial number of patients treated with phosphoinositol-3-kinase inhibitors, IRAEs may also affect the lungs.

Inhibitors of angiogenetic pathways have increased the antineoplastic portfolio. However, vessel formation is also essential for regeneration and tissue repair. Therefore, severe vascular side effects, including thromboembolic events, gastrointestinal bleeding or perforation, hypertension, and congestive heart failure, compromise antitumor efficacy.

The limited knowledge of the pathophysiology and management of life-threatening complications relating to new cancer drugs presents a need to provide ICU staff, oncologists, and organ specialists with evidence-based algorithms.

No MeSH data available.


Related in: MedlinePlus

Management of patients suspected or diagnosed with pneumonitis (risk stratification adapted from [26]). CMV cytomegalovirus, LDH lactate dehydrogenase, PCP Pneumocystis jirovecii pneumonia, PI3K phosphoinositol-3-kinase
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Fig2: Management of patients suspected or diagnosed with pneumonitis (risk stratification adapted from [26]). CMV cytomegalovirus, LDH lactate dehydrogenase, PCP Pneumocystis jirovecii pneumonia, PI3K phosphoinositol-3-kinase

Mentions: Pneumocystis jirovecii and cytomegalovirus are the main infectious agents for pneumonia in immunocompromised patients; for these patients lymphoproliferative malignancies, long-term use of glucocorticoids, lymphocytopenia (CD4 < 200/μL), and allogeneic hematopoietic stem cell transplantation are known risk factors [27]. Guidelines for the management of P. jirovecii pneumonia in non-HIV-infected hematological patients were recently updated by the European Conference on Infections in Leukemia (ECIL) [26]. The authors emphasized the need for immediate treatment which should not be delayed by diagnostic procedures. The severity grading which categorizes HIV-positive P. jirovecii pneumonia patients into mild, moderate, or severe cases was recommended only for dichotomized use in the non-HIV population (mild versus moderate-to-severe; Fig. 2). This differentiation might be helpful in patient allocation between normal and ICUs as well as in deciding how to administer the antimicrobial agents (orally versus intravenously). High-dose cotrimoxazole (90–120 mg/kg/day, intravenously over ≥14 days) remains the treatment of choice for first-line therapy. An oral route from the beginning is an option only in stable patients with mild disease, which are rarely seen in hematology. Pentamidine (4 mg/kg/d i.v.) or the combination of primaquine (30 mg/d) and clindamycin (3× 600 mg/d) can be considered in patients with contraindications to, or relapsing after, cotrimoxazole. The ECIL authors pointed out that evidence from randomized clinical trials examining the role of adjunctive corticosteroids is available only for HIV-positive patients, but not for the non-HIV population. Therefore, the routine use of corticosteroids in this cohort was not recommended.Fig. 2


New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management
Management of patients suspected or diagnosed with pneumonitis (risk stratification adapted from [26]). CMV cytomegalovirus, LDH lactate dehydrogenase, PCP Pneumocystis jirovecii pneumonia, PI3K phosphoinositol-3-kinase
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5391608&req=5

Fig2: Management of patients suspected or diagnosed with pneumonitis (risk stratification adapted from [26]). CMV cytomegalovirus, LDH lactate dehydrogenase, PCP Pneumocystis jirovecii pneumonia, PI3K phosphoinositol-3-kinase
Mentions: Pneumocystis jirovecii and cytomegalovirus are the main infectious agents for pneumonia in immunocompromised patients; for these patients lymphoproliferative malignancies, long-term use of glucocorticoids, lymphocytopenia (CD4 < 200/μL), and allogeneic hematopoietic stem cell transplantation are known risk factors [27]. Guidelines for the management of P. jirovecii pneumonia in non-HIV-infected hematological patients were recently updated by the European Conference on Infections in Leukemia (ECIL) [26]. The authors emphasized the need for immediate treatment which should not be delayed by diagnostic procedures. The severity grading which categorizes HIV-positive P. jirovecii pneumonia patients into mild, moderate, or severe cases was recommended only for dichotomized use in the non-HIV population (mild versus moderate-to-severe; Fig. 2). This differentiation might be helpful in patient allocation between normal and ICUs as well as in deciding how to administer the antimicrobial agents (orally versus intravenously). High-dose cotrimoxazole (90–120 mg/kg/day, intravenously over ≥14 days) remains the treatment of choice for first-line therapy. An oral route from the beginning is an option only in stable patients with mild disease, which are rarely seen in hematology. Pentamidine (4 mg/kg/d i.v.) or the combination of primaquine (30 mg/d) and clindamycin (3× 600 mg/d) can be considered in patients with contraindications to, or relapsing after, cotrimoxazole. The ECIL authors pointed out that evidence from randomized clinical trials examining the role of adjunctive corticosteroids is available only for HIV-positive patients, but not for the non-HIV population. Therefore, the routine use of corticosteroids in this cohort was not recommended.Fig. 2

View Article: PubMed Central - PubMed

ABSTRACT

Pharmacological and cellular treatment of cancer is changing dramatically with benefits for patient outcome and comfort, but also with new toxicity profiles. The majority of adverse events can be classified as mild or moderate, but severe and life-threatening complications requiring ICU admission also occur. This review will focus on pathophysiology, symptoms, and management of these events based on the available literature.

While standard antineoplastic therapy is associated with immunosuppression and infections, some of the recent approaches induce overwhelming inflammation and autoimmunity. Cytokine-release syndrome (CRS) describes a complex of symptoms including fever, hypotension, and skin reactions as well as lab abnormalities. CRS may occur after the infusion of monoclonal or bispecific antibodies (MABs, BABs) targeting immune effectors and tumor cells and is a major concern in recipients of chimeric antigen receptor (CAR) modified T lymphocytes as well. BAB and CAR T-cell treatment may also be compromised by central nervous system (CNS) toxicities such as encephalopathy, cerebellar alteration, disturbed consciousness, or seizures. While CRS is known to be induced by exceedingly high levels of inflammatory cytokines, the pathophysiology of CNS events is still unclear. Treatment with antibodies against inhibiting immune checkpoints can lead to immune-related adverse events (IRAEs); colitis, diarrhea, and endocrine disorders are often the cause for ICU admissions.

Respiratory distress is the main reason for ICU treatment in cancer patients and is attributable to infectious agents in most cases. In addition, some of the new drugs are reported to cause non-infectious lung complications. While drug-induced interstitial pneumonitis was observed in a substantial number of patients treated with phosphoinositol-3-kinase inhibitors, IRAEs may also affect the lungs.

Inhibitors of angiogenetic pathways have increased the antineoplastic portfolio. However, vessel formation is also essential for regeneration and tissue repair. Therefore, severe vascular side effects, including thromboembolic events, gastrointestinal bleeding or perforation, hypertension, and congestive heart failure, compromise antitumor efficacy.

The limited knowledge of the pathophysiology and management of life-threatening complications relating to new cancer drugs presents a need to provide ICU staff, oncologists, and organ specialists with evidence-based algorithms.

No MeSH data available.


Related in: MedlinePlus