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

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.

Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead

“…Moreover, immunohistochemistry has a lower sensitivity compared to studies measuring PD-L1 mRNA expression [74] . Anti-PD-1 and anti-PD-L1 antibody treatments are currently the most investigated ICIs because they have shown less severe toxicity, or high-grade "immunerelated adverse effects" (irAEs), than anti-CTLA-4 antibody treatments (5-20% compared to 10-40% respectively) [75][76][77][78][79] . The wide ranges in the percentages of adverse effects reported reflect the variabilities associated with single or multiple drug regimens, dosage levels, and types of malignancies treated.…”

“…The more common side effects are fatigue (with or without associated endocrinopathies), dermatologic and mucosal toxicities, diarrhea/colitis, and hepatotoxity. Corticosteroids or other immunomodulators can reverse nearly all of the toxic manifestations of these drugs [75][76][77][78] . Pneumonitis is an uncommon but potentially severe complication, and rarely deaths have occurred [80] .…”

Anti-Stress and Glial Differentiation Effects of a Novel Combination of Cucurbitacin B and Withanone (CucWi-N): Experimental Evidence

“…It is directly involved in initiation of stress signaling, persistence, and attenuation. Although several synthetic and natural anti-stress molecules are available as nutraceuticals in the market, they are limited in terms of experimental evidence to their claimed effects and often raise undesired adverse effects [32]. There is a compelling need to develop natural, efficient, and welfare combinatorial compounds/extracts with broad and safe spectrum of effects in functional preventive and therapeutic medicine.…”

Avancées médicamenteuses en oncologie thoracique

“…Il est parfois difficile de le distinguer d'une progression tumorale vraie. Le profil de tolérance des anti-PD1 est globalement favorable, mais avec des effets secondaires fréquents et d'intensités variables [13]. Ils surviennent le plus souvent dans les 12 premières semaines mais peuvent également survenir plusieurs semaines après l'arrêt de l'immunothérapie.…”

“…Ainsi chez un patient traité par immunothérapie qui présente une pneumopathie interstitielle diffuse, il sera souvent difficile d'en identifier la cause : toxicité de l'immunothérapie, pneumopathie infectieuse potentiellement à germe opportuniste ou progression tumorale. Il est proposé de réaliser rapidement une fibroscopie bronchique avec lavage bronchoalvéolaire pour orienter le diagnostic et proposer un traitement adapté [13]. Les colites peuvent également être graves et doivent entraîner la suspension du traitement, un bilan étio-logique complet (scanner et rectosigmoïdoscopie avec biopsies) et un traitement rapide par corticoïdes, voire dans les formes les plus sévères par anti-TNF.…”