An estimated number of 19.3 million new cancer cases and nearly 10.0 million deaths have been diagnosed in 2020, identifying cancers as the most impactful disease worldwide. Immunotherapy is now considered the last frontier in the fight against cancer and is based on the induction and amplification of an immune response that eliminates immunological tolerance by acting indirectly on the tumor and targeting the defense mechanisms used by the immune system. The distinguishing feature of immunotherapy can be identified in the use of immune system molecules and cells that are naturally part of the body, such as lymphocytes. Some classes of immunotherapy drugs have been associated with the rising of a new subset of autoimmune-type toxicities, known as immune-related adverse events, irAEs, with delayed onset and prolonged duration. Dermatologic irAEs are among the most frequently reported toxicities in immunotherapy. They affect approximately 47-68% of patients treated with anti-CTLA-4 antibodies and 30-40% of patients treated with anti-PD-1/anti-PD-L1 antibodies and may result in dose reduction, addition of systemic steroids, and/or discontinuation of therapy. Therefore, all drugs are continuously subjected to post-marketing surveillance, called pharmacovigilance. The National Pharmacovigilance Network (RNF) is a system for monitoring the safety of medicines in Italy that allows the collection of reports of suspected ADRs to medicines. Purpose: The project is a retrospective observational study involving the collection of clinical data from 500 patients treated or being treated with immunotherapy according to clinical practice, to assess the type, frequency and severity of related skin toxicities and compare the results obtained with what was reported in RNF. Materials: The medical records of 500 patients treated with immunotherapy were analyzed to obtain patient attributes, possible skin toxicities and therapies given. By means of AIFA registries, the dates of administration at which patients reported skin ADRs and the date of initiation of therapy were collected. Using the National Pharmacovigilance Network portal, it was possible to proceed with the extraction of ADR reports entered at national level, so that a direct comparison could be obtained with what was found at the European Institute of Oncology. Results: During the chosen time frame, 218 ADRs occurred, a number that differs little from what was obtained at the national level (238) and clearly highlights the phenomenon of underreporting. The irAEs showed different severity and timing of onset. 24.3% of ADRs occurred during the first six months of treatment, while 17 patients were affected by toxicity directly during the first administration, and in 3 of these subjects the adverse reaction was the predisposing condition for immediate treatment discontinuation. Only 10% of the total ADRs were classified as serious, less than half of what was recorded nationally, and among the 12 drugs under study, 5 did not result in G3- and/or G4-grade ADRs, while panitumumab caused the occurrence of 8 G3-grade ADRs, of which 6 resulted in discontinuation of immunotherapy treatment. Conclusions: The study showed a different detection of dermatological adverse events at the National level compared to the individual reality, so it would be interesting to consider the totality of therapies taken by the patient in order to assess whether the different distribution of adverse events could be linked to drug interactions or different premedication. On average, however, immunologic oncology therapies were found to be safe on the dermatologic profile.
Nel mondo, si stima che nel 2020 siano stati diagnosticati circa 19,3 milioni di nuovi casi di cancro e quasi 10,0 milioni di decessi, che identificano i tumori come la patologia più impattante a livello mondiale. L’immunoterapia è oggi considerata l’ultima frontiera della lotta al cancro e si basa sull’induzione e sull’amplificazione di una risposta immunitaria che elimina la tolleranza immunologica agendo in modo indiretto sul tumore e andando a colpire i meccanismi di difesa usati dal sistema immunitario. La caratteristica peculiare dell’immunoterapia è identificabile nell’utilizzo di molecole e cellule del sistema immunitario che fanno naturalmente parte dell’organismo, come i linfociti. Alcune classi di farmaci immunoterapici sono state associate all'emergere di un nuovo sottoinsieme di tossicità di tipo autoimmune, note come immune-related adverse event, irAE, con un esordio ritardato e una durata prolungata. Gli irAEs dermatologici sono tra le tossicità più frequenti riportate in immunoterapia. Colpiscono circa il 47-68% dei pazienti trattati con anticorpi anti-CTLA-4 e il 30-40% dei pazienti trattati con anticorpi anti-PD-1/anti-PD-L1 e possono comportare la riduzione della dose, l’aggiunta di steroidi sistemici, e/o l’interruzione della terapia. Pertanto, tutti i farmaci sono costantemente sottoposti ad una sorveglianza post-marketing, chiamata farmacovigilanza. La Rete Nazionale di Farmacovigilanza (RNF) è un sistema per il monitoraggio della sicurezza dei medicinali in Italia che permette la raccolta delle segnalazioni di sospette ADR a medicinali. Il progetto è uno studio osservazionale retrospettivo che prevede la raccolta di dati clinici di pazienti in trattamento con immunoterapia secondo pratica clinica, così da valutare il tipo, la frequenza e la gravità delle tossicità cutanee correlate e confrontare i risultati ottenuti con quanto segnalato in RNF. Sono state analizzate le cartelle cliniche di 500 pazienti in trattamento con immunoterapia dalle quali sono state ricavate le specifiche del paziente, le eventuali tossicità cutanee e le terapie effettuate. Attraverso l’utilizzo dei registri AIFA sono state raccolte le date di somministrazione alle quali i pazienti hanno riportato ADR cutanee e la data d’inizio della terapia. Attraverso l’utilizzo del portale della Rete Nazionale di Farmacovigilanza è stato possibile procedere con l’estrazione delle segnalazioni di ADR inserite a livello nazionale, così da poter ottenere un confronto diretto. Durante l’arco temporale prescelto si sono verificate 218 ADR, un numero che poco si discosta da quanto ottenuto a livello nazionale (238) e che evidenzia in modo chiaro il fenomeno della sottosegnalazione. Gli irAEs hanno mostrato gravità e tempi d’insorgenza differenti. Il 24,3% delle ADR si sono verificati durante i primi sei mesi di trattamento, mentre 17 pazienti sono stati colpiti da tossicità direttamente durante la prima somministrazione e in 3 di questi soggetti la reazione avversa è stata la condizione predisponente all’immediata interruzione del trattamento. Solo il 10% delle ADR totali sono state classificate come gravi, meno della metà rispetto a quanto registrato a livello nazionale e tra i 12 farmaci oggetto di studio, 5 non hanno dato luogo ad ADR di grado G3 e/o G4, mentre il Panitumumab ha causato l’insorgenza di 8 ADR con grado G3, di cui 6 hanno comportato l’interruzione del trattamento immunoterapico. Lo studio ha evidenziato una diversa rilevazione degli eventi avversi dermatologici a livello Nazionale rispetto alla singola realtà, per questo motivo sarebbe interessante considerare la totalità delle terapie assunte dal paziente in modo da valutare se la differente distribuzione degli eventi avversi possa essere imputabile a interazioni farmacologiche o a una differente premedicazione. In media, però, le terapie immunologiche oncologiche si sono rivelate sicure.
Eventi avversi dermatologici e immunoterapia: studio osservazionale di Farmacovigilanza promosso dalla Farmacia dell’Istituto Europeo di Oncologia
PROVERA, SILVIA
2021/2022
Abstract
An estimated number of 19.3 million new cancer cases and nearly 10.0 million deaths have been diagnosed in 2020, identifying cancers as the most impactful disease worldwide. Immunotherapy is now considered the last frontier in the fight against cancer and is based on the induction and amplification of an immune response that eliminates immunological tolerance by acting indirectly on the tumor and targeting the defense mechanisms used by the immune system. The distinguishing feature of immunotherapy can be identified in the use of immune system molecules and cells that are naturally part of the body, such as lymphocytes. Some classes of immunotherapy drugs have been associated with the rising of a new subset of autoimmune-type toxicities, known as immune-related adverse events, irAEs, with delayed onset and prolonged duration. Dermatologic irAEs are among the most frequently reported toxicities in immunotherapy. They affect approximately 47-68% of patients treated with anti-CTLA-4 antibodies and 30-40% of patients treated with anti-PD-1/anti-PD-L1 antibodies and may result in dose reduction, addition of systemic steroids, and/or discontinuation of therapy. Therefore, all drugs are continuously subjected to post-marketing surveillance, called pharmacovigilance. The National Pharmacovigilance Network (RNF) is a system for monitoring the safety of medicines in Italy that allows the collection of reports of suspected ADRs to medicines. Purpose: The project is a retrospective observational study involving the collection of clinical data from 500 patients treated or being treated with immunotherapy according to clinical practice, to assess the type, frequency and severity of related skin toxicities and compare the results obtained with what was reported in RNF. Materials: The medical records of 500 patients treated with immunotherapy were analyzed to obtain patient attributes, possible skin toxicities and therapies given. By means of AIFA registries, the dates of administration at which patients reported skin ADRs and the date of initiation of therapy were collected. Using the National Pharmacovigilance Network portal, it was possible to proceed with the extraction of ADR reports entered at national level, so that a direct comparison could be obtained with what was found at the European Institute of Oncology. Results: During the chosen time frame, 218 ADRs occurred, a number that differs little from what was obtained at the national level (238) and clearly highlights the phenomenon of underreporting. The irAEs showed different severity and timing of onset. 24.3% of ADRs occurred during the first six months of treatment, while 17 patients were affected by toxicity directly during the first administration, and in 3 of these subjects the adverse reaction was the predisposing condition for immediate treatment discontinuation. Only 10% of the total ADRs were classified as serious, less than half of what was recorded nationally, and among the 12 drugs under study, 5 did not result in G3- and/or G4-grade ADRs, while panitumumab caused the occurrence of 8 G3-grade ADRs, of which 6 resulted in discontinuation of immunotherapy treatment. Conclusions: The study showed a different detection of dermatological adverse events at the National level compared to the individual reality, so it would be interesting to consider the totality of therapies taken by the patient in order to assess whether the different distribution of adverse events could be linked to drug interactions or different premedication. On average, however, immunologic oncology therapies were found to be safe on the dermatologic profile.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/14358