Tamoxifene

Ultimo aggiornamento 23/07/2023

Il tamoxifene (C₂₆H₂₉NO) è un farmaco che appartiene alla classe degli antiestrogeni non steroidei; è un derivato del trifeniletilene, precursore anche del più utilizzato clomifene citrato. 

Introdotto in commercio negli anni ’90, rappresenta ancora oggi il cardine della terapia endocrinologica del carcinoma della mammella femminile e maschile sia dopo l’intervento chirurgico di prima istanza, sia dopo l’eventuale recidive, in caso di positività recettoriale.

La terapia con TMX determina un miglioramento assoluto del 9% in termini di sopravvivenza a 10 anni nelle pazienti con cancro mammario. E’ inoltre utilizzato per la prevenzione del cancro mammario controlaterale (riduzione del 50% del rischio). 

Il tamoxifene (Nolvadex® cpr 10 mg, 20 mg), agisce con meccanismo di competizione recettoriale con gli estrogeni (SERM):

1. occupando il sito recettoriale estrogenico ipofisario  impedisce l’effetto feed-back negativo degli estrogeni sulla secrezione gonadotropinica.  

2. legandosi ai recettori estrogenici nei tumori ER-positivi svolge un’efficace azione antineoplastica. 

Il TMX è commercializzato in Italia con il nome di Nolvadex® che si presenta in forma di compresse da 10 e 20 mg. La posologia post-chirurgica del cancro mammario è di 20 mg/die, da assumersi preferibilmente sempre alla stessa ora; viene assorbito a livello intestinale e viaggia in circolo legato all’albumina plasmatica per raggiungere gli organi target.

Giacché il tamoxifene può causare senso di nausea e  lasciare un sapore metallico in bocca, alcune pazienti preferiscono prenderlo durante i pasti. Normalmente il trattamento con il tamoxifene è prescritto per cinque anni, anche se alcuni oncologi lo prescrivono per due anni e altri a tempo indeterminato. Attualmente si ritiene che cinque anni siano la durata ideale per le pazienti in pre-menopausa, mentre per le pazienti in post-menopausa la durata è variabile.

EFFETTI COLLATERALI 

• SINDROME PRE-MENOPAUSALE. Vampate di calore, sudorazioni notturne, perdite vaginali, secchezza e prurito vaginale, riduzione del desiderio sessuale e dispareunia sono comuni durante il trattamento. I sintomi tendono ad essere più accentuati nelle pazienti in premenopausa e nelle donne in post-menopausa precedentemente trattate con terapia ormonale sostitutiva. I disturbi vasomotori divengono meno pronunciati dopo alcuni mesi di terapia e tendono a scomparire gradualmente col tempo, ma non per tutte le pazienti. Può giovare ridurre il consumo di tè, caffè, tabacco e alcool anche se alcuni studi confermano l’effetto adiuvante del caffè nel potenziamento dell’efficacia del TMX. Anche la somministrazione di progesterone e alcuni farmaci antidepressivi può essere efficace nel lenire i disturbi vasomotori. 
• Nausea e indigestione. Sono abbastanza frequenti all’inizio del trattamento, ma tendono a scomparire dopo le prime settimane. La nausea scompare spesso spontaneamente, ma se persiste può essere trattata con efficacia con i farmaci antiemetici.  Può giovare assumere le compresse a stomaco pieno o con il latte.
• Aumento dell’appetito. È l’effetto collaterale più comune. Un regime dietetico adeguato può servire a limitarne le conseguenze.
• Modificazioni del ciclo mestruale. Le donne che non sono ancora in età menopausale potrebbero notare che il ciclo mestruale si modifica: le mestruazioni diventano irregolari, scarse o talvolta addirittura scompaiono. 
• Depressione, stanchezza e vertigini. Alcune pazienti si sentono depresse durante il trattamento con tamoxifene, ma ciò può dipendere da altre cause.
• Cefalea. Alcune pazienti sofferenti di emicrania hanno descritto un aumento del disturbo. Può giovare bere molto, 
• Trombosi venose superficiali e profonde e trombosi polmonari. Compaiono dolore, sensazione di calore, gonfiore o sensibilità localizzati a un arto, oppure dolore toracico.
• Trombocitopenia (generalmente limitata a valori compresi tra 80.000 e 90.000/mmc, senza conseguenze emorragiche) e leucopenia. Raramente tali fenomeni sono di gravità tale da provocare la sospensione della terapia. Si consiglia comunque un controllo dell’emocromo e delle piastrine dopo 15-20 giorni dall’inizio del trattamento e, successivamente, ogni 6 mesi.
• Disturbi della vista. Opacità subcapsulari posteriori del cristallino (cataratta)  sono le patologie oculari più comuni. Riportati casi di retinopatia utilizzando dosi elevate di TMX, non confermati però da studi condotti utilizzando dosi standard del farmaco. 
• Modificazioni della voce. Sono state riferite da alcune pazienti, e chi è cantante di professione potrebbe richiedere una consulenza specifica.

iPERPLASIA E CARCINOMA DELL’ENDOMETRIO: è il più temuto fra gli effetti collaterali del TMX.

Il TMX benchè agisca come antagonista estrogenico sulla mammella, su altri organi estrogeni positivi, come l’endometrio, agisce come agonista. Alcuni studi hanno dimostrato che le pazienti che assumono tamoxifene in dosi elevate per un lungo periodo hanno un rischio leggermente accresciuto di sviluppare ispessimento dell’endometrio >5 mm,  iperplasia endometriale con atipie, polipi endometriali, endometriosi  e leiomiomi.

Siccome anche le cellule stromali contengono recettori per gli estrogeni, possono insorgere anche sarcomi e tumori mesodermici misti maligni dell’utero.

Le pazienti in terapia con TMX  più facilmente vanno incontro a curettage, isterectomia e annessiectomia bilaterale.

Solamente tra le donne in premenopausa si è avuto un rischio significativamente aumentato di cisti ovariche. Tuttavia, questi rischi devono essere valutati rispetto ai benefici derivanti dal trattamento, che per la maggior parte delle pazienti sono di gran lunga superiori ai rischi.  

TMX e induzione dell’ovulazione in pazienti PCOS – il TMX potrebbe essere utilizzato, come alternativa o in associazione al Clomifene, per indurre ovulazione nelle pazienti PCOS anovulatorie resistenti al clomifene (127,128). Induce un’aumentata secrezione di gonadotropine ma presenta un importante effetto antiestrogenico perfiferico.

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