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Terapia Antitumorale e diabete
Alessandro Comandone, Ilaria Messuti, Simona Chiadò Cutin, Fabio Orlandi
SC Oncologia & SS Endocrinologia Ospedale Gradenigo Torino
Quesiti fondamentali
•Ci sono farmaci oncologici che possono slatentizzare il diabete?
•Quali precauzioni vanno prese in un Paziente diabetico che debba intraprendere una terapia oncologica?
A number of chemotherapeutic regimens administered for the treatment of various solid tumors were evaluated for
hyperglycemic-inducing properties, divided by tumor site.
FARMACO PATOLOGIA VIA SOMMINISTRAZIONE
GRADO DI TOSSICITA’
ESTRAMUSTINA FOSFATO PROSTATA OS IPERGLICEMIA
ASPARAGINASI LLA IM EV DIMINUITA TOLLERANZA
MEDROSSIPROGESTERONE MAMMELLA ENDOMETRIO SUPPORTO OS IM
IPERGLICEMIA
MEGESTROLO MAMMELLA ENDOMETRIO SUPPORTO OS
IPERGLICEMIA
TALIDOMIDE MIELOMA OS IPERGLICEMIA (5%)
Quali farmaci antitumorali interferiscono con il metabolismo glicidico? (ESMO Clin Pharm 2014)
Quali farmaci antitumorali interferiscono con il metabolismo glicidico? (ESMO Clin Pharm 2014)
FARMACO PATOLOGIA VIA SOMMINISTRAZIONE
GRADO DI TOSSICITA’
TEMSIROLIMUS RENE EV IPERGLICEMIA (89%) 16% GRADO 3
EVEROLIMUS RENE,MAMMELLA, NET OS
IPERGLICEMIA (50%) 12% GRADO 3
VORINOSTAT LINFOMA CUTANEO A CELLULE T OS
IPERGLICEMIA (64%)
IGF-1R INIBITORI SARCOMA EWING, GIST CARCINOMA SURRENE OS EV
IPERGLICEMIA (20%)
STREPTOZOTOCINA NET DIABETE ( 0-90%)
ESTRAMUSTINA FOSFATO
17β)-17-idrossiestra-1(10),2,4-trien-3-yl bis(2-cloroetil)carbamato
MEDROSSIPROGESTERONE
17-acetil-17-idrossi- 6,10,13-trimetil- 1,2,6,7,8,9,10,11,12,13,14,15,16, 17- tetradecaidrociclopenta[a] fenantren-3-one
MEGESTROLO ACETATO
ASPARAGINASI
TALIDOMIDE
TEMSIROLIMUS
EVEROLIMUS
Rugo et al, Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2, Annals of Oncology 2013
Pritchard et al, Safety and Efficacy of Everolimus With Exemestane vs. Exemestane Alone in Elderly Patients With HER2-Negative, Hormone ReceptorePositive Breast Cancer in BOLERO-2, Clinical Breast Cancer 2013
EVEROLIMUS Bolero-2
TUMOR SITE: BREAST
Everolimus administered to postmenopausal patients with hormone-receptor–positive advanced breast cancer is associated with grade 3 or 4 hyperglycemia
Reduced insulin production; reduced insulin output
IGF-1R INIBITORI
IGF-1R ACTION
STREPTOZOTOCINA
Segnalazioni occasionali
GnRH analogues alone or in conjunction with androgen receptor antagonists
Serum testosterone level below the normal range is an independent risk factor for diabetes and metabolic syndrome in men (Haffner et al, 1996; Muller et al, 2005)
TUMOR SITE: PROSTATE
ADT is associated with an increased risk for altered body composition, metabolic complications including insulin resistance, T2D, dyslipidemia, metabolic syndrome, osteoporosis, cardiovascular disease, and mortality from cardiovascular disease
ADT results in an unfavorable body composition
METABOLIC EFFECT OF ADT: decreased libido, impotence, decreased lean
body mass (LBM) and muscle strength, increased fat mass, decreased quality of life,
and osteoporosis
Increase in adiposity increasing insulin levels metabolic dysregulation elaboration of
adipokines and inflammatory cytokines
+ Decrease in muscle mass decreased glucose
uptake by the muscle fibers
INSULIN RESISTANCE AND DIABETES
MECHANISM:
Metabolic changes after short-term (3–6 months) ADT
Increase in fasting insulin levels without any changes in fasting glucose
Insulin resistance develops within a few months of starting ADT
Metabolic changes after long-term (≥12 months) ADT
↑ insulin levels ↑ glucose levels
↑ insulin resistence (HOMA index) ↑ leptin levels
↑ RISK OF CARDIOVASCULAR EVENTS
HYPERGLYCEMIA 7%
DOCETAXEL results to promote hyperglycemia.
However it was always evaluated
in combination with other chemotherapies.
Because of the varying combinations of chemotherapeutic
agents administered with docetaxel, hyperglycemic
findings cannot be attributed to docetaxel alone.
TUMOR SITE: BREAST
MECHANISM: UNKNOWN
The incidence of hyperglycemia in patients treated for colorectal cancer is higher than other solid tumors. This may be related to the combination
of CT agents used to treat colon cancer; other factors such as cancer stage, lifestyle, BMI and preexisting comorbidities may also play a role.
In particular secondary diabetes associated with 5-fluorouracil (5-FU)-
based CT occurs in 10% of patients who did not have preexisting diabetes, with a significant negative impact on clinical outcome.
Feng, J.P., Yuan, X.L., Li, M., Fang, J., Xie, T., Zhou, Y., . . . Ye, D.W. (2012). Secondary diabetes associated with 5-fluorouracil-based chemotherapy regimens in non-diabetic patients with colorectal cancer:
Results from a single centre cohort study. Colorectal Disease, 17, 1463–1318
TUMOR SITE: COLORECTAL
ONLY 2 PREVIOUS PAPERS:
Tayek and Chlebowski , Metabolic response to chemotherapy in colon cancer patients 1992: 5 days of continuous 5-FU chemotherapy was associated with a significant elevation in the fasting plasma glucose and an abnormal glucose tolerance (42%). Ko¨hne et al., Modulation of 5-fluorouracil with methotrexate and low-dose N-(phosphonacetyl)- L-aspartate in patients with advanced colorectal cancer. Results of a phase II study. Eur J Cancer 1997: among 26 patients 3 had increased FPG, 2 with pre-existing insulin-dependent diabetes experienced an increase in insulin requirement and 1 patient died from ketoacidosis.
76.2% developed the disease during chemotherapy and 23.8% after it had finished,
implying that 5-FU-based chemotherapy might damage beta-cell function via two
different mechanisms: the early phase diabetes might be regarded as due to acute
beta-cell damage and the later phase as chronic beta-cell damage.
11.6% diabetes; 11.3% IFG.
5-FU alone (5-FU ⁄ leucovorin), 5-FU combined with other drugs (oxaliplatin in the FOLFOX regimen, irinotecan in the FOLFIRI regimen or mitomycin in the MF regimen) and capecitabine (an 5-FU
derivative) alone.
MECHANISM: UNKNOWN
Lodish et al, Endocrine Related Cancer 2010
TKIs: BOTH ELEVATED AND DECREASED BLOOD GLUCOSE LEVELS
IMATINIB: hyperglycemia in 0.1–1% of patients Mostly glucose-lowering effects: regression of long-standing T2DM, reduction in insulin dosage or oral antidiabetes therapy, hypoglycemia
SUNITINIB: Prescribing information: hyperglycemia in 15% of patients (Pfizer). Proposed mechanism: regression of pancreatic islets, modulation of IGF-1 signaling, decreased glucose uptake.
NILOTINIB: hyperglycemia in 12% of patients in phase II trial. Prescribing information: increased blood glucose as a common adverse reaction (<5%) (Novartis)
MECHANISM: UNKNOWN
VORINOSTAT (HDAC)
N-hydroxy-N'-phenyl-octanediamide
Conclusioni • Il diabete indotto da terapie oncologiche è stato un argomento poco
approfondito per la bassa incidenza dell’evento • Nessun farmaco storico si dimostra chiaramente causale nei confronti
dell’insorgenza di diabete • Sono maggiormente implicati i farmaci orali e dopo lungo periodo di
assunzione di quanto non siano i farmaci endovena • Gli inibitori di mTOR tra i nuovi farmaci risultano essere i più implicati • Sicuramente il tipo di diabete più comune tra i Pazienti oncologici è
quello metasteroideo, per l’ampio impiego di corticosteroidi in questa popolazione.
Conclusioni
• Pur nella rarità dell’evento, la glicemia va controllata durante le terapie oncologiche, al pari della funzionalità midollare, renale ed epatica.
• Un aspetto particolare del rapporto diabete e cancro va ricercata nelle situazioni di terminalità quando all’uso molto comune di corticosteroidei e progestinici di associano in generale condizioni di malnutrizione e di disidratazione