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