HOT TOPICS MALATTIA METASTATICA

Terapia delle metastasi

Alfredo BerrutiUniversità degli Studi 

di BresciaAzienda Ospedaliera

Spedali CiviliBrescia

Quando è indicato il trattamentoQuando è indicato il trattamento con ac. zoledronico? 

Time to SRE Proportion  of SRE

ZOL PLAC

J Natl Cancer Inst 2002;94:1458–68

Linee guida AIOM Neoplasia prostatica metastatica

• L’acido zoledronico si è dimostrato efficace nel ridurre le complicanze scheletriche di pazienti con metastasi ossee da carcinoma prostatico 

Evidenza I; Grado di raccomandazione: A• Ancorché vi sia un chiaro razionale, i dati disponibili non consentono di raccomandare 

fortemente l’uso dei bisfosfonati nel paziente con metastasi ossee da carcinoma prostatico ormonosensibile. L’uso di questi farmaci in questo contesto deve essere valutato caso per caso. 

E id VI d di d i BEvidenza VI; grado di raccomandazione: B• I bisfosfonati possono essere efficaci nel controllo del dolore osseo 

Evidenza I; Grado di raccomandazione B

Quale paziente deve essere avviato a trattamento con acido zoledronico?a trattamento con acido oledronico?

Il paziente a rischio di complicanze scheletriche:Il paziente a rischio di complicanze scheletriche:

Estensione di malattiaEstensione di malattia

Dolore osseoDolore osseo

Clin Cancer Res 17: 4854‐4861, 2011

EnzalutamideEnzalutamide

Abiraterone

Bisogna utilizzare supplementazioni di calcio e vitamina D durante la terapia con difosfonati? 

VITAMIN D SUPPLEMENTATION AND BISPHOSPHONATESVITAMIN D SUPPLEMENTATION AND BISPHOSPHONATES IN OSTEOPOROTIC PATIENTS

Vitamin D supplementation is mandatory in association withBisphosphonates in osteoporotic patients with vitamin D Deficiency and insufficiency

Controversial role in patients with vitamin D in the normal range

Carmel AS, Osteoporos Int. 2012; 23(10):2479-87Bourke S et al Osteoporos Int. 2013; 24(1):349-54

1. The total daily intake of elemental calcium (through diet and supplements) for individuals over age 50 should be 1200 mg [grade B].

2. For healthy adults at low risk of vitamin D deficiency, routine supplementation with 400–1000 IU (10–25 μg) vitamin D3 daily is recommended [grade D].

3 F d lt 50 t d t i k f it i D d fi i l t ti ith 8003. For adults over age 50 at moderate risk of vitamin D deficiency, supplementation with 800–1000 IU (20–25 μg) vita min D3 daily is recommended. To achieve optimal vitamin D status, daily supplementation with more than 1000 IU (25 μg) may be required. Daily doses up to 2000 IU (50μg) are safe and do not necessitate monitoring [grade C].( μg) g [g ]

4. For individuals receiving pharmacologic therapy for osteoporosis, measurement of serum 25-hydroxyvitamin D should follow three to four months of adequate supplementation and should

t b t d if ti l l l ( 75 l/L) i hi d [ d D]not be repeated if an optimal level (ε 75 nmol/L) is achieved [grade D].

Linee guida AIOMLinee guida AIOM

Take home message: A tutti i pazienti che effettuano bisfosfonati per via endovenosa o orale è raccomandata una supplementazione di calcio e vitamina D. E’ lt b bil h l d i d t 500 di l i 400 UIE’ molto probabile che le dosi raccomandate: 500 mg di calcio e 400 UI non siano adeguate e debbano essere raddoppiate. E’ consigliabile somministrare a tutti i pazienti oncologici che devono iniziare una terapia con bifosfonati una dose di 1000 UI al giorno di vitamina D p ge di 500 mg al giorno di calcio, possibilmente in formulazioni farmaceutiche separate. Utile monitoraggio di calcemia (ionizzata o corretta per albumina) durante il t tt t bi f f ti l fi di l i i l i i iil trattamento con bisfosfonati al fine di correggere valori ipocalcemici severi.

Median Percent Change From Baseline in Serum Parathyroid Median Percent Change From Baseline in Serum Parathyroid Hormone by Treatment  (IntentHormone by Treatment  (Intent‐‐toto‐‐Treat Patients)Treat Patients)

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PTHPTH

Brian Ell and Yibin Kang Cell 151, October 26, 2012

2012;17: 645-652.

Univariate Model of Overall Survival in PC Patients3‐Month PTH as Quartiles

Placebo P value

.7040.89(vs 0 ≤ 3M PTH < 2.10 pmol/L)

4450.80

2.10 ≤ 3 M PTH < 3.10.445

.4010.77

3.10 ≤ 3 M PTH < 4.454.45 ≤ 3 M PTH

Z l d i id

.2741.30

Zoledronic acid(vs 0 ≤ 3M PTH < 3.10 pmol/L)

3.10 ≤ 3 M PTH < 5.10.006

1.88

<.00013.04

5.10 ≤ 3 M PTH < 8.80

8.80 ≤ 3 M PTH

0 1.0Risk ratio

2.0 3.0 4.0

(4.7)

Reduced risk of death Increased risk of deathIncreased risk of death

Zoledronic acid vs. placeboP value

.0150.72

Normal PTH < 5.2 pmol/L

.1151.50

Elevated PTH > 5.2 pmol/L

.1080.82

Overall

0.5 1.0Risk ratio

1.5 2.0 2.5

Eur Urol 2013, in press

Quale sarà il ruolo del Denosumab: la 1° linea di trattamento, l’associazione l’ac. zoledronico, o la 2° linea? 

Lancet 2011; 377: 813–22

DenosumabMaggior efficacia

Ac ZoledronicoMinori costi

Denosumab is superior to zoledronic acid in delaying SREs. p y g

The toxicity profile of denosumab lacks nephrotoxicity and acute-phase reactions. However, hypocalcemia is more common with denosumab.

In patients with severe renal dysfunction (GFR <30 ml/min), zoledronic acid is contraindicated.

In patients with more modest degrees of renal impairment, if potential h t i it i th d b b f dnephrotoxicity is a concern, then denosumab may be favored.

While denosumab lacks nephrotoxicity and is not metabolized by the kidneys there is concern that rates of hypocalcemia may be higher in thekidneys, there is concern that rates of hypocalcemia may be higher in the setting of severe renal dysfunction.

PAZIENTE CON CARCINOMA PROSTATICOCON METASTASI OSSEECON METASTASI OSSEE

QUALI INDICAZIONI PER DENOSUMAB?

Alto rischio di SRE

Insufficienza renale

AssociazioneAc Zoledronico + Denosumab NO

SequenzaAc Zoledronico Denosumab SI

SequenzaDenosumab Ac Zoledronico ?

Study SchemaStudy SchemaDesign: Randomised, double-blind, placebo-controlled, multicentre

Study protocol amended from 2 to 3 years to extend period for safety and fracture evaluation

RAN

Men with nonmetastatic prostate cancer

receiving continuous

Denosumab60 mg SC Q6M (× 6 doses)

(n=734)NDOMIS

receiving continuous ADT (n=1468)

Stratified by• Age (<70 y vs ≥70 y)

( )

PlaceboSC Q6M (× 6 doses)

( 734)

Baseline 36 months

SE

ge ( 0 y s 0 y)• Prior ADT duration

(≤6 mo vs >6 mo)

(n=734)

End points

Supplemental calcium and vitamin D

End points

Primary • Percentage change from baseline at month 24 in lumbar spine BMD

Secondary • Incidence of new vertebral fractures over 36 months P t h f b li t th 36 i l b i BMD• Percentage change from baseline at month 36 in lumbar spine BMD

• Percentage change from baseline at 24 and 36 months in total hip and femoral neck BMD

• Fracture at any site (morphometric/clinical vertebral or nonvertebral)y ( p / )• Time to first clinical fracture• Safety events Smith MR, Egerdie B, Toriz NH, et al. N Engl J Med. 2009;361:745-755.

Secondary End Point: New Vertebral yFractures

SC D b ( 679)Pl b ( 673) SC Denosumab (n = 679)Placebo (n = 673)

12 24 36

Month

6 RR 0.15P = .004

RR 0.31P = .004

RR 0.38P = .006

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01.9% 0.3% 3.3% 1.0% 3.9% 1.5%Subject Incidence

26 1013 2 22 7RR = relative risk.

Nb patients

Smith MR, Egerdie B, Toriz NH, et al. N Engl J Med. 2009;361:745-755. Copyright © 2009 Massachusetts Medical Society. All rights reserved.