1

Les toxicités du cancer: l’os…

Matti S. AaproCancer Center

GenolierSwitzerland

COI

Dr Aapro is/was a consultant for Amgen, BMS, Celgene, Clinigen, Eisai, Genomic Health, GSK, Helsinn, Hospira, JnJ, Novartis, Merck, Merck Serono, Pfizer,

Pierre Fabre, Roche, Sandoz, Tesaro,Teva, Vifor

and has received honoraria for lectures at symposia of Amgen, Bayer Schering, Biocon, Cephalon, Chugai, DRL, Eisai,

Genomic Health, GSK, Helsinn, Hospira, Ipsen, JnJ OrthoBiotech, Kyowa Hakko Kirin, Merck, Merck Serono, Novartis, Ono

Pharmaceuticals, Pfizer, Pierre Fabre, Roche, Sandoz, Sanofi, Tesaro, Taiho, Teva, Vifor

No responsibility accepted forinvoluntary errors or omissions. The list may be incomplete, and does not reflect consultancy for NGOs, Universities, Governmental agencies, and others

WHOM TO THANK?

Laura BiganzoliRobert Coleman

Luis CostaDiana Crivellari

Jean-Pierre DrozArti Hurria

Juan MoroteHans Wildiers

And many others

Si c’est le cancer, alors…c’est l’ostéosarcome

ou la métastase

Disease

Bone metastases

Fracture

Hypercalcemia

Surgery to bone(incl. cementoplasty)

Radiation

to bone

SREs

Spinal cord

compression

Loss of

autonomy

Consequences

Significant morbidity

Bone pain

Decreased survival

Increased healthcare

costs and resources

Bone metastases can have debilitating consequences 1

SREs = Skeletal-related events

1. Adapted from Kinnane N. Eur J Oncol Nurs 2007;11(Suppl.):S28-S31; 2. Weinfurt KP, et al. Ann Oncol 2005;16:579-584.

Ultimateconsequence

Reduced qualityof life 2

www.esmo2012.org

Denosumab is also effective in pain control

� Time to pain worsening (≥ 2-point increase)

*223 ZA patients and 219 denosumab patients reported baseline worst pain scores of 9 and 10 and were thus ineligible to reach a 2-point increase.

Pain worsening was delayedwith denosumab compared

with zoledronic acidDenosumabZoledronic Acid

Pro

port

ion

of S

ubje

cts

With

out

a ≥ 2

-Poi

nt In

crea

se

0.8

0.6

0.4

0.2

0.0

1.0

Study WeekBL 13 25 37

DenosumabZoledronic Acid 2440 1303 914 692

2476 1391 955 719

Subjects at Risk*

HR 0.92 (95% CI: 0.86–0.99)P = 0.026

KM Estimate of Median Days:

DenosumabZoledronic Acid

181169

Cleeland CS, et al. Ann Oncol 2010;21:8s (abstract 1248P)

When to start Bone Targeted Therapy

� It takes some months before the benefit is evident as bone lesions need time to heal

� Thus guidelines indicate: start immediately after diagnosis of bone metastases

� BUT use clinical judgment: if the patient’s life expectancy is very short, it might not be useful

Aapro et al Annals of Oncology 2008

Denosumab efficacy results across pivotal studies in patients with bone metastases*

*All data come from the primary analysis phase of these studies

1Stopeck AT, Lipton A, Body JJ, et al. J Clin Oncol 2010;28:5132-5139.2Fizazi K, Carducci M, Smith M, et al. Lancet 2011;377:813-822.3Henry DH, Costa L, Goldwasser F, et al. J Clin Oncol 2011;29:1125-1132.

Study Month

0.0

0.2

0.4

0.6

0.8

1.0

24 30

Breast Cancer (n=2046)1Other Solid Tumors orMultiple Myeloma (n=1776)3Prostate Cancer (n=1901)2

HR 0.82 (95% CI: 0.71, 0.95)P<0.001 (Non-inferiority)

P = 0.01 (Superiority)

HR 0.82 (95% CI: 0.71, 0.95)P=0.0002 (Non-inferiority)

P=0.008 (Superiority)

HR 0.84 (95% CI: : 0.71, 0.98 )P=0.0007 (Non-inferiority)

P=0.06 (Superiority)

12 180 6

Study Month

24 3012 180 6

Study Month

24 3012 180 6

Pro

port

ion

of s

ubje

cts

with

out S

RE

Similar overall disease-progression and survival

Study Month

0 6 12 18 24 30

Pro

port

ion

of S

ubje

cts

with

out

Dis

ease

Pro

gres

sion

1.0

0.8

0.6

0.4

0.2

0

HR 1.02 (95% CI: 0.95, 1.08)P=0.63

Overall Disease Progression

Study Month

0 6 12 18 24 30

1.0

0.8

0.6

0.4

0.2

0

HR 0.99 (95% CI: 0.91, 1.07)P=0.71

Overall Survival

Pro

port

ion

of S

ubje

cts

Sur

vive

d

KM Estimate of Median Months

Zoledronic Acid 8.8

Denosumab 8.6

KM Estimate of Median Months

Zoledronic Acid 22.3

Denosumab 22.5

Lipton A, Siena S, Rader M, et al. ESMO 2010: abstract 1249P and poster presentation.

Adverse events in the presence of MONTHLYdenosumab or zoledronic acid: ONJ and others

Patient incidence, n (%) Zoledronic Acid (n=2836) Den osumab (n=2841)

Adverse events (AEs) 2745 (96.8) 2734 (96.2)

Most common AEs

Nausea 895 (31.6) 876 (30.8)

Anaemia 859 (30.3) 771 (27.1)

Fatigue 766 (27.0) 769 (27.1)

Back pain 747 (26.3) 718 (25.3)

Decreased appetite 694 (24.5) 656 (23.1)

CTCAE Grade 3, 4 or 5 AEs 2009 (70.8) 2000 (70.4)

Serious AEs 1620 (57.1) 1599 (56.3)

AEs leading to study discontinuation 280 (9.9) 270 (9.5)

Infectious AEs 1218 (42.9) 1233 (43.4)

Infectious serious AEs 309 (10.9) 329 (11.6)

Acute phase reactions (first 3 days) 572 (20.2) 246 (8.7)

Renal AEs* 335 (11.8) 262 (9.2)

Cumulative rate of ONJ 37 (1.3) 52 (1.8)

Year 1 15 (0.5) 22 (0.8)

Year 2 28 (1.0) 51 (1.8)

Hypocalcemia 141 (5.0) 273 (9.6)

New primary malignancy 18 (0.6) 28 (1.0)

*Includes increased blood creatinine, renal failure, acute renal failure, proteinuria, renal impairment, oliguria, increased blood urea, hypercreatininemia, decreased urine output, anuria, decreased creatinine renal clearance, azotemia, chronic renal failure, abnormal renal function test and abnormal blood creatinine. ONJ; osteonecrosis of the jaw.

Lipton A, Siena S, Rader M, et al. ESMO 2010: abstract 1249P and poster presentation.

WHAT DOSE OF BPs TO USE in M1 BrCA

PLEASE NOTICE THAT RECENT STUDIESINDICATE THAT MONTHLY ZOLEDRONIC ACID

MAY NOT BE NEEDED FOR LONG-TERM CONTROL OF SREs

HOWEVER EXPERT CONSENSUS SUGGESTS MONTHLY FOR 3-6 MONTHS before 3 monthly

Amadori Lancet 2014; Hortobagyi ASCO 2014; Himelstein ASCO 2015

Himelstein ASCO 2015

NOT IN GUIDELINES:FIRST YOU EVALUATETHE FRACTURE RISK…

HOW?

Harrington’s was…and is not used anymore

SINS score(Spinal Instability Neoplastic Score )

22

Evaluation of spinal fracture risk:

• Score 0-6 : stable

• Score 7-12 : moderate risk

• Score 13-18 : unstable

Fourney et al JCO 2011

www.esmo2012.org

KYPHOPLASTY

Si c’est le TRAITEMENT du cancer, alors…

ce n’est pas seulementles anti-aromatases

Mais il est vrai que…

After forgetting Diel, Powles, Saarto and clodronateDealing only

with « SREs » in Metastatic Cancer,oncologists woke up

to Ais in adjuvant

7 trials; 30.023 patients

Limitations:• Literature rather than individual patient data meta-analysis• Reports of trials with different durations of follow-up • Information on the potentially confounding baseline host factors (eg, obesity,

hypertension, diabetes, and family history of events of interest) or the use of concurrent medications was not reported

= � �� �

26

ZO-FAST (N = 1,065):

ZOL � BMD During AI Therapy—60-Month Results

24 mo 36 mo 48 mo 60 mo

264

264

290

294

313

311

339

343

360

369

P < .0001 for each

Abbreviations: BMD, bone mineral density; LS, lumbar spine; ZOL, zoledronic acid.

Reprinted from de Boer R, et al. SABCS 2010, poster P5-11-01.

Δ 5.8% Δ 8.1% Δ 8.6% Δ 8.9% Δ 9.7%

Primary Endpoint: Percentage change from baseline in

lumbar spine BMD vs Placebo

*P < 0.0001 versus Placebo Months

Cha

nge

Fro

m B

asel

ine

( ±95

% C

I)

Ellis GK et al. J Clin Oncol. 2008;26:4875-4882. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

8

6

4

2

0

-2

7

5

3

1

-1

-3

**

**

*

1 3 6 12 24

Denosumab (n = 123)Placebo (n = 122)

7.6% Differenceat Month 24

5.5% Differenceat Month 12

Bone Recurrence Breast Cancer Mortality

Adjuvant bisphosphonates reduce the rate of bone metastasis and improve breast cancer survival

by 3.3% in post-menopausal patients

EBCTCG Lancet 2105

Do you think this difference is

big enough to justify

consideration of adjuvant BPs in

routine?

Adjuvant AIs reduce the rate relapse and improve breast cancer survival

by 2.1% in post-menopausal patients compared to tamoxifen

EBCTCG Lancet 2105

Not forgetting PrCa

• Bone loss with increasedrisk of fracture1,2

LESS is BETTER ...

• Baseline bone density

• Prevent risk of osteoporosis

Androgen deprivation therapy: Side effects

• Increased risk of diabetes3

• Increased risk of fatal cardiac events4–6

Years

0

10

20

30

40

50

Cu

mu

lati

ve

fra

ctu

re

inci

de

nce

(%

)

0 1 2 3 4 5 6 7 8 9

Orchiectomy

No orchiectomy

Caution in patients with:

• History of stroke

• Chronic heart failure

• Myocardial infarction

1. Daniell et al. J Urol 1997;157:439–444. 2. Shahinian VB et al.

N Engl J Med 2005;352:154–164. 3. Keating NL et al. JCO 2006;27:4448–4456.

4. D‘Amico et al. JCO 2007;25:2420–2425. 5. Hayes et al. BJU Int 2010;106:979–85.

6. Nguyen et al. Int J Radiat Oncol Biol Phys 2011 [Epub ahead of print]

Click to edit Master title style

Click to edit Master subtitle style

1. Higano CS. Nat Clin Pract Urol. 2008; 5:24-34;2. Eastell R, et al. J Bone Miner Res 2006; 21:1215-23;3. Maillefert JF, et al. J Urol 1999; 161:1219-22;4. Gnant MF, et al. Lancet Oncol 2008; 9:840-9;5. Shapiro CL, et al. J Clin Oncol 2001; 19:3306-11.

CTIBL is more rapid than naturally occurring bone loss

Click to edit Master title style

� Click to edit Master text styles– Second level

• Third level– Fourth level

1. Higano CS. Nat Clin Pract Urol 2008;5:24-4; 2. Eastell R, et al. J Bone Miner Res 2006;21:1215-23; 3. Maillefert JF, et al. J Urol 1999;161:1219-22; 4. Gnant MF, et al. Lancet Oncol 2008;9:840-9; 5. Shapiro CL, et al. J Clin Oncol 2001;19:3306-11

Bone loss induced by ADT for prostate cancer is rapid and clinically significant

0.51.0

2.02.6

4.6

7.47.7

0

2

4

6

8

10

Bon

e lo

ss a

t 1 y

ear

(%) Naturally occurring

bone lossCTIBL

GUIDELINES

43

ESMO clinical practice guideline: Bone health in cancer patients

• Clinicians treating cancer patients need to be aware of:

• Treatments to reduce skeletal morbidity in metastatic disease

• Strategies to minimise cancer treatment-induced skeletal damage

• ESMO guidelines “provide a framework for maintaining bone health in patients with cancer”

Coleman R et al. Ann Oncol 2014;00:1–14.

44

Prevention of bone loss in patients with treatments known to increase the risk of fractures

• e.g. age >65 years, smoking, oral corticosteroid use >6 months, low BMI (<20 ), family history of hip-fracture, personal history of fragility fracture after age 50

Baseline fracture risk factor assessment

Bone mineral density (BMD) measurement

• Take more weight-bearing exercise• Stop smoking• Reduce alcohol consumption

Lifestyle changes

• Adequate calcium (1000 mg/day) intake• Supplementary vitamin D (to total intake of 1000–2000 units/day)

Dietary measures and supplements

In selected cases – bone directed anti-resorptive therapy to manage low BMD or rapid bone loss

Coleman R et al. Ann Oncol 2014;00:1–14.

45

Regulatory approval for anti-resorptive agents in cancer patients

Indication Regulatory approval

Prevention of skeletal-related events

Zoledronic acid 4 mg i.v. every 3–4 weeksDenosumab 120 mg s.c. every 4 weeksPamidronate 90 mg i.v. every 3–4 weeksClodronate 1600 mg p.o. daily Ibandronate 50 mg p.o. dailyIbandronate 6 mg i.v. monthly

All solid tumours and multiple myelomaAll solid tumoursBreast cancer and multiple myelomaOsteolytic lesions*Breast cancer* Breast cancer*

Prevention of breast cancer metastases

Zoledronic acid 4 mg i.v. 6 monthlyZoledronic acid 4 mg i.v. monthly x 6, then 3–6 monthly Clodronate 1600 mg daily

NoneNoneNone

Prevention of prostate cancer metastases

Denosumab 120 mg s.c. monthly None

Prevention of treatment-induced bone loss

Denosumab 60 mg s.c. 6 monthly Zoledronic acid 4 mg i.v. 6 monthlyAlendronate 70 mg p.o. weekly Risedronate 35 mg p.o. weekly Ibandronate 150 mg p.o. monthlyPamidronate 90 mg i.v. every 3 months

Prostate and breast cancerNoneNoneNoneNoneNone

*European approval only (not US)i.v. – intravenous; s.c. subcutaneous; p.o. per oral

Coleman R et al. Ann Oncol 2014;00:1–14.

46

Treatment recommendations

• Bisphosphonates and denosumab prevent bone loss associated with ovarian suppression/aromatase inhibitors in early breast cancer and androgen deprivation therapy in prostate cancer

Prevention of

treatment-induced

bone loss

Coleman R et al. Ann Oncol 2014;00:1–14.

Save the Date 2017

THANK YOU

to all the patients

and their

physicians, nurses and carers