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