SUPPORTIVE CAREMatti AaproMatti Aapro

Genolier

FOR MORE INFORMATIONwww.mascc.orgwww.mascc.org

www.qualityoflife.elsevierresource.com

www.afsos.org

• Supportive Care is the prevention andmanagement of the adverse effects of cancerand its treatment.

• This includes physical and psychosocial

Definition of Supportive Care

• This includes physical and psychosocialsymptoms and side effects across the entirecontinuum of the cancer experience includingthe enhancement of rehabilitation andsurvivorship.

SOME AREAS OF SUPPORT

Hairloss: remains an issue

Depression: underdiagnosed

Nausea/Vomiting: MASCC guidelines are not applied

Neutropenia: EORTC guidelines

Febrile Neutropenia: but are MASCC guidelines applied?

Anemia: EORTC guidelines

Diarrhea: guidelines exist

Mucositis: MASCC guidelines

AIBL /CTIBL: Expert opinions / upcoming ESMO guidelines

Pain: « WHO guidelines »: but morphine is still not

available worldwide!

etc etc (elderly; palmo-plantar dysesthesia; skin toxicity)

Chosen chapters in Supportive Care

Why supportive / palliative care

The limits of futile treatment

G-CSFG-CSF

Antiemetics

Bone Health

ABOUT THE VALUE OF PROPER SUPPORTIVE AND PALLIATIVE CARE

Aapro M.S. EditorialAnn Oncol 2012See also Temel JS et alNEJM 2010; 363:733-42Zimmerman C et alLancet Oncol 14:219-227

INDICATORS OF SURVIVAL IN PHASE I STUDIESScore max 11 points[ECC 2013, Abs 1745].

Factors Points

Met sites ≥ 3 1

PS 1 1

LDH between 250 and 600 U/l 1

Hb < 6,2 mmol/l ( 110 g/l ) 1

Albuminemia < 35 g/l 2

LDH > 600 U/l 2

PS ≥ 2 3

Rotteveel K et al. Abstract 1745 ESMO 2013.

4 GROUPSMEDIAN SURVIVAL (MS) and MORTALITY D90

- Score ≥ 4: MS de 2,6 mths and D90 79%,- Score = 3: MS de 5,0 mths and D90 43%,- Score = 2: MS de 7,1 mths and D90 31%,- Score = 1: MS de 9,5 mths and D90 28%,- Score = 1: MS de 9,5 mths and D90 28%,- Score = 0: MS de 15,0 mths + D90 17%.

Rotteveel K et al. Abstract 1745 ESMO 2013.

The Facts

and my thoughts…

CASE ANNA

Anna is a healthy 68 years old patient with a history of recurrrent

urinary tract infections.

She is diagnosed with triple-negative breast cancer T2 N1(3/17)MO.

Adjuvant therapy with docetaxel / cyclophosphamide is planned.

What do you suggest?

1.Pegfilgrastim prophylaxis of FN

2.Filgrastim/lenograstim prophylaxis

3.Either one combined with a fluoroquinolone

4.No primary prophylaxis

5.Other choice

Febrile neutropenia

Chemotherapy for cancer is a cause of febrile neutropenia(FN: « fever « and less than 500 neutrophils )

FN is a high-risk situation for some and specially elderlypatients

G-CSF, not antibiotics, are the recommended prophylaxis G-CSF, not antibiotics, are the recommended prophylaxis

Hospitalized Cancer Patients with Febrile NeutropeniaMortality and Comorbidities

38.3

28.9

47.4

57.4

40

50

60

70

Documented infectionPresumed infection

Mort

alit

y(%

)

12 Kuderer et al. CANCER 2006;106:2258-66

1.2

6.7

12.9

23.8

4.9

14.7

28.9

0

10

20

30

0 1 2 3 >4Number of Major Comorbidities*

Mort

alit

y(%

)

*Major comorbidities are major organ dysfunction requiring diagnostic or therapeutic intervention,such as heart, lung, renal, or liver disease, diabetes mellitus, or anemia.

G-CSF supportive therapy reduces mortality:HR: 0.897 (95% CI, 0.857 to 0.938; p<0.001)

Greater mortality

reduction in:

larger trials

greater RDI

dose-densechemo

Lyman GH et al. J Clin Oncol 2010;28:2914–2924

chemo

More secondary

AML and MDS

RR: 1.92

AR: 0.41%

Updated Guidelines: 2011

PROPHYLACTIC APPROACH, NOT A REACTIVE ONE

20102010additions

And if FN hits?

De Narois et al: Management of Febrile Neutropenia:ESMO clinical practice guidelinesAnn Oncol 2010; 21:v252-v256 downloadable www.esmo.org

Score derived from the logistic equationof the MASCC predictive model

(1386 patients with FN)

CharacteristicCharacteristic PointsPoints

Burden of illnessBurden of illness

No or mild symptomsNo or mild symptoms 55

Moderate symptomsModerate symptoms 33

17J. Klastersky et al., J. Clin. Oncol. 2001

Moderate symptomsModerate symptoms 33

No hypotensionNo hypotension 55

No chronic obstructive pulmonary diseaseNo chronic obstructive pulmonary disease 44

Solid tumor or no previous fungal infection inSolid tumor or no previous fungal infection inhematological cahematological ca

44

Outpatient statusOutpatient status 33

No dehydrationNo dehydration 33

Age < 60 yearsAge < 60 years 22

Threshold: score ≥ 21(maximum 26) predicting lessthan 5% of severe complications

CASE ANNA

Anna is a healthy 68 years old patient with a history of recurrrent

urinary tract infections.

She is diagnosed with triple-negative breast cancer T2 N1(3/17)MO.

Adjuvant therapy with docetaxel / doxorubicin/ cyclophosphamide isplanned.

What do you suggest?

1. Pegfilgrastim prophylaxis of FN

2. Filgrastim/lenograstim prophylaxis

3. Either one combined with a fluoroquinolone

4. No primary prophylaxis

5. Other choice

CASE BIRGIT

Birgit is a 46 years old patient diagnosed with endocrine-responsive (ER 50% PgR 30) G3 Ki 67 30% HEr-2 neg (FISH)breast cancer T2 N0 MO.Adjuvant therapy with doxorubicin / cyclophosphamide followedby a taxane is planned. What do you USE as an acute-phaseantiemetic ?

1. (Fos)aprepitant + setron + corticosteroid

2. Palonosetron + corticosteroid

3. Setron + corticosteroid

4. Metoclopramide ( or similar ) + corticosteroid

5. Other choice

ANTIEMETICS

Nausea and vomiting (N/V) due tochemotherapy are unacceptable in the XXIcentury

Patients are at risk of renal and otherPatients are at risk of renal and othercomplications in case of N/V

Neurotransmitters/TreatmentsAssociated With Emesis

Histamine

Endorphins

Dopamine/DA RAs

Serotonin/5-HT3 RAs

Emetic reflex

GABA

Acetylcholine

Cannabinoids

Substance P/

NK-1 RAs

DA = dopamine; GABA = gamma-aminobutyric acid; NK = neurokinin; RAs = receptor antagonists.

ANTIEMETIC GUIDELINE CONSENSUS- Official Process Subscribed to by manyInternational Oncology Groups -

www.mascc.orgUpdated 2014 corrections to come

AND

Ann Oncol 2010; Supplt 5: v232-v243

AND

JSCC 2011

Aprepitant Drug Interactions

Should not be usedconcomitantly withPimozideTerfenadineAstemizoleCisapride

Caution withDocetaxelVinblastineVincristineIfosfamideother chemotherapy agents

metabolized primarily byCYP3A4 that were notstudied: oral vinorelbine;studied: oral vinorelbine;trabectedin

Based on and modifyingAprepitant package insert 2008

Oral dexamethasone dose should be decreased by50% when administered with aprepitant

Prothrombin time and INR may be decreased whenwarfarin is administered concomitantly with aprepitant

Not far from grapefruit juice or clarithromycinReview by Aapro and Walko, Annals of Oncology,2010

Potential Side Effects of Dexamethasone

M. Aapro,A. Fabi,F. Nolè,M. Medici,G. Steger,C. Bachmann,S. Roncoroni,and F. Roila

Double-blind, randomised, controlled study of theefficacy and tolerability of palonosetron plusefficacy and tolerability of palonosetron plusdexamethasone for 1 day with or withoutdexamethasone on days 2 and 3 in the preventionof nausea and vomiting induced by moderatelyemetogenic chemotherapy

Ann Oncol (2010) 21(5): 1083-1088

See also Celio et al, J Supp Care, 2010

MASCC/ESMO Antiemetic GuidelineMASCC/ESMO Antiemetic GuidelineSummary of Acute and Delayed PreventionSummary of Acute and Delayed Prevention

Emeticrisk group

Risk(% pts)

Acute prevention Delayed prevention

High >90%5-HT3 RA

+ DEX + (fos)aprepitantDEX + aprepitant

AC combinations -5-HT3 RA *

+ DEX + (fos)aprepitantaprepitant

* If a NK-1 RA is not available then palonosetron is the preferred5-HT3 RA also in AC regimens

www.mascc.org

Moderate 30-90% Palonosetron + DEX DEX

Low 10-30% single agent (DEX, 5-HT3 DRA) No routine prophylaxis

Minimal <10% No routine prophylaxis No routine prophylaxis

Recommended 5-HT3 RAs: Palo, Grani, Onda, Dola oral, TropiDEX, dexamethasone; AC, anthracycline-cyclophosphamide DRA: dopamine receptor antagonistAprepitant in delayed phase depends on (fos)apretitant use in acute phase

Emetic

risk group

Risk

(% pts)Acute prevention* Delayed prevention

High and ACcombinations

>90%

5-HT3 RAs (D.O.G.P)

palonosetron preferred

+ DEX + aprepitant

lorazepam H2 blocker orproton pump inhibitor

DEX + aprepitant**

lorazepam H2 blocker orproton pump inhibitor

5-HT3 RAs (D.O.G.P) 5-HT3 RA or DEX

Guideline RecommendationsGuideline RecommendationsNCCN Antiemesis Guidelines v.1. 2014NCCN Antiemesis Guidelines v.1. 2014

Moderate 30-90%

5-HT3 RAs (D.O.G.P)palonosetron preferred+ DEX +/- aprepitant

lorazepam H2 blocker orproton pump inhibitor

5-HT3 RA or DEX

Or aprepitant+/-dex

lorazepam H2 blocker orproton pump inhibitor

Low 10-30%

DEX, prochlorperazine, ormetoclopramide or

5-HT3 RAs (D.O.G )

lorazepam H2 blocker orproton pump inhibitor

No preventive measures

Minimal <10% No routine prophylaxis No preventive measures

Recommended 5-HT3 RAs: Palo, Grani, Onda, DolaDEX, dexamethasone; AC, anthracycline-cyclophosphamide** not if fosaprepitant 150 mg iv on day 1

* Olanzapine palo dex also considered for HEC and MEC

A LOOK INTO THE NOT TOO DISTANT FUTURE

ROLAPITANT: oral and iv forms under development

NETUPITANT

Various formulations of existing agents

Efficacy and safety of NEPA, a fixed-dose combination of netupitantand palonosetron, in preventing chemotherapy-induced nausea and

vomiting (CINV) in patients receiving moderately emetogenicchemotherapy (MEC)

M. Aapro1, G. Rossi2,G. Rizzi2, M. E. Borroni2, V. Lorusso3, M. Karthaus4,S. Grunberg5

Study Design:•Phase 3, multinational, randomized, double-blind study in chemotherapy-naïve patientsundergoing AC chemotherapyundergoing AC chemotherapy

•Patients randomized to receive one of the following prior to chemotherapy on Day 1 :

Oral NEPA + Oral DEX 12 mg

(NEPA = NETU 300 mg + PALO 0.50 mg)

Oral PALO 0.50 mg + Oral DEX 20 mg

N = 1455

Randomized1:1

Presented in part at MASCC, ASCO and ECCO 2013

• NEPA was superior to PALO for complete response in the delayed 25-120h (77% vs70%, respectively), acute 0-24h (88% vs 85%, respectively) and for the secondaryendpoints in the overall phase:

Results: Complete Response in the Delayed (Primary Endpoint),Acute and Overall (Key Secondary Endpoints)

Overall (0-120h) % PatientsNEPA

(N=724)PALO

(N=725)

Complete ResponseComplete Protection

74.3*63.8*

66.657.9Complete Protection

No EmesisNo Significant Nausea

63.8*79.8*74.6*

57.972.169.1

• NEPA showed superior complete response rates compared with PALO during theacute, delayed, and overall phases following MEC

• NEPA was superior to PALO for secondary endpoints• NEPA was well tolerated with a similar safety profile to PALO

Conclusions:

* p-value <0.05

CASE BIRGIT

Birgit is a 46 years old patient diagnosed with endocrine-responsive (ER 50% PgR 30) G3 Ki 67 30% HEr-2 neg (FISH)breast cancer T2 N0 MO.Adjuvant therapy with doxorubicin / cyclophosphamide followedby a taxane is planned. What do you USE as an acute-phaseantiemetic ?

1.Aprepitant + setron + corticosteroid

2.Palonosetron + corticosteroid

3.Setron + corticosteroid

4.Metoclopramide ( or similar ) + corticosteroid

5.Other choice

CASE CHIARA

Chiara is a 71 years old patient who exercises daily ANDsmokes a pack/day. She has endocrine-responsive ( ER 50%PgR 30%) G2 Ki 67 15% HEr-2 neg (FISH) breast cancer T1N0 MO. Adjuvant therapy with an aromatase inhibitor is plannedand her BMD score is T-1.8. What would you suggest (assumethere is no restriction)

1.Calcium + vitD + bisphosphonate / denosumab

2.Calcium + vitD

3.Calcium + vitD + zoledronic acid every 6 months

4.Use tamoxifen

5.Tamoxifen +Calcium + vitD + oral bisphosphonate

BONE

Osteopenia/osteoporosis is prevalent among many male andfemale cancer patients

Bisphosphonates (BPs) and denosumab are established agentsfor supportive care in case of bone metastases

BPs might be more than supportive care?BPs might be more than supportive care?( on going studies with denosumab )

UPDATE PLANNED FOR 2010

7

16

2

ABCSG-12 (62 mo)

free

su

rviv

al,

%

ZOL vs no ZOL

Fir

st

even

tp

er

pati

en

t,n

Death without prior recurrence

Secondary malignancy

Contralateral breast cancer

Distant recurrence

Locoregional recurrence

ZOL

NO-ZOL

100

90

80

70

60

120

100

80

56

29

Time since randomization, months

Dis

ease-f

ree

su

rviv

al,

%

(n = 903)

No ZOL

(n = 900)

ZOL

Fir

st

even

tp

er

pati

en

t,n

NO-ZOL

HR = 0.68P = 0.008

Median follow-up = 62 mo

Gnant M, et al. J Clin Oncol 28:15s, 2010 (suppl; abstr 533).

60

50

40

30

20

10

0

12 24 36 48 60 72 84 96 1080

60

40

20

0

44

6

110

15

No-ZOL (110 events) vs. ZOL (76 events)Absolute Difference = 34

Myeloma IX (MRC) –ZOL Improved OS and PFS vs CLOa

ZOL significantly reduced the relative risk of death by 16% vs CLO(HR = 0.842; 95% CI = 0.736, 0.963; P = .0118)Median survival improved by 5.5 months (50 vs 44.5 months)

Riskreduction P value

0.842OS

Abbreviations: CLO, clodronate; OS, overall survival; PFS, progression-free survival; ZOL,zoledronic acid.a Cox model adjusted for chemotherapy, and minimization factors.

Hazard ratio (ZOL versus CLO)

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2

.01180.842

16%

In favor of ZOL In favor of CLO

OS

.017912%0.883

PFS

Morgan GJ, et al. J Clin Oncol 28:15s, 2010 (suppl; abstr 8021).

Denosumab in Early Adjuvant BC: ABCSG-18 & D-CARE Trials

ABCSG-18:

• Primary Endpoint: Rate of 1st clinical fracture

• Secondary Endpoints: Bone metastasis-free survival (BMFS), DFS, OS

Placebo SC q6 mo3,460 EBCpts R

Studyduration:

96 monthsDmab 60 mg SC q6 mopts R96 months

D-CARE:

• Primary Endpoint: Bone metastasis-free survival

Placebo 120mg SC monthly x 6 mo, q 3 mo for 4.5 yrs

Dmab 120mg SC monthly x 6 mo, q 3 mo for 4.5 yrs

4,500 EBCpts R

Treatment duration 5 yrs

http://www.abcsg.org/trials/trial18.html, http://clinicaltrials.gov/ct2/show/NCT01077154?term=d-care&rank=1

T-score < –2.0Any 2 of the following risk factors:

• T-score < –1.5

• Age > 65 years

• Low BMI (< 20 kg/m2)

• Family history of hip fracture

• Personal history of fragility fracture after age 50

• Oral corticosteroid use of > 6 months

T-score ≥ –2.0,No risk factors

Recommendations for Women With Breast Cancer Initiating AITherapyRecommendations for Women With Breast Cancer Initiating AITherapy

• Smoking (current and history of)

Monitor risk statusand BMD at

1 year

Bisphosphonate*

calcium and vitamin Dsupplements

EXERCISE

Monitor BMD…every 1-2 years if

oral BPs

Calcium and vitamin Dsupplements

EXERCISE

*≥ 10% drop in BMD (4-5% if osteorotic )

should trigger treatment. Use lowest T-score from 3 sites.

Adapted from Hadji P, et al. in press Annals of Oncology 2011

• *DENOSUMAB is a potential option for somepatients. Oral health precautions needed for BPsand denosumab

San Antonio Breast Cancer Symposium – December 10-14, 2013Cancer Therapy and Research Center at UT Health Science Center

Effects Of Bisphosphonate Treatment OnRecurrence And Cause-specific Mortality

In Women With Early Breast Cancer:A Meta-analysis Of Individual Patient Data

From Randomised Trials

This presentation is the intellectual property of the EBCTCG. Contact r.e.coleman@sheffield.ac.uk for permission to reprint and/or distribute.

R Coleman, M Gnant, A Paterson, T Powles, G von Minckwitz,

K Pritchard, J Bergh, J Bliss, J Gralow, S Anderson, D Cameron,

V Evans, H Pan, R Bradley, C Davies, R Gray.

Early Breast Cancer Trialists’ Collaborative Group(EBCTCG)’s Bisphosphonate Working Group.

San Antonio Breast Cancer Symposium – December 10-14, 2013Cancer Therapy and Research Center at UT Health Science Center

Mortality In Post-menopausal Women

Breast cancer mortality All cause mortality

1146 events 1524 events

This presentation is the intellectual property of the EBCTCG. Contact r.e.coleman@sheffield.ac.uk for permission to reprint and/or distribute.

CASE CHIARA

Chiara is a 71 years old patient who exercises daily AND smokes apack/day. She has endocrine-responsive ( ER 50% PgR 30%) G2 Ki 6715% HEr-2 neg (FISH) breast cancer T1 N0 MO. Adjuvant therapy withan aromatase inhibitor is planned and her BMD score is T-1.8. Whatwould you suggest (assume there is no restriction), besides exercise

1. Calcium + vitD + bisphosphonate / denosumab1. Calcium + vitD + bisphosphonate / denosumab

2. Calcium + vitD

3. Calcium + vitD + zoledronic acid every 6 months

4. Use tamoxifen

5. Tamoxifen +Calcium + vitD + oral bisphosphonate

FOR MORE INFORMATIONwww.mascc.orgwww.mascc.org

www.qualityoflife.elsevierresource.com

www.afsos.org