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Dubai, April 2018ESMO Summit Middle EAST

Supportive Care

M. Dicato, M.D., FRCP(Edin).

Hematology- Oncology

Luxembourg Medical Center

L- 1210 Luxembourg

Supportive CareSupportive Care in Cancer is the prevention and management of the adverse effects of cancer and its treatment. This includes management of physical and psychological symptoms and side effects across the continuum of the cancer experience from diagnosis through anticancer treatment to post-treatment care. Enhancing rehabilitation, secondary cancer prevention, survivorship and end of life care are integral to Supportive Care.

MASCC homepage 2015

Supportive Care:- alleviates symptoms and complications of cancer- reduces or prevents toxicities of treatment- supports communication with patients about their disease and prognosis- allows patients to tolerate and benefit from active therapy more easily- eases emotional burden of patients and care givers- helps cancer survivors with psychological and social problems

MASCC homepage 2015

SUPPORTIVE AND PALLIATIVE CARE

Historical reasons have led to the development of specialist groups with expertise towards issues

• frequent at the end of life (often called palliative care)

• around treatment management, and post-treatment issues (supportive care)

Courtesy: M. Aapro 2015

PREDICTING SURVIVAL[ECC 2013, Abs 1745].

Predictive Factors Points

Metastatic Sites ≥ 3 1

PS 1 1

LDH 250 - 600 U/l 1

Hb < 6,2 mmol/l 1

Albuminemia < 35 g/l 2

LDH > 600 U/l 2

PS ≥ 2 3

Rotteveel K, et al. Abstract 1745 ESMO 2013.

FOUR GROUPS MEDIAN SURVIVAL (MS) AND MORTALITY (M)

AT 90 DAYS (D90)

• - Score ≥ 4: MS 2.6 ms D90 M 79%

• - Score = 3: MS 5.0 ms D90 M 43%

• - Score = 2: MS 7.1 ms D90 M 31%

• - Score = 1: MS 9.5 ms D90 M 28%

• - Score = 0: MS 15 ms D90 M 17%

Rotteveel K, et al. Abstract 1745 ESMO 2013.

LES RÉFÉRENTIELS EN SOINS DE SUPPORT AFSOS

Arrêt des traitements spécifiques

Abords et dispositifs veineux

Activité physique adaptée

Anémie

Antinauséeux/antiémétiques

Biphosphonates hypercalcémie

Confusion

Dépression

Douleur

Dyspnée

Epilepsie

Escarres

Fatigue

Fièvre

HTIC-céphalées-déficit neurologique

Reinsertion sociale et PEC de la précarité

Onco sexo: Gestion des complications

induites par CT

Réeducation fonctionnelle et cognitive en

neuro-oncologie

Lymphœdèmes

Mucites et candidoses

Nutrition

Prise en charge sociale

Sexualité et fertilité

Soins bucco-dentaires

Thrombose et cancer

Toxicités des thérapies ciblées

Urgences en cancérologie

Place des PNCAVT

Prise en charge dans les 1eres 20h d’un

patient pour syndrome confusionnel

Troubles de la fonction rénale et CT

Anxiété en cancérologie

Reconstruction mammaire

Toxicités des CT: Docetaxel

Neuropathies périphériques

80 référentiels existants à ce jour:

Survie Globale

Early Palliative Care

▪ Standard Care▪ Early Palliative Care

Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:733-742.

Overall survival results of a randomized trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment (NCT00578006)

Presented By Ethan Basch at 2017 ASCO Annual Meeting LBA2

Study Design

Presented By Ethan Basch at 2017 ASCO Annual Meeting

Patient Self-Reporting Interface


Results


Potential Mechanisms of Action


Febrile Neutropenia

Pegfilgrastim clearance is self-regulating, in contrast to that of filgrastim

Daily G-CSF: Filgrastim

Filgrastim is a recombinantgrowth factorthat regulatesthe number of

circulatingneutrophils

Neutrophil

Recepto

rFilgrastim

Filgrastim is cleared by both glomerular filtration and by neutrophils

Pegfilgrastim

Receptor

Neutrophil

Pegfilgrastim

Pegfilgrastim appears to have mainly neutrophil-mediated clearance

Pegfilgrastim is formed by

the addition of a

polyethylene glycol (PEG) group to the

N-terminus of filgrastim

Komrokji RS, et al. Expert Opin Biol Ther 2004;4:1897-910.

Theoretical Pegfilgrastim and Lipegfilgrastim Receptor Binding

Possibility of

steric interference

with the receptor

Low possibility of

steric interference

with the receptor

*Developed on the basis of crystallographic modelling of G-CSF/G-CSF-receptor binding.44

41. Pasut G, Veronese FM. J Control Release. 2012;161(2):461-472; 43. DeFrees S, et al. Glycobiology. 2006;16(9):833-843;

44. Tamada T, et al. Proc Natl Acad Sci U S A. 2006;103(9):3135-3140; 45. Zündorf I, Dingermann T. Pharmazie. 2014;69(5):323-

326.

Short-Acting vs Long-Acting G-CSF: Effect on Absolute Neutrophil Count (ANC)

• Study design: Randomised, multicentre study of patients with high-risk stage II-IV breast cancer (n = 310)

undergoing myelosuppressive chemotherapy with doxorubicin 60 mg/m²and docetaxel 75 mg/m²

• Filgrastim administered daily starting at day 2, continuing until a documented ANC ≥10 109/L after the

expected nadir or for up to 14 d, whichever occurred first

Holmes FA et al. J Clin Oncol. 2002;20:727-731.

ANC Profile of the Median ANC for All 4 Cycles

Lipegfilgrastim: Phase III Study in Breast Cancer (XM22-03): ANC During First Chemotherapy Cycle

Secondary Endpoint: Lipegfilgrastim vs Pegfilgrastim – Median Absolute Neutrophil Count (ANC) by Day in Chemotherapy Cycle 1 (per-protocol population)

ANC, absolute neutrophil count.

1.5-day difference in least

squares mean (p = 0.0026)

Adapted from Bondarenko et al 2013 (figure 3, page 9/12) to depict timepoint of

G-CSF administration on day 2 following chemotherapy treatment in cycle 1.

Day within chemotherapy cycle

55. Bondarenko I, et al. BMC Cancer. 2013;13:386.

Median Number of Daily G-CSF Injections:

Potential Impact on Outcomes

G-CSF Usage Daily G-CSF (n = 111) Pegfilgrastim (n = 75)

Primary prophylaxis, % 39.6 38.7

Median injections/cycle, n

(minimum, maximum)6 (1, 13) 1 (1, 3)

• Study design: LEARN was a multicentre, retrospective observational study in

Spain comparing patterns of use of daily G-CSF and pegfilgrastim and

CIN-related outcomes1,a

• Clinical studies suggest an average of 11 injections per chemotherapy cycle are required to achieve recovery of the ANC to within the normal range2

• Onset and duration of nadir are important to establish starting day and duration of G-CSF administration after chemotherapy3

• Long-acting G-CSF may provide benefits over filgrastim if current guidelines for daily administration cannot be realised4

a In adults with nonmyeloid malignancies receiving myelosuppressive chemotherapy.

CIN: chemotherapy-induced neutropenia.

1. Almenar D et al. Eur J Cancer Care (Engl). 2009;18:280-286. 2. Cooper KL et al (published online). BMC Cancer. 2011;11:404.

doi: 10.1186/1471-2407-11-404 3. Ria R et al. Hematology. 2013;18(3):131-7. 4. Aapro M et al. Eur J Cancer. 2011;47:8-32.

Anemia

Anaemia occurs most frequently in patients

receiving chemotherapy

Anaemia prevalence in patients receiving different cancer treatments

Ludwig H, 2004

Anaemia was defined as Hb<12g/dL

CT= Chemotherapy, RT= Radiotherapy

Anemia and Iron Deficiency

• Absolute Fe deficiency: Ferritin <100ng/ml

• Functional Fe deficiency: Ferritin >100 ng/ml + Tsat <20%

IL-6hepcidin Fe unavailability

Pathophysiology of Anemia of Cancer and of Chronic Disease*

a.

b.

*Modified from Nouwrousian1996 . M. DICATO, Curr. Opinion Oncol. 2010

GATA 1 & 2

F. Morceau, M. Dicato, M. Diederich: Mediators of inflammation, 2009

TNFa

TNFa inhibits induction of erythroid differentiation

inhibits expression of erythroid specific genes:

y-globin and EpoR

effects induced transcription factor GATA-1

Blocks binding of GATA-1 to its DNA sequence

Conclusion: TNFa acts at several levels of the regulation of

erythroid genes, in particular GATA- 1.

Inhibition of GATA-1 correlates to increased NF-kB activity

M.Dicato, et al.: Ann. Oncol. 2010

Tumour cells

Inhibition of EPO production and iron metabolism

causes anaemia of chronic disease (ACD)

1. Adamson JW, 2008; 2. Birgegard G, 2005; 3.Grotto HZW, 2008; 4 Weiss G, 2005; 5. Nowrousian MR, 2008; 6. Hedenus M, 2009

Inhibit

production

of EPO

Hypoproliferative

anaemia

Activated immune

system

Over-production of

cytokines

TNF-α, Interferon-γ, IL-1 Decreased Fe

absorption

Hepcidin

Inhibit

erythropoiesis

IL-6

Six published studies show higher haematologic

response with I.V. iron supplementation of ESAs

• Improved haematopoietic response although most patients were iron replete

at enrolment ESAs need mobilisable iron

1. Auerbach, JCO 2004;22:1301; 2. Hedenus; Leukemia 2007;21:627; 3. Henry, Oncologist 2007;12:231; 4. Bastit, JCO

2008;26:1611; 5. Pedrazzoli, JCO 2008;26:1619; 6. Auerbach, Am J Hematol 2010;85:655; 7. Steensma, JCO 2011;29:97.

ESA + I.V. iron

0

10

20

30

40

50

60

70

80

90

100

Resp

on

se r

ate

(%

)

73

86

Bastit

20084

25

68

Auerbach

20041

62

77

Pedrazzoli

20085

63

82

Auerbach

20106

6570

Steensma

20117

*

36

53

Henry

20073

*53

87

Hedenus

20072

* **

*

ESA alone* p<0.05

Tumour cells

Inhibition of EPO production and iron metabolism

causes anaemia of chronic disease (ACD)

1. Adamson JW, 2008; 2. Birgegard G, 2005; 3.Grotto HZW, 2008; 4 Weiss G, 2005; 5. Nowrousian MR, 2008; 6. Hedenus M, 2009

Inhibit

production

of EPO

Hypoproliferative

anaemia

Activated immune

system

Over-production of

cytokines

TNF-α, Interferon-γ, IL-1 Decreased Fe

absorption

Hepcidin

Inhibit

erythropoiesis

IL-6

ESMO Clinical Practice Guidelines: Anemia 2018

International Consensus Definition of “Cancer Cachexia”“Multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without fat mass) that

cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment.”

Fearon K, et al. Lancet Oncol. 2011 May;12(5):489-95.

Nutrition- Cachexia- Sarcopenia

SARM: selective androgen receptor modulators:- Enobosarm

Anagrelin:- Anamorelin

Cannabis:- Dronabinol

Dobs et al. Lancet Oncol.

Dobs et al. Lancet Oncol. 2016

Dobs et al. Lancet Oncol 2016

Trial Design• ROMANA 1 (NCT01387269) is

one of two international,

double-blind, Phase 3 trials

• Patients with unresectable

stage III or IV NSCLC and

cachexia (≥5% weight loss

within prior 6 months or BMI

<20 kg/m2)

• Randomized (2:1) to receive

either 100 mg ANAM or

placebo, administered daily

orally for 12 weeks

• Assess ANAM efficacy and

safetyANAM, anamorelin HCl; BMI, body mass index; NSCLC, non-small cell lung cancer; QD, once a day.

Bonomi, et al. 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology

EMA website. Last update 30.11.2017

Cannabis

• Dronabinol: 1985: FDA approval for anorexia in HIV and for N/V in cancer patients

As RP for anorexia in Cancer Patients:

- Older studies, non conclusive.

- 2006 Strasser study: n= 243 pts; no significance vs placebo

Clinical Practice Guidelines on

Cancer CachexiaConsensus

Recommendations

Enteral nutritional therapy Yes

Parenteral nutritional

therapy

No

Supplements Insufficient data

Non-pharmacologic therapy Yes

Nutritional counseling Yes

Psychotherapeutic

interventions

Yes (QOL)

Physical training Yes

European Palliative Care Research Collaborative. Clinical Practice Guidelines on Cancer Cachexia in Advanced Cancer Patients with

a Focus on Refractory Cachexia – European Clinical Guidelines. Available at:

www.epcrc.org/publication_listfiles.php?id=mWdBCMI5eXVlcNFk7Gnq. 2011

Pharmacologic TherapyConsensus

Recommendations

Thalidomide Insufficient data

Cannabinoids May increase appetite

Omega-3-fatty acids Insufficient data

Megestrol/progestins Stimulate appetite +

increase weight, but not

muscle

Steroids Yes (short term)

Anti-inflammatory agents Little benefit

Prokinetics Yes, for GI symptoms

Clinical Practice Guidelines on

Cancer Cachexia

European Palliative Care Research Collaborative. Clinical Practice Guidelines on Cancer Cachexia in Advanced

Cancer Patients with a Focus on Refractory Cachexia – European Clinical Guidelines. Available at:

www.epcrc.org/publication_listfiles.php?id=mWdBCMI5eXVlcNFk7Gnq. 2011

Emesis

ASCO 2014: 50 years

• MOPP

• BEP

• Ondansetron

• Imatinib

• HPV

Gralla RJ et al. N Engl J Med 1981;305.905-909.

26-30 September 2014, Madrid, Spain esmo.org

Under-reporting

34

1724

15

35

13

52

28

0

20

40

60

80

100

Acute

Nausea

Acute

Vomiting

Delayed

Nausea

Delayed

Vomiting

Perc

en

t o

f P

ati

en

ts

MD/RN prediction

Patient experience

Physicians and nurses from 14 oncology practices in 6 countries

Patients: 75% women; 78% Mod emetic chemo; 50% breast cancer; 18% lung cancer

Perceptions and Reality- Underestimation of emesis with chemotherapy -

Grunberg et al. (2004). Cancer, 100, 261-268

Prevalence of guideline-consistent CINV prophylaxis (GCCP) for cycle 1 single-day

chemotherapy, by emetogenicity of chemotherapy and for the total study population.

Aapro M., Molassiotis A., Dicato M. et al.: Ann Oncol 2012;23:1986-1992

© The Author 2012. Published by Oxford University Press on behalf of the European Society for

Medical Oncology. All rights reserved. For permissions, please email:

[email protected]


Anorexia Nausea Vomiting Constipation Diarrhea Hair loss

Toxicity reported by:

Patient: NO

Physician: NO51.4% 44.5% 76.7% 59.3% 73.1% 55.6%

Patient: NO

Physician: YES2.4% 10.1% 6.4% 3.2% 4.2% 1.7%

Patient: YES

Physician: NO37.0% 24.6% 9.7% 29.7% 13.9% 28.8%

Patient: YES

Physician: YES9.2% 20.8% 7.2% 7.8% 8.9% 13.9%

Cohen's ĸ* 0.162 0.280 0.377 0.183 0.396 0.323

Association between patient reporting (any severity)

and physician reporting (any grade) – 2482 cycles

* ĸ>0.75: excellent agreement; ĸ=0.40-0.75: fair to good agreement; ĸ<0.40: poor agreement.(Fleiss JL . New York: John Wiley 1981)


Anorexia Nausea Vomiting Constipation Diarrhea Hair loss

Toxicity reported by:

Patient: NO

Physician: NO51.4% 44.5% 76.7% 59.3% 73.1% 55.6%

Patient: NO

Physician: YES2.4% 10.1% 6.4% 3.2% 4.2% 1.7%

Patient: YES

Physician: NO37.0% 24.6% 9.7% 29.7% 13.9% 28.8%

Patient: YES

Physician: YES9.2% 20.8% 7.2% 7.8% 8.9% 13.9%

Under-reporting by

physicians80.2% 54.2% 57.5% 79.2% 61.0% 67.4%

Association between patient reporting (any severity)

and physician reporting (any grade) – 2482 cycles

Points of Relevance

• Separate i-v vs p.o. agents• Underestimation of acute and delayed N/V• Combination of drugs. Usually the most

emetogenic agent. Separate category AC.• Palonosetron: prolonged half life: delayed emesis• Olanzapine• NK1-RA: Netupitant. NEPA > Palo-dex in HEC and

AC, over multiple cycles• Rolapitant: half-life 180h, CYP3A4; (+ CYP2D6: P-

glycoprotein PG-170)• Genetics of N/V: CYP, MDR- PGP, SNPs ethnicity…

Take Home

• HEC: 3 drug combo: NK-RA, 5HT3-RA, Dexa, if no NK1-RA available, Palo preferred

• MEC: 5HT3-RA (Palo preferred) + Dexa

• Low: single: dexa or 5HT3-RA

• Refractory: different group, check dose, olanzapine in HEC

• Anticipatory: Balint, anxiolytics, cannabis…?

R. Navari: Oncology Journal March 15, 2018

Case Study

• 31 year old female patient presents withabdominal discomfort and back pain.

• CT-Scan: abdominal-retroperitoneal mass, 15 cm diameter, vascular structures in vicinity, level of ombilicus.

• Tumor board:

- Preoperative Radiotherapy: 50 Gy

N/V prevention?

• 1. No antiemetic

• 2. 5HT3-RA before each RT +5d dexamethasone

• 3. 5HT3-RA before, 5 d dex optional

• 4. 5HT3-RA optional, if necessary

• 2. 5HT3-RA + dex

• Tolerance excellent. Tumor mass regressed to 6cm on control CT. Surgery is performed. Clips left in place at resection borders.

• Histology: leiomyosarcoma, grade 3, no nodal involvement, some microscopic necrosis, no vascular invasion, no R0, involved margins.

• Tumor Board:

1. Additional Radiotherapy, e.g. 20-24 Gy

2. Chemotherapy: CYVADIC, Adria- Ifosfamide

3. Pazopanib, Regorafenib

Chemotherapy: CYVADIC

• 1. 5HT3-RA + dex

• 2. 5HT3-RA, NK1 +dex

• 3. 5HT3-RA

Chemotherapy: Adria- Ifos

• 1. 5HT3-RA + dex

• 2. 5HT3-RA, NK1 +dex

• 3. 5HT3-RA

Radiotherapy

• 1. 5HT3-RA + dex

• 2. 5HT3-RA

• 3. Metoclopramide + dex

• 4. Antiemetic if necessary

• 5. 1 + 3 are correct

Targeted Treatment

• 1. 5HT3-RA, NK1 + dex

• 2. 5HT3-RA +dex

• 3. 5HT3-RA

• 4. Dex

• 5. None

• 6. 1-4 are correct

Immuno-oncology

Pictures: courtesy of Dr. Mario Lacouture, MSKCC NY. NY.

ESMO guidelines

Weber et al. ASCO 2015

Nivolumab(n=474)

Minkis et al, JAAD 2013; Photo courtesy of Prof A Hauschild; Robert et al, NEJM 2015; Hamid et al, NEJM 2013; Margolin et al, Lancet Oncol 2012; Rosenberg et al, Lancet 2016

Maculopapular rash

• Incidence

• Ipilimumab:19%

• Nivolumab: 34%

• Ipi+nivo: 40%

• Pembrolizumab: 39%

• Atezolizumab: 10%

• Treatment

• Grade 1/2

• Oral Antihistamines

• Top Steroids

• Grade 3

• PO steroids

• Incidence: 2.4% (n=82)

• Tense bullae

• Pruritus

• Anti-BP180/230 Abs

• Oral involvement

Naidoo et al, Cancer Immunol Res 2016: Curry et al, J Cut Pathol 2016; Hwang et al, JAAD 2015

• Treatment

• Steroids

• MMF

• Azathioprine

Dermatomyositis (n=3) Psoriasis (n=21)

Lacouture , unpublished; Bonigen et al, 2016; Sibaud et al ,2016

Keratoacanthomas (n=4)

Lacouture , unpublished; Bonigen et al, 2016; Sibaud et al ,2016

Rosacea (n=3)

H&E

CD4

CD8

• Incidence

• Ipilimumab: 4%

• Nivolumab: 17%

• Ipi+Nivo: 33%

• Pembrolizumab: 21%

• Atezolizumab: 7%

Ensslin et al, JAAD 2014; Sanlorenzo et al, 2014Valentine et al, JAAD 2015; Santoni et al, 2015; Rosenberg et al, 2016

Excoriations

Santini et al, Lancet Oncol 2012

• First line therapy for pruritus:

• PO antiH1/steroids

• Topical steroids/anti pruritics (menthol, pramoxine)

• 93% of patients responded to aprepitant (>50% reduction in pruritus)

• Median duration of one cycle effect 30 days (range 7-90 days), >50% did not recur

Patient-reported Pruritus

Robert et al, NEJM 2015; Hamid et al, NEJM 2013; Margolin et al, Lancet Oncol 2012; Hua et al, JAMA Derm 2015

Pembrolizumabn=67

Vitiligo

Risk Factors for VTE

• Previous venous thromboembolism

• Increased age

• Surgery

• Trauma - major, local leg

• Immobilization - bedrest, stroke, paralysis

• Malignancy and its treatment (CTX, hormonal..)

• Heart or respiratory failure

• Estrogen use, pregnancy, postpartum, SERMs

• Central venous lines

• Thrombophilic abnormalities

Relative Risk of VTE in Cancer Patients

Stein, Am J Med, 2006

« Markers » of Duration of VTE treatment

• D-dimer

• Tissue Factor

• Residual Venous thrombosis on compression US

Ambulatory Prophylaxis of VTE in Cancer Patients

U. Pelzer et al :CONKO- 004 Trial , JCO 2015

• Open label unblinded randomized study

• No baseline screening at study entrance

• No stratification for chemo agent (cDDP -> VTE..)

• Pancreatic Ca: 43% of patients no other risk factor versus others with risk factors:

- VTE: 2.6% if no other risk factor vs 6.3% if one or 10.5% >1 risk factor.

Novel Anticoagulants

Limitations of vitamin K antagonists (VKAs)

• Unpredictable pharmacology

• Narrow therapeutic window• Difficult to keep within

therapeutic range

• Multiple drug–drug and food–drug interactions

• Dosing problems in the initial phase of therapy

• Increased risk of major and minor bleeding

Warfarin thrombosis

Warfarin bleeding

DoseT

hro

mb

osis

Ble

ed

ingNarrow

therapeutic

window

Ansell et al., Chest 2004; Hirsh et al., Chest 2004

Percentage of Patients in therapeutic range (INR 2-3) with Coumarins

•Warfarin ~ 45% at 4 weeks ( S.Kimmel NEJM 2013)

•Acenocoumarol & Phenprocoumon ~60% at 10 weeks (T Verhoef NEJM 2013)

Limitations of prolonged LMWH

• Daily injections

• Platelet monitoring

• HIT

• Cost: 8- 16 €

• Nurse (?)

• Bruising- hematomas

• Difficult to use over prolonged periods

• Recurrent VTE: 5% to 7% at 3 or 6 months

• Bleeding risk 5% to 7% not lower than VKA

New Anticoagulants

• FXI-ASO: FXI antisense oligonucleotide

• Semuloparin

• Oral: Dabigatran

Rivaroxaban

Apixaban

Edoxaban

FXI-ASO (ISIS Pharmaceuticals) 2e generation diminishes synthesis of FXI

N=300 pts. Knee replacement, Venography

FXI-ASO (200 vs 300mg) vs enoxaparine 40mg/j:

• Result similar for 200mg vs enoxaparine.

• For 300mg vs enoxaparine:

- VTE 3/71pts (4%) vs 21/69 (30%), p<0.001.

- Bleeding 3% vs 8%

➢ Antithrombotic with low risk of bleeding

Semuloparin in ambulatory cancer patients

Presented By Stephan Moll at 2016 ASCO Annual Meeting

Novel oral anticoagulants

- Comparator non-inferiority studies on NOAC have been done with short initiation LMWH followed by AVK. No direct comparison with LMWH

- Treated cancer patients are small subgroups of patients within the general medical population treated.

- Specific Ca patient studies on-going NOAC vs LMWH

Presented By Stephan Moll at 2016 ASCO Annual Meeting

Abstract 625: Prospective randomised open label trial comparingDalteparin (D) to Rivaroxaban ®N= 406 patients

• Recurrent VTE: 11% vs 4%• Major bleeds: 6/6 vs 9/8 patients• Clinically relevant non major bleeds: 5/5 vs 28/27 patients

ASH 2017: Select-d trial: Rivaroxaban vs Dalteparin in

• N= 406 patients

• At 6 months: recurrence R vs D 4% vs 11%

major bleeding: R vs D 9 vs 6

clinically relevant non major bleeding: 28 vs 5

major + clin relev. R vs D: 37 vs 11 bleeds ( 35 vs 11 patients)

• Open label, non inferiority study comparing Edoxaban (E) to Dalteparin (D). N= 1046 pts.

• Primary event: E vs D: 62/522 (12,8%) vs 71/524(13,5%).

p= 0.006 for non-inferiority, 0.87 for superiority

• Recurrent VTE: E vs D: 41(7.9%) vs 59(11.3%)

• Major bleeding 36(6.9%) vs 21(4%)

Hemostasis: Case Study

• 62 y old Caucasian male with non-valvular atrial fibrillation is on rivaroxaban since 2010 and doing fine.

• 2012: Colorectal cancer with liver metastases is diagnosed. The patient is given chemotherapy (FOLFOX) and after 4 cycles is on partial remission but not resectable.

• Before his 5th cycle (to be switched to FOLFIRI), a diagnosis of left leg DVT is made.

• What to do?

Slide 1

1. Increase dosage of rivaroxaban?

2. Switch to AVK

3. Switch to LMWH followed by AVK?

4. Only LMWH?

Slide 2

• The patient was treated with LMWH only

• He continued his chemotherapy and while on LMWH for 2 months, he had again a DVT.

• What next?

Slide 3

1. Increase dose of LMWH?

2. LMWH 2x/day?

3. Inferior Vena Cava filter?

4. 1 & 3

Slide 4

• The patient had a retrievable IVC filter and LMWH once daily.

• 10 weeks after insertion of filter, the patient is doing fine with LMWH, on chemotherapy.

• Cancer regressed and the patient has become operable. After surgery the patient is still on LMWH.

• Complete remission from CRC.

• LMWH is given now for 6 months postoperatively. To be given for how long?

Slide 5

1. Indefinitely ?

2. If patient remains in complete remission, to be stopped after x more months and switched to rivaroxaban?

• It was decided, following also the patient’s request, to stop LMWH after 3 more months and go back to rivaroxaban. The IVC filter was retrieved. The patient is fine.

• The patient, always in complete remission, now February 2016, wants to visit his nephew in Canada.

• His wife had a DVT after hip replacement 2 years ago. Does she need anticoagulation for the journey?

Slide 7

« Economy Class Syndrome »

1. Does not exist?

2. It is a reality?

3. May exist sometime?

Slide 8

If it exists. What to do?

1. LMWH

2. Rivaroxaban

3. ASA

4. 1 & 3 are correct

5. 1, 2 & 3 are correct

6. If it does not exist, no therapy is necessary.

Slide 9

Economy Class Syndrome Traveler’s VTE

• If risk factor and long distance (>4h), consider Rp

• No ASA?

• (NEJM: T. Brighton 2012, Nov 4, 2012: Low dose aspirin to prevent recurrent Venous thromboembolism)

Slide 10

• We gave aspirin. The couple had an uneventful trip.

• March 2018: the patient is in complete remission

• This is a real patient’s history

• I thought at some point making up this patient’s wife as a femalepatient with breast cancer and bringing in a hormone story, but as you have stood through a whole program so far, we’ll leave it at thatand

Slide 11

Financial ToxicityESMO grades for drug benefit in PFS and/or OS

2nd Edition

Fertility in Cancer Patients

Berrington de Gonzalez A. et al.: BodyMass Index and mortality among 1,46 million white adults N. Engl. J. Med 2010

BMI HR

« Normal » 18.5-<25 1.00

0verweight 25-<30 0.94

Obesity grade 1 30-<35 0.95

Obesity grade 2+3 =>35 1.29

All cause mortality, corrected for smoking, no cause-specific mortality

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