Le Linee Guida AIOM: La terapia antiemetica

SURVEY SUL CONFLITTO DI INTERESSE IN

ONCOLOGIA PROMOSSO DAL CIPOMO 1-31 MARZO

PARTECIPATE TUTTI

www.cipomo.it; nicsonet.it

LINEE GUIDA AIOM:

LA TERAPIA ANTIEMETICA

Fausto Roila

S.C. Oncologia Medica, Terni

CONFLICT OF INTEREST: DISCLOSURE

No conflict of interest

Coordinatore Fausto Roila AIOM Oncologia Medica - A.O. S.Maria - Terni

Segretario Lucia Mentuccia AIOM Oncologia Medica - Ospedale SS Trinità - Sora (FR)

Estensori Claudia Caserta AIOM Oncologia - A.O. Santa Maria - Terni

Sonia Fatigoni Oncologia - A.O. Santa Maria - Terni

Revisori Silvana Chiara AIOM Oncologia Medica - A.O.U. San Martino-IST - Genova

Alessandra Fabi AIOM Oncologia Medica I - I.F.O. Regina Elena - Roma

Maria Cristina Locatelli AIOM Oncologia Medica - A.O. S.Carlo Borromeo - Milano

Ernesto Maranzano AIRO Radioterapia oncologica - A.O. Santa Maria - Terni

Mimma Raffaele AIOM Oncologia - Inrca-Ist.naz.rip.e Cura Anziani - Roma

EMETOGENIC POTENTIAL OF SINGLE INTRAVENOUS CHEMOTHERAPY AGENTS

EMETIC RISK AGENT

HIGH

Cisplatin

Mechlorethamine Streptozocin

Cyclophosphamide > 1500 mg/m² Carmustine

Dacarbazine

AC or EC regimens (breast cancer pts)

ANTIEMETICS FOR THE PREVENTION OF

CISPLATIN-INDUCED ACUTE AND DELAYED EMESIS

day 1 days 2-3 day 4 Aprepitant 125 mg 80 mg -

Ondansetron 32 mg - - Dexamethasone 12 mg 8 mg 8 mg Ondansetron 32 mg - -

Dexamethasone 20 mg 8 mg bid 8 mg bid

Aprepitant p.o. Ondansetron i.v. Dexamethasone p.o.

TWO RCT ON APREPITANT (2003)

Protocol 052 Protocol 054

AOD OD AOD OD No. pts 264 266 283 286 Complete response (%)

Day 1 89 78 ^11% 83 68 ^15%

Day 2-5 75 56 ^19% 68 47 ^21%

no nausea (%) 48 44 49 39

RESULTS

MASCC/ESMO 2010 RECOMMENDATIONS ON ANTIEMETIC PROPHYLAXIS

ACUTE DELAYED

Cisplatin 5HT3+DEX+Apr DEX+Apr

SINGLE-DOSE FOSAPREPITANT FOR THE PREVENTION OF CHEMOTHERAPY-

INDUCED NAUSEA AND VOMITING

ASSOCIATED WITH CISPLATIN THERAPY:

RANDOMIZED, DOUBLE-BLIND STUDY PROTOCOL EASE

Grunberg S, et al. J Clin Oncol 2011; 29: 1495-501

D1 D2 D3 D4 Aprepitant po 125 mg 80 mg 80 mg - Ondansetron 32 mg - - - Dexamethasone 12 mg 8 mg 8 mg 8mg Fosaprepitant iv 150 mg - - - Ondansetron 32 mg - - -

Dexamethasone 12 mg 8mg 8 mg bid 8 mg bid ondansetron iv desametasone po

STUDY DESIGN (2247 pts)

RESULTS (% COMPLETE RESPONSE)

FOD AOD p day 1 89.0 88.0 n.s.

days 2-5 74.3 74.2 n.s.

days 1-5 71.9 72.3 n.s.

Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of

chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose- ranging pivotal study

Hesketh PJ, et al. Ann Oncol 2014; 25: 1340-1346

D1 D2-3 D4

PALO Palo 0.50mg+ Dex 8 mg bid Dex 8 mg bid Dex 20 mg po

NEPA100 netu100 +Palo Dex 4 mg bid Dex 4 mg bid + Dex 12 mg po

NEPA200 netu200 +Palo Dex 4 mg bid Dex 4 mg bid + Dex 12 mg po

NEPA300 netu300 +Palo Dex 4 mg bid Dex 4 mg bid + Dex 12 mg po

APR+OND apr 125mg + Apr 80mg + Dex 4 mg bid OND 32mg iv + Dex 4 mg bid

Dex 12 mg po

DESIGN OF THE STUDY ^{(694 pts)}

D1-D5 D1 D2-D5 PALO 76.5 89.7 80.1 NEPA100 87.4* 93.3 90.4*

NEPA200 87.6* 92.7 91.2*

NEPA300 89.6* 98.5* 90.4*

APR+OND 86.6 94.8* 88.8*

* Statistically significant with respect to PALO

RESULTS (% COMPLETE RESPONSE)

Safety and efficacy of rolapitant, for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two

randomised, active-controlled, double-blind, phase III trials

Rapoport BL, et al. Lancet Oncol 2015; 16: 1079-89

D1 D2-3 D4 Rolapitant 200 mg - - Granisetron 10 µg/kg - -

Dexamethasone 20 mg 8 mg bid 8 mg bid Granisetron 10 µg/kg - -

Dexamethasone 20 mg 8 mg bid 8 mg bid

Rolapitant po Granisetron iv Dexamethasone po

STUDY DESIGN

RGD GD P Day 1 83.4 ^3.9% 79.5 n.s.

Day 2-5 70.1 ^8.2% 61.9 0.043 Day 1-5 67.5 60.4 n.s.

no nausea (%) 55.5 44.0 0.009

RESULTS (555 pts)

RGD GD P Day 1 83.7 ^10% 73.7 0.005 Day 2-5 72.7 ^14.3% 58.4 <0.001 Day 1-5 70.1 56.5 <0.001

RESULTS (532 pts)

- The addition of an NK1 receptor antagonists in pts

submitted to cisplatin chemotherapy increased the complete response on day 1 from 4% to 15% and on days 2-5 from 8% to 21%.

- Part of this increase is due to a dependence effect (the better results achieved on the day 1 which induced an increase of the complete responses on days 2-5)

CONCLUSIONS

APREPITANT VERSUS METOCLOPRAMIDE, BOTH COMBINED WITH DEXAMETHASONE, FOR THE PREVENTION OF CISPLATIN-

INDUCED DELAYED EMESIS: A

RANDOMIZED, DOUBLE-BLIND STUDY

Roila F, et al. Ann Oncol 2015; 26: 1248-1253

METHODS

STUDY DESIGN

- A randomized double-blind study comparing aprepitant versus

metoclopramide, both combined with dexamethasone, was carried out in naive cancer pts treated with cisplatin-based chemotherapy.

-Before chemotherapy, all patients were treated with intravenous

palonosetron 0.25 mg and dexamethasone 12 mg and oral aprepitant 125 mg

ANTIEMETIC TREATMENTS

-Oral dexamethasone 8 mg once daily on days 2-4 plus aprepitant 80 mg daily on days 2-3

-Oral dexamethasone 8 mg bid on days 2-4 plus metoclopramide 20 mg 4 times daily on days 2-4

RESULTS IN THE DELAYED PHASE (284 pts)

MTC + DEX

APR + DEX p

No. of patients (%) 137 (%) 147 (%)

RESPONSES

complete response 113 (82.5) 118 (80.3) ^n.s.

complete protection 102 (74.5) 108 (73.5) ^n.s.

total control 97 (70.8) 102 (69.4) ^n.s.

no vomiting 120 (87.6) 129 (87.8) ^n.s.

no nausea 100 (73.0) 105 (71.4) ^n.s.

no significant nausea

(VAS < 25 mm)

111 (81.0) 114 (77.6) ^n.s.

mean number of emetic episodes (sd) 7.9 (7.4) 8.4 (11.8) ^n.s.

mean maximum severity of nausea (sd) 44.8 (25.5) 44.9 (26.2) ^n.s.

mean duration of nausea, hours (sd) 13.5 (16.5) 15.4 (19.0) ^n.s.

CONCLUSIONS

- Recently EMA reduced the dose and the duration of the

antiemetic treatment with oral metoclopramide to 10 mg TID for maximum 1 week (risk of neurological side effects such as short-term extrapyramidal disorders). Therefore, our

metoclopramide regimen is not utilizable in the clinical practice.

MASCC/ESMO 2016 RECOMMENDATIONS

ACUTE DELAYED Cisplatin 5HT3+DEX+NK1 DEX

5HT3+DEX+APR DEX+APR or MTC

ANTIEMETICS FOR THE PREVENTION OF ACUTE AND DELAYED EMESIS INDUCED BY AC/EC REGIMENS

MASCC/ESMO 2010 RECOMMENDATIONS

ACUTE DELAYED

AC 5HT3+DEX+Apr Apr

D1 D2-3 Aprepitant 125 mg 80 mg

Ondansetron 8/8 mg - Desametasone 12 mg -

Ondansetron 8/8 mg 8/8 mg Dexamethasone 20 mg -

Aprepitant po Ondansetron po Dexamethasone po

Breast cancer pts

treated with CTX ± DOX or EPI (2005)

AOD OD P No. pts 438 428

Day 1-5 51 42 0.015 Day 1 76 69 ^7% 0.034 Day 2-5 55 49 ^6% 0.064 No nausea days 1-5 33 33 n.s.

*Complete response: no vomiting and no rescue therapy

RESULTS*

A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of

netupitant and palonosetron, for prevention of

chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy

Aapro M, et al. Ann Oncol 2014; 25: 1328-1333

Double-blind, randomized study in chemotherapy-naive patients undergoing anthracycline-cyclophosphamide

chemotherapy submitted to:

- oral NEPA + oral dexamethasone 12 mg (NEPA= NETU 300 mg + PALO 0.50 mg)

- oral PALO 0.50 mg + oral dexamethasone 20 mg

Primary endpoint: complete response during delayed phase

DESIGN OF THE STUDY ^{(1455 pts)}

D2-D5 D1 D1-D5 PALO + DEX 69.5

85.0

66.6 NEPA + DEX 76.9* 88.4** 74.3*

* P = 0.001

** P = 0.047

RESULTS (% COMPLETE RESPONSE)

Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after

administation of moderately emetogenic chemotherapy or anthacycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-

blind, phase 3 trial

Schwartzberg LS et al. Lancet Oncol 2015; 16: 1071-78

D1 D2-3 Rolapitant 200 mg -

Granisetron 2mg 2 mg Dexamethasone 20 mg

Granisetron 2 mg 2 mg Dexamethasone 20 mg

Rolapitant po Granisetron po Dexamethasone po Primary Endpoint: complete response on days 2-5

STUDY DESIGN (1332 pts)

RGD GD P Day 1 83.5 ^3.2% 80.3 n.s.

Day 2-5 71.3 ^9.7% 61.6 <0.001 Day 1-5 68.6 57.8 <0.001

RESULTS (% complete response)

- The addition of an NK1 receptor antagonists

increased the complete response in pts submitted to AC/EC on day 1 from 3% to 7% and on days 2-5 from 6% to 10%

- Part of this increase is due to a dependence effect (the better results achieved on the day 1 which

induced an increase of the complete responses on days 2-5)

CONCLUSIONS

Aprepitant versus dexamethasone for preventing

chemotherapy-induced delayed emesis in patients with breast cancer: a randomized double-blind study

Roila F, et al. J Clin Oncol 2014; 32: 101-106

METHODS

- A randomized double-blind study comparing aprepitant

versus dexamethasone was carried out in naive breast cancer patients treated with anthracyclines + cyclophosphamide

- Before chemotherapy, all patients were treated with

intravenous palonosetron 0.25 mg and dexamethasone 8 mg plus oral aprepitant 125 mg

- On days 2 and 3 patients randomly received oral dexamethasone 4 mg bid or aprepitant 80 mg qd

Primary endpoint was rate of complete response (no vomiting, no rescue treatment) from days 2-5 after chemotherapy

RESULTS IN THE DELAYED PHASE ^{(551 PTS)}

Dexameth. Aprepit. P Value

No. of patients (%) 273 (%) 278 (%)

Complete response 217 (79.5) 221 (79.5) n.s.

Complete protection 164 (60.1) 152 (54.7) n.s.

Total control 131 (48.0) 120 (43.2) n.s.

No vomiting 250 (91.6) 248 (89.2) n.s.

No nausea 134 (49.1) 122 (43.9) n.s.

No significant nausea 174 (63.7) 158 (56.8) n.s.

Mean number of emetic episodes (sd)* 5.7 (6.5) 9.2 (9.4) n.s.

Mean maximum severity of nausea (sd)° 42.8 (25.9) 45.5 (24.1) n.s.

Mean duration of nausea, hours (sd)° 14.1 (18.4) 16.6 (21.4) n.s.

* in patients who had delayed vomiting (dexamethasone: 23 patients; aprepitant: 30 patients)

° in patients suffering from delayed nausea (dexamethasone: 139 patients; aprepitant: 156 patients)

- No comparative studies have been carried out to

identify differences in efficacy and toxicity between the three NK-1 receptor antagonists.

- Therefore, when available, the choice may be

dependent on the respective convenience and cost.

NK-1 RECEPTOR ANTAGONISTS

OLANZAPINE

• Olanzapine is an antipsychotic approved drug that blocks multiple neurotransmitters in the central nervous system:

dopamine D₁, D₂, D₃ receptors, serotonin 5-HT_2a, 5.HT_2c, 5-HT₃ and 5-HT₆ receptors, α₁ adrenergic receptors,

muscarinic receptors and histamine H₁ receptors.

• Some phase II studies seems to suggest an important antiemetic activity

OLANZAPINE VERSUS APREPITANT FOR THE PREVENTION OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING: A RANDOMIZED

PHASE III STUDY

Navari RM , et al. J Support Oncol 2011; 9: 188-195

g. 1 g. 2 g. 3 g. 4 Aprepitant po 125 mg 80 mg 80 mg - Palonosetron iv 0.25 mg - - -

Dexamethasone 12 mg 4mg bid 4mg bid 4mg bid

Olanzapine po 10 mg 10 mg 10 mg 10 mg Palonosetron iv 0.25 mg - - - Dexamethasone 20 mg - - -

dexamethasone iv on day 1 and orally on day 2-4

DESIGN OF THE STUDY (241 pts)

RESULTS (% COMPLETE RESPONSES)

OPD APD p Day 1 97.0 87.0 n.s.

Day 2-5 77.0 73.0 n.s.

Day 1-5 77.0 73.0 n.s.

SHORTCOMINGS

• It is an open study

• Due to the small sample size, the study was only powered to investigate large differences such as a 15% difference in

complete response on day 1-5.

• It was not defined if the study was designed as a superiority, non inferiority or equivalence study.

• An unplanned interim analysis was carried out but the significance level was not modified according to

Bonferroni’s inequality.

OLANZAPINE FOR THE PREVENTION OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING

Navari RM , et al. N Engl J Med 2016; 375: 134-42

DAY

Fosaprepitant iv 150 mg - - -

5-HT3 RA iv day 1 - - - Dexamethasone po 12 mg 8 mg 8 mg 8 mg

Olanzapine po 10 mg 10 mg 10 mg 10 mg Fosaprepitant iv 150 mg - - - 5-HT3 RA iv day 1 - - - Dexamethasone po 12 mg 8 mg 8mg 8 mg

DESIGN OF THE STUDY (380 pts)

RESULTS (% NO NAUSEA)

OFPD FPD p Day 1 73.8 45.3 <0.001 Day 2-5 42.4 25.4 0.001

Day 1-5 37.3 21.9 0.002

RESULTS (% COMPLETE RESPONSES)

OFPD FPD p Day 1 85.7 64.6 <0.001 Day 2-5 66.9 52.4 0.007

Day 1-5 63.6 51.8 <0.001

A DOUBLE-BLIND RANDOMIZED PHASE II

STUDY OF 10 MG VERSUS 5 MG OLANZAPINE FOR EMESIS INDUCED BY HIGHLY

EMETOGENIC CHEMOTHERAPY WITH CISPLATIN

Hashimoto H, et al. J Clin Oncol 2016; 34 (suppl; abstr 10111)

GIORNO

Olanzapina os 5 mg 5 mg 5 mg 5 mg

Aprepitant os 125 mg 80 80

Palonosetron ev 0.75 mg - - -

Desametasone os 9.9 mg 6.6 mg 6.6 mg 6.6 mg Olanzapina os 10 mg 10 mg 10 mg 10 mg Aprepitant os 125 mg 80 80 -

Palonosetron ev 0.75 mg - - -

Desametasone os 9.9 mg 6.6 mg 6.6 mg 6.6 mg

DISEGNO DELLO STUDIO (153 pts)

RESULTS (% COMPLETE RESPONSES)

OFPD 10mg OFPD 5mg p Day 1 100.0 98.7 n.s Day 2-5 77.6 85.7 n.s.

Day 1-5 77.6 85.7 n.s

Sedation 53.3 45.5 n.s

ANTIEMETICS FOR THE PREVENTION OF ACUTE AND DELAYED EMESIS INDUCED BY MODERATELY

EMETOGENIC CHEMOTHERAPY

EMETIC RISK AGENT

MODERATE

Oxaliplatin

Cytarabine > 1 gr/m² Carboplatin

Ifosfamide

Cyclophosphamide < 1500 mg/m² Doxorubicin

Daunorubicin Epirubicin Idarubicin Irinotecan Bendamustine Alentuzumab Azacitidine

EMETOGENIC POTENTIAL OF SINGLE INTRAVENOUS CHEMOTHERAPY AGENTS

MODERATELY EMETOGENIC CHEMOTHERAPY

• The category of MEC includes antineoplastic agents with a very large risk of emesis (30% to

90%) if no antiemetics are used. This broad range

makes it difficult to give one recommendation for

antiemetic treatment that is appropriate for all the

drugs of this category.

• For the prevention of acute emesis induced by MEC we have to use a 5-HT3 antagonist plus

dexamethasone

• In pts receiving MEC with known potential for delayed emesis (e.g., oxaliplatin, doxorubicin,

cyclophosphamide), the use of dexamethasone for days 2-3 can be considered. No routine prophylaxis can be recommended for all other pts receiving MEC.

2016 MASCC/ESMO RECOMMENDATIONS

NK1 ANTAGONISTS FOR THE PROPHYLAXIS OF CARBOPLATIN-INDUCED ACUTE AND DELAYED

EMESIS

NK1 ANTAGONISTS FOR CARBOPLATIN-BASED CT

• Six studies evaluated the role of the addition of a NK1 antagonist to a 5-HT3 antagonist plus dexamethasone in carboplatin-treated pts.

• Three of the six studies presented a subgroup analysis or post hoc analysis of studies involving both AC and non-AC-treated pts.

• In these studies the addition of an NK1 antagonist increased the complete response by approximately 10- 15%.

NK1 ANTAGONISTS FOR CARBOPLATIN-BASED CT

• In a phase III, double-blind study, 297 naїve patients with ovarian, endometrial and cervical cancer scheduled to receive carboplatin plus paclitaxel, were randomized patients to aprepitant or placebo, both combined to a 5-HT3 antagonist plus dexamethasone

(Yahata H, Int J Clin Oncol 2016; 21: 491-497)

• The primary endpoint was complete response, no vomiting and no significant nausea on days 2-5.

NK1 ANTAGONISTS FOR CARBOPLATIN-BASED CT

• All the primary endpoints were significantly superior with the addition of aprepitant (complete response 61.6% versus 47.3%, no vomiting 78.2% versus 54.8%

and no significant nausea 85.4% versus 74.7%).

• For the prevention of carboplatin-induced acute nausea and vomiting a combination of a NK1 antagonist,

dexamethasone and a 5-HT3 antagonist is recommended

• If patients received fosaprepitant, netupitant or rolapitant on day 1, no antiemetic prophylaxis for delayed emesis is required. If pts received aprepitant on day 1, aprepitant on days 2 and 3 is recommeded

2016 MASCC/ESMO RECOMMENDATIONS

MASCC/ESMO 2016 RECOMMENDATIONS

ACUTE DELAYED Carboplatin 5HT3+DEX+NK1 -

5HT3+DEX+APR APR Oxaliplatin 5HT3+DEX DEX*

Other MEC 5HT3+DEX DEX*

* In pts receiving MEC with known potential for

delayed emesis

EMETOGENIC POTENTIAL OF SINGLE

INTRAVENOUS CHEMOTHERAPY AGENTS

GRADO FARMACO

LOW

Docetaxel Aflibercept

Paclitaxel Belinostat

Mitoxantrone Blinatumomab

Topotecan Brentuzimab

Etoposide Cabazitaxel

Pemetrexed Carfilzomib

Methotrexate Eribulin

Mitomycin Ipilimumab

Gemcitabine Pertuzumab

Cytarabine ≤ 100 mg/m2 Trastuzumab-emtansine 5-Fluorouracil Vinflunine

Bortezomib Nab-paclitaxel

Ixabepilone Temsirolimus

Pegylated liposomal doxorubicin

MASCC/ESMO 2016 RECOMMENDATIONS

ACUTE DELAYED Low emetogenic DEX or 5HT3 -

chemotherapy or a dopamine RA

EMETOGENIC POTENTIAL OF SINGLE INTRAVENOUS CHEMOTHERAPY AGENTS

GRADO FARMACO

MINIMAL

Bleomycin Busulfan

2-Chlorodeoxyadenosine Fludarabine

Vinblastine Vincristine Vinorelbine Nivolumab Ofatumumab Pembrolizumab Pixantrone

Pralatrexate Bevacizumab

MASCC/ESMO 2016 RECOMMENDATIONS

ACUTE DELAYED Minimal emetogenic

chemotherapy

RECOMMENDED DOSES OF 5-HT3 RA

Agent Route Antiemetics

Ondansetron IV 8 mg or 0.15 mg/kg

oral 16 mg

Granisetron IV 1 mg or 0.01 mg/kg

oral 2 mg (or 1mg)

Dolasetron oral 100 mg

Tropisetron IV 5 mg

oral 5 mg

Palonosetron IV 0.25 mg

oral 0.5 mg

RECOMMENDED DOSES OF DEXAMETHASONE

dexamethasone dose and schedule High risk

acute emesis 20 mg once [12 mg when used fos(aprepitant) or netupitant]

delayed emesis 8 mg bid for 3-4 days [8 mg once daily when used with (fo)aprepitant or netupitant]

Moderate risk

acute emesis 8 mg once

delayed emesis 8 mg daily (or 4 mg bid) for 2-3 days Low risk

acute emesis 4 – 8 mg once

RECOMMENDED DOSES OF NK1 RA

NK1 receptor antagonist dose and schedule Aprepitant and fosaprepitant

acute emesis APR 125 mg once on the day of CT or or FOS 150 mg iv once on the day of CT delayed emesis 80 mg orally once daily for the 2 days

after CT; or none if FOS is used

Rolapitant 180 mg orally once on the day of CT Netupitant 300 mg netupitant/0.5 mg palonosetron

orally once on the day of CT

PREVENTION OF NAUSEA AND VOMITING INDUCED BY MULTIPLE-DAY CISPLATIN

CHEMOTHERAPY

Randomized Phase III Double-Blind Placebo-Controlled Crossover Study Evaluating the Oral Neurokinin-1

Antagonist Aprepitant in Combination with a 5HT3

Receptor Antagonist and Dexamethasone in Patients with Germ Cell Tumors Receiving 5 day Cisplatin Combination Chemotherapy Regimens: a Hoosier Oncology Group

(HOG) Study

Albany C, et al, J Clin Oncol 2012; 30: 3998-4003

day 1-2 day 3 day 4-5 day 6-7 day 8 Aprepitant ─ 125 mg 80 mg 80 mg ─

5-HT3 r.a. ● ● ● ─ ─

Dex 20 mg ─ ─ 4mgx2 4mgx2 Placebo ─ ● ● ● ─

5-HT3 r.a. ● ● ● ─ ─

Dex 20 mg ─ ─ 8mgx2 4mgx2

oral aprepitant 5-HT3 iv oral dexamethasone

DESIGN OF THE STUDY ^{(69 PTS)}

RESULTS (% COMPLETE RESPONSE)

APR PL p

Day 1-5 47.0 15.0 <0.0001 Day 6-8 63.0 35.0 <0.0004

Day 1-8 42.0 13.0 <0.0001

MASCC/ESMO 2016 RECOMMENDATIONS

ACUTE DELAYED

Multiple-day CDDP NK1+5HT3+DEX DEX

c

BREAKTHROUGH CHEMOTHERAPY-INDUCED EMESIS AND REFRACTORY EMESIS

MASCC/ESMO 2016 RECOMMENDATIONS

Breakthrough CT-induced - olanzapine Emesis

Refractory emesis - another 5-HT3

- add DA or benzodiazepines - metopimazine

- NK1 antagonist

PREVENTION OF ANTICIPATORY NAUSEA AND VOMITING

MASCC/ESMO 2016 RECOMMENDATIONS

Anticipatory nausea - use the best control of acute and and vomiting delayed nausea and vomiting

- benzodiazepines (alprazolam, diazepam and lorazepam)

- behavioural therapies (progressive muscle relaxation training, hypnosis and systematic desensitisation

PREVENTION OF NAUSEA AND VOMITING INDUCED BY HIGH-DOSE CHEMOTHERAPY

MASCC/ESMO 2016 RECOMMENDATIONS

ACUTE DELAYED High dose CT APR+5HT3+DEX APR

PREVENTION OF RADIOTHERAPY-INDUCED NAUSEA AND VOMITING

MASCC/ESMO 2016 RECOMMENDATIONS:

Emetic Risk Area of treatment antiemetics high TBI P 5HT3+DEX moderate upper abdomen P 5HT3 ± DEX

craniospinal

low cranium, P or R DEX head and neck,

thorax , pelvis P or R DEX, DA or 5HT3 minimal extremities, breast R DEX, DA or 5HT3 P= prophylaxis R= rescue

MASCC/ESMO 2016 RECOMMENDATIONS:

Emetic Risk = concomitant chemo-radiotherapy

antiemetic prophylaxis should be according to the guidelines for chemotherapy-induced nausea and vomiting. However, in case the emetic risk of RT is higher than that of the

concomitant CT, then the risk level of RT has to be chosen to tailor the antiemetic regimen

EFFICACY AND SAFETY OF FOSAPREPITANT FOR THE PREVENTION OF NAUSEA AND EMESIS DURING 5

WEEKS OF CHEMORADIOTHERAPY FOR CERVICAL CANCER (THE GAND-EMESIS STUDY): A

MULTINATIONAL, RANDOMISED, PLACEBO-

CONTROLLED, DOUBLE-BLIND, PHASE 3 TRIAL

Ruhlmann CH , et al. Lancet Oncol 2016;

- Fosaprepitant vs placebo in 246 cervical cancer pts submitted to fractionated radiotherapy and weekly CDDP (40 mg/m

) for 5 weeks. All pts received palonosetron 0.25 mg iv and oral DEX 16 mg

before CDDP and oral DEX 8 mg bid on day 2, 4mg bid on day 3 and 4 mg on day 4. The antiemetic

treatment was repeated for 5 weeks

- Primary endpoint: proportion of pts with sustained no emesis after 5 weeks

STUDY DESIGN

- The proportion of pts with sustained no emesis after 5 weeks was significantly superior with

fosaprepitant (65.7% vs 48.7%).

- Fosaprepitant was superior even in the day 1- day 35 rates of complete response, no emesis, no nausea

and no rescue medication.

- Antiemetic treatments were generally well tolerated

RESULTS