Systemic management of pancreatic cancer:

Supportive care

Snežana Bošnjak

Institute for Oncology and Radiology of SerbiaDept. Supportive Oncology & Palliative Care

Serbia, Belgrade

Integrative Oncology

Patient-centered model of care: Integrates disease-directed interventions

with patient-family directed interventions (supportive & palliative care)

Involves patients in the decision-making process (PROs)

Improves patient’s QoL and overall clinical outcomes (including survival)

Jordan K, Aapro M, Kaasa S, et al. Annal Oncol 2018; 29: 36–43Basch E, Deal AM, Dueck AC et al. JAMA 2017; 318(2): 197–198.

Hui D, Bruera E. Nat Rev Clin Oncol 2016; 13: 159–17

ESMO position statement on supportive and palliative careJordan K, et al., Annals of Oncology 29: 36–43, 2018

Patient-centered Care (ESMO)

„The oncologist role is not only to deliver the best quality anticancer treatment but also to consider the

impact of the disease and treatment on each patient’s life“

ESMO position paper on supportive and palliative care, Jordan K, et al. Annals of Oncology 2018; 29: 36–43

Metastatic Pancreatic Cancer : Patient Centered Care (ASCO, 2018)

• Assessment: Symptom burden, psychological status,

and social supports as early as possible, preferably at the first visit

• Treatment: Aggressive Tx of the pain and Sx of the

cancer and / or the cancer-directed therapy • A formal PC consult and services

Metastatic Pancreatic Cancer: ASCO Guideline.Sohal DPS et al. J Clin Oncol 2016 34:2784-2796

Guideline Update. Sohal DPS et al. DOI: 10.1200/JCO.2018.78.9636 Journal of Clinical Oncology - published online before print May 23, 2018

Palliative careSupportive care

Hospice care

Conceptual framework for supportive care, palliative care and hospice care, based on the systematic literature review.

No evidence of disease

Curable cancer Incurable cancer Bereavement

Death

Conceptual Framework for Supportive and Palliative Care

Hui D, Bruera E. Nat Rev Clin Oncol 2016; 13: 159–171.

Metastatic Pancreatic Cancer : Supportive Care Guidelines

• Antiemetics (ESMO, 2016)

• Oral and GI mucosal injury (ESMO, 2015)

• Febrile neutropenia (ESMO, 2016)

• Chemotherapy induced peripheral neuropathy (CIPN) (ASCO, 2014)

www.esmo.orgwww.asco.org

FOLFIRINOX vs Gemcitabine: AEs

Grade 3/4 AE, % FOLFIRINOX (n = 171)

Gemcitabine (n = 171)

P Value

Hematologic Neutropenia 45.7 21.0 < .001 Febrile neutropenia: 43% w/GCSF 5.4% 1.2 .03 Thrombocytopenia 9.1 3.6 .04

Nonhematologic Fatigue 23.6 17.8 NS Vomiting 14.5 8.3 NS Diarrhea 12.7 1.8 < .001 Sensory neuropathy 9.0 0 < .001 Elevated ALT 7.3 20.8 < .001

* Conroy T, et al. N Engl J Med. 2011;364:1817-1825.Slide credit: clinicaloptions.com

MPACT: Gemcitabine ± NAB-Paclitaxel—AEs

Event Gem + NAB-Pacli(n = 421)

Gem (n = 402)

AE leading to death 4 4Hematolgic AEs grade ≥ 3 Neutropenia 38% 27% Leukopenia 31 % 16 % Thrombocytopenia 13 % 9 % Anemia 13 % 12 %

Receipt of growth factors 26 % 15 %Febrile neutropenia 3 % 1 %Nonhematologic AEs grade ≥ 3*Fatigue 17 % 7 %Peripheral neuropathy 17 % 1 %Diarrhea 6 % 1 %*≥ 5% of pts.Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703. Slide credit: clinicaloptions.com

Chemotherapy induced nausea and vomiting (CINV)

The risk for CINV: • FOLFIRINOX: moderate, determined by oxaliplatin /

irinotecan • Gemcitabine: low • Gem+ Nab-Paclitaxel: low

Supportive Care Goal: Prevention and control of CINV (0-120h) Gr ¾ vomiting: 15% after FOLFIRINOX

Overall risk for nausea & vomiting after chemotherapy

• Emetogenicity of chemotherapy • Patient-related risk factors for CINV*

• Disease-associated symptoms & concomitant medications

Nausea and vomiting due to advanced cancer, the use of opioids for pain

Roila F et al. MASCC / ESMO consesus guidelines Ann Oncol (2016) 27 (suppl 5): v119-v133

Dranitsaris G, et al. Annals Oncol 2017; 28: 1260-1267

Increased riskFemale genderYounger age

Morning sicknessAnxiety

Decreased risk

Chemotherapy-naïveAlcohol abuse

CINV prevention: MEC groupACUTE DELAYED

Carboplatin 5HT3+DEX+NK1 -5HT3+DEX+APR APR

Oxaliplatin 5HT3+DEX DEX*

Irinotecan 5HT3+DEX None

Roila et al., Annals of Oncology 2016; 27 (Supplement 5): v119–v133Hesketh PJ, et al. J Clin Oncol 2017; 35(28):3240. Epub 2017 Jul 31.

Hesketh Pj, Bosnjak S, Nikolic V, Rapoport B. Support Care Cancer 2011; 19: 2063-66

Febrile neutropenia FOLFIRINOX: Intermediate risk (10-20%); Gemcitabine + Nab-Paclitaxel: Low (< 10%) Gemcitabine: Low (< 10%)

ESMO FN guidelines 2016NCCN myeloid GFs guidelines 20178

Conroy T, et al. N Engl J Med 2011; 364:1817-25Hosein PJ, et al. BMC Cancer 2012; 12:199

Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703

Oncologic emergencySupportive Care goal: prevention & empirical treatment

FOLFIRINOX: FN: 5% (43.% with GCSF)NAB-Paclitaxel: FN:3% (26% with GCSF)

Patient risk factors for FN

• Age ≥ 65 yrs • Advanced disease • History of prior FN • Poor performance / nutritional status • Mucositis • Liver disfunction (elevated bilirubin), renal

disfunction (creatinine clearance < 50 ml/min)

ESMO FN Guidelines, 2016ASCO WBC GFs Guidelines, 2015

NCCN Myeloid GFs Guidelines, 2017

Chemotherapy related FN risk

≥ 20%

Prophylactic G-CSF

<10%

NO Prophylac

tic G-CSF

10%-20%

Patient & Disease related risk

Risk of FN ≥ 20% Risk of FN <20%

• ESMO 2016 • ASCO 2015• NCCN 2017 guidelines

FN: Primary prophylaxis Alternative regimens

Overall FN risk

Neutropenic patient

• Altered ability to mount a normal immune response

• Signs & symptoms of infection may be minimal

• Fever: the principal, the earliest and commonly the only sign of infection

• Afebrile neutropenic patient who is receiving corticosteroids, NSAIDs

• Unless recognized & treated, infection can quickly progress to sepsis and death

Febrile + neutropenicBlood

cultures & Empiricaltherapy

Modification of empirical regimen :

Clinical and / or microbiological demonstration of infection

Afebrile + neutropenic + SIRS or clinical focus of infection

ESMO FN 2016 guidelines www.esmo.org

RISK PREDICTION FOR FN: MASCC SCORE

Burden of illness

No/ mild symptoms 5

Moderate symptoms 3

NO hypotension (systolic BP > 90mm Hg) 5

NO COPD 4

Solid tumor or lymphoma with no previous fungal infection 4

No dehydration 3

Outpatient status (at the onset of fever) 3

Age < 60 yrs 2MASCC score ≥ 21: low risk of complicationsMASCC score < 15: a high mortalty rate

www.mascc.org

Febrile neutropenia

Clinical criteria (ASCO, 2018)Risk assessment tools (ie. MASCC score)

High risk Low risk:

HospitalisationIV antibiotics:

PIP-TZCefepimCeftazIMPMER

± Aminoglycoside

CIP or Levo PO+AM-CL or Clinda PO

Outpatient management ?

ESMO FN 2016; ASCO outpatient management of FN 2018

Diarrhoea

• Assessment: NCI-CTCAE & PROs FOLFIRINOX: 13% (gr 3 & 4) Gemcitabine + Nab-Paclitaxel: 6% (gr 3& 4) Gemcitabine: 1-1.8% (gr 3 & 4)

• 5FU: bolus IV vs. infusion regimen• Irinotecan: acute and late diarrhoea • Mechanism: mucositis, panenteritis,

enterocolitis

Conroy T, et al. N Engl J Med 2011; 364:1817-25Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703

Andreyev J., et al. Lancet Oncol 2014; 15: e447-60

Diarrhea: Consequences

• Volume depletion • Renal insufficiency• Electrolyte disorders • Intestinal hemorrhage / perforation • Infection / sepsis (neutropenia!)• Abdominal cramps • Malnutrition• Decrease in QoL, dignity• Reduced compliance with treatment

Complicated diarrhea: warning signs

• Fever (is the patient neutropenic?)• Abdominal cramping • Anorexia, nausea, vomiting• Increased weakness• Decreased urine output • Gastrointestinal bleeding • Deteriorated PS

Andreyev J., et al. Lancet Oncol 2014; 15: e447-60

Diarrhea: treatment• Is it complicated (gr 3&4 or 1&2 w/ warning

signs) ?• Pharmacological• Loperamide: first-line Tx for CID• Octreotide: first & second-line Tx for CID• Steroids (oral, IV): immunotherapy • Antibiotics Non-pharmacological • Fluid and electrolyte replacement• Dietary modifications

ASCO 2004; MASCC / ISOO 2104Andreyev et al., Lancet Oncol 2104; 15: 447-60

Chemotherapy-induced peripheral neuropathy (CIPN)

The risk for CIPN: • FOLFIRINOX: 9%• Gem+ Nab-Paclitaxel: 17%

Supportive Care Goal: Screen for CIPN and diagnose it early

Conroy T, et al. N Engl J Med 2011; 364:1817-25Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703

CIPN: Oxaliplatin• Acute neurotoxicity (sensory & motor Sx)• Chronic, cumulative, dose-dependent: mainly

sensory, similar to cisplatin• Prevention Acute neurotoxicity: avoid exposure to cold No established agents recommended for the

prevention of chronic CIPN except decreasing the dose or duration of oxaliplatin

ASCO recommends against the use of IV Ca/ Mg supplementation / any other agent

„Stop & go“ preventive approach

ASCO guidelines Hershman DL, et al. J Clin Oncol. 2014;32:1941-67.

IDEA: Safety

Slide credit: clinicaloptions.com

Grothey, A.F. Sobrero, A.F. Shields, et al., N Engl J Med 2018; 378:1177-88

AE, %FOLFOX CAPOX

3 Mos 6 Mos P Value* 3 Mos 6 Mos P Value*Any event† Grade 2 Grade 3/4

3238

3257

< .0001 4124

4837

< .0001

Neurotoxicity Grade 2 Grade ¾

143

3216

< .0001 123

369

< .0001

Diarrhea Grade 2 Grade 3/4

115

137

< .0001 107

139

.0117

*For Chi-squared test for trend.†19 grade 5 events reported.

Safety: main nonhematologic AEs

Presented By Thierry Conroy at 2018 ASCO Annual Meeting

CIPN: Treatment • For the treatment of established painful CIPN,

clinician “may offer” duloxetine• Inconclusive data, but therapeutic trials

“reasonable” nortriptyline, desipramine

pregabalin, gabapentin

compounded topical gel (baclofen, amitriptyline HCL, ketamine)

ASCO guidelines Hershman DL, et al. J Clin Oncol. 2014;32:1941-67.

Learning to Care