L’ASSISTENZA ONCOLOGICA NELLE
PICCOLE ISOLE
ATTESE, RISORSE, CRITICITÀ
Le emergenze oncologiche,
la terapia di supporto e la qualità di vita
La gestione dei sintomi (anemia, neutropenia, nausea)
F. Tomao
Università Sapienza –Roma-
Supportive Care
1960
Dott. Cecily Sanders
“Treatment administered with the intent to maximize
quality of life without a specific antineoplastic regimen,”
(antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions,
nutritional support, and focal external-beam radiation for control of pain, cough,
dyspnea, or hemoptysis)
Jassem et al. J Clin Oncol 2008
Supportive Care Toxicity Targets
Hematologic
• Myelosuppression
Gastrointestinal
• Nausea/vomiting
• Constipation/diarrhea
• Mucositis
Cardiovascular
• Thrombosis
• Cardiac
Neurologic
• Peripheral neuropathy
• Cognitive
 Pulmonary
Renal
Cutaneous
• Alopecia
• Rash
Anemia
Hgb < 14g/dl
Hgb < 12g/dl
Grade Toxicity
NCI Score
WHO Score
0
None
12-16 g/dL
>11
1
Mild
10g/dL-LLN
9.5-10 g/dL
2
Moderate
8-10 g/dL
8-9.4 g/dL
3
Severe
6.5-7.9 g/dL
6.5-7.9 g/dL
4
life-threatening or disabling
<6.5 g/dL
<6.5 g/dL
Anemia in cancer patients: the ECAS study
Prospective study
15.367 pts
748 cancer centres, 24 countries
Hgb <12.0 g/dl=49.1%
Ludwig et al. Eur.J.Cancer 2004
Causes and Effects of Cancer – related Anemia
Causes
Effects
Disease – related
factors1
 Decrease in
QOL2,3,4
Folate, Vit B12,
Iron deficiency1
 Increase in
transfusion rates5
Anemia of chronic
disease1
 Probable decrease
in survival6,7,8
Chemotherapy1
1- Grotto, Med Oncol, 2008; 2- Gabrilove, JCO 2001; 3- Littlewood, JCO 2001; 4- Cella D. Ann Oncol, 2003; 5-Benoist
S., Surgery, 2001; 6- Caro, Cancer 2001; 7- Waters, JCO 2002; 8- Fuso L. Gynecol Oncol 2005
Incidence of anemia associated with chemotherapeutic agents and regimens
Agent
Grade 1-2 (%)
Grade 3-4 (%)
Cancer
Cisplatin
NR
11
H&N
Docetaxel
73-85
58-60
2-10
27-42
NSCLC
Ovarian
5-FU
NR
50-54
11
5-8
H&N
Colorectal
Paclitaxel
93
7
Breast
Topotecan
NR
67
32
32
SCLC
Ovarian
Vinorelbine
67-71
5-14
Breast
Regimen
Grade 1-2 (%)
Grade 3-4 (%)
Cancer
Cisplatin-Ciclophosphamide
43
9
Ovarian
Cisplatin-Etoposide
59
16-55
NSCLC
VIP
NR
52
SCLC
5-FU-Carboplatin
93
7
H&N
CHOP
49
17
NHL
Paclitaxel-Doxorubicin
78-84
8-11
Breast
Paclitaxel-Carboplatin
10-59
5-34
NSCLC
Treatments for Anemia
 Transfusions
 ESAs
 Non ESAs:
- Fe++
- Lattoferrina
 Dietary supplementation
Benefits and Risks of RBC
Transfusions
Quick enhancement of HB level:
1 U of RBC (circa 300 cc)
• Graft-versus-host disease
• Transfusion Related
Acute Lung Injury (TRALI)
• Non emolitic fever related
Reactions
• Acute Emolisis
• Allergy
• Anafilaxis
1/g/dL icrease
in 1 hour
•More peri-operative infections
•Infectious (HIV, HBV, HCV, HTLV
West Nile, Bacteria)
•More relapses
•Worst prognosis
Upile, T, et al. Clinical Advances in Hematology & Oncology, 2009
Use of ESAs in cancer patients
N° of publications about the use of ESAs in cancer patients
4000
3500
3000
2500
2000
1500
N° of publications about the use
of ESAs in cancer patients
1000
500
0
BLOOD TRASFUSION RATE:
ESAs significantly reduced the RR of RBC transfusions (RR 0.64; 95% CI 0.60
to 0.68, 42 trials, n = 6,510).
Pubmed
Bohlius J et al. Cochrane Database Syst Rev, 2006
rHuEPOs
TYPE OF SYNTETIC
ERYTHROPOIETIN
COMMERCIAL NAME
MOLECULARE
STRUCTURE
HALF LIFE
EPOETIN α
Eprex®
Epogen®
Procrit®

aa sequence identical to
endogenous Epo.
 Different composition and
arrangements of the sugar
moieties.
7–8h
EPOETIN β
NeoRecormon®

Higher MW than Epoetin
α
4 – 12 h
Lower number of
sialylated glycan residues

DARBEPOETIN α
Aranesp®

2 N- lynked glycosylation
sites, above and beyond the
3 normally present in
endogenous Epo
24 h
EPOETIN δ
Dynepo®

Human- type glycosylation
profile (engineered in
human fibrosarcoma cell
line HT - 1080)
9 – 13 h
C.E.R.A. (Continuous
MIRCERA®

Integration of amide
bonds between amino group
 Integration of MPGBA
135 h
Erythropoietin Receptor
Activator)
Bunn H.F., Blood, 2007; Deicher R. et al., Drugs, 2004;
Osterborg, bjh, 2007; Llop E. et al., Analytical Biochemistry, 2008
Use of ESAs in cancer patients
Epo
Hb (g/dl)
12
Transfusion
10
8
6
transfusions
4
0
30
60
90
Österborg. Med Oncol 1998; 15 (Suppl 1): S47–9
Ludwig et al. N Engl J Med 1990; 322: 1693–9
120
150
180
210
ESAs: improvement in CRF.
Haemopoetic growth factors versus no intervention.
Minton O et al. Cochrane Database Syst Rev 2008
Studies with FACT F.
“Is it all over for erythropoietin?”
 The role of
erythropoietin receptors
on the tumour cell
surface
 Risk of
Thromboembolic events
Burton A., Lancet Oncology, 2007; Murat O. Arcasoy, Clin Cancer Res, 2008
ESAs and prognosis
Survival, Tumor Progression, TVE*
ENHANCE
2003‡
BEST
2005‡
EPO-CAN-20
2007‡
20000161
4/05, 4/07†
20010103
1/07†
PREPARE
11/07†
GOG-191
2007†
DAHANCA
12/06†
*8 trials selected by FDA for label inclusion out of 57 total, ‡ publication date, † = date data reported to FDA
HR for mortality significantly higher for patients with cancer who were treated with ESA vs
the control (placebo) group (HR, 1.10; 95% CI, 1.01-1.20;P=.03)
Bennett CL et al, JAMA, 2008
 ESA treatment in cancer patients increased on study mortality and worsened overall
survival.
 For patients undergoing chemotherapy the increase was less pronounced, but an adverse
effect could not be excluded.
cHR for on study mortality for OS:
53 trials
1.17 (95% CI 1.06-1.30)
1.10 (95% CI 0.98-1.24) and 1.04; 95% CI
0.97-1.11) in pts receiving CT.
Bohlius J et al., Cochrane Database Syst Rev, 2010
91 trials
20102 patients
 ESAs increase mortality HR1.17 (CI 1.06 to 1.29)
 ESAs decrease overall survival HR 1.05 (CI 1.00 to 1.11)
 ESAs Increase Risk ratio for thromboembolic omplications RR 1.52(CI 1.34 to 1.74)

 ESAs may also increase risk for hypertension RR 1.30 (CI 1.08 to 1.56) and
thrombocytopenia/haemorrhage RR 1.21 (CI 1.04 to 1.42)
 Insufficient evidence to support an effect of ESA on tumour response
Bohlius J et al., Cochrane Database Syst Rev, 2012
91 trials
20102 patients
 ESAs increase mortality HR1.17 (CI 1.06 to 1.29)
 ESAs decrease overall survival HR 1.05 (CI 1.00 to 1.11)
 ESAs Increase Risk ratio for thromboembolic omplications RR 1.52(CI 1.34 to 1.74)

 ESAs may also increase risk for hypertension RR 1.30 (CI 1.08 to 1.56) and
thrombocytopenia/haemorrhage RR 1.21 (CI 1.04 to 1.42)
 Insufficient evidence to support an effect of ESA on tumour response
Bohlius J et al., Cochrane Database Syst Rev, 2012
2010
- 60 studies analized, 15323 patients
- SETTING: chemotherapy/radiochemotherapy, radiotherapy only treatment or
anemia for cancer
MORTALITY : OR 1.06
DISEASE PROGRESSION : OR 1.01
RISK OF VENOUS TROMBOEMBOLIC EVENTS: OR: 1.48
No significant effect of ESAs on survival or disease progression
Glapsy J et al, Br J Cancer. 2010
GOG STUDY
Citokine use and survival in the first line treatment of ovarian cancer
MEDIAN SURVIVAL
PTS RECEIVING
ESA
PTS NOT
RECEVING ESA
34 MO
38 MO
MEDIAN SURVIVAL
P=NS
PTS
RECEIVING
G-CSF
PTS NOT
RECEVING G-CSF
40 MO
37 MO
P=NS
This study do not support existing literature which suggests that ESA
or G-CSF use may be associated with adverse ovarian cancer
progression and death
Study-level meta-analysis
- 9 studies
- 2342 pts receving CT
Mortality OR
0,87
(CI 0.63-1.09)
Mortality risk difference -0,02
( CI -0,06-0,04)
Disease progression
0,84
(CI 0,65-1.09)
Trasfusion incidence
0,34
(CI 0,28-0.41)
J. Vansteenkiste et al. / Lung Cancer 76 (2012)
…and what about iron
supplementation?
Not rigorously applied because….
1) False perception that cancer patients do not have decreased iron
stores (as measured by serum ferritin) and thus the belief that they do
not to require iron supplementation also during ESA therapy;
2) Failure to appreciate the relative blockade in access to storage
iron pools or dietary iron that frequently exists in patients with
chronic inflammatory illnesses such as cancer;
3) Misinformation and misinterpretation of the incidence and
clinical nature of serious adverse events of iv iron.
Pedrazzoli P et al, Cancer 2009
Iron i.v.: another way to treat
cancer-related anemia
Control group
Cervical cancer
patients
n = 45
undergoing
concurrent
Chemoradiotherapy
Patients (n = 75)
Study Group
Study group
200 mg of
iron sucrose
40%
n = 30
60%
Patients transfused
P = 0.04
Patients not transfused
3,58
Control group
36%
64%
Patients transfused
Patients not transfused
Mean transfusion units
4,00
P = 0.04
3,50
3,00
2,50
1,87
2,00
1,50
1,00
0,50
0,00
Study group
Kim YT et al., Gynecol Oncol, 2007
Control group
ESAs-Iron supplementation
157 PTS
• Hb 105 g/L,
• Serum ferritin 450 pmol/L or 675 pmol/L
• Transferrin saturation 19%
rHuEPO 40,000 U once weekly to
No-iron
Oral iron 325 mg twice daily
Iron dextran repeated 100mg IV bolus
Iron dextran total dose infusion (TDI).
> Hb level
Auerbach M et al, JCO 2004
< Non responders
Iron supplementation: oral vs iv
Plus Darbopoetin
502 Pts
Steensma DP et al, JCO 2011
Addition of IV ferric
gluconate to darbepoetin
failed to provide
additional benefit
compared with oral iron
or oral placebo.
149 Pts
P = .0033
In patients with chemotherapy-related anemia and no iron deficiency, IV iron
supplementation significantly reduces treatment failures to darbepoetin without additional
toxicity.
Pedrazzoli P et al., JCO 2008
Functional iron deficiency (FID)or
Absolute iron deficiency
30-50 % pts treated by ESAs are non-responders: Dysregulation of iron metabolism
FID: imbalance between iron needs
in the erythropoietic bone marrow
and iron supply (ESAs)
TSAT:10-20%;
Ferritin < 800 ng/ml
Absolute iron deficiency: lower
absorption, constitutional defects
TSAT<10%;
Ferritin < NV
IRON STATUS
Pedrazzoli P et al, Cancer 2009
Guidelines
ESA treatment may improve fatigue or QOL
Goal of ESA therapy for patients with CIA is to reduce RBC
transfusion requirements.
In patients treated with chemotherapy and an Hb level of <10 g/dl,
with target Hb ≤12 g/dl.
ESAs should not be given to patients who are being treated for
cancer when the goal is to cure the patients (of cancer).
ESAs have been found to shorten overall survival and cause
thromboembolism (always informed consent).
ESAs should not be given in patients who are not receiving CT o
who are receiving RT
Guidelines
IV iron products alone (without an ESA) are recommended for iron
repletion in patients with cancer with absolute iron deficiency
(ferritin < 30 ng/mL, transferrin saturation < 15%).
ESAs should be used in addition to iv iron for patients with CIA and
functional iron deficiency (no data about IV iron alone)
There are no evidences about a real efficacy of oral iron
supplementation.
There are no data about the effects of adequate diet on anemia and
prognosis of cancer patients.
NEUTROPENIA
GRADE
SEVERITY
NATIONAL CANCER
INSTITUTE
GUIDELINES
WHO
GUIDELINES
0
Absent
>2000
>1500
1
Light
1500-2000
1000-1500
2
Mild
1000-1500
750-999
3
Severe
500-1000
500-749
4
Risk for Life
< 500
< 500
Rarely neutropenia is associated with fever…. NF
Absolute neutrophil count of less than 500 cells per cubic millimeter and a temperature of more than 38.5° C.
More than 60,000 pts are admitted for the treatment of FN annually, or 8 cases per 1000 patients receiving cancer CT.
Overall, in-hospital mortality was 9.5%.
Mean (median) length of stay was 11.5 days, and the mean (median) cost was $19,110 ($8,376) per episode of FN.
ASCO 2006/ AIOM 2009 Guidelines
Fever in Neutropenic patients
ETIOLOGY IN CANCER
35
30
25
20
15
10
5
0
Bacteria
Fungi
Viruses
21%
35%
39%
5%
Neutropenia in CT regimens
REGIMEN
Neutropenia
WHO Classification
FEC 100
25%
TAC
66%
PEB
59%
CMF
78%
GemOx
20%
FOLFOX-4
41%
FOLFOXIRI
50%
EOX
28%
DCF
82%
M-VAC
82%
Caelyx
37%
Carboplatino and Paclitaxel
37%
CDDP
85%
Topotecan
89%
Review of Literature
STIMULATING FACTOR
GM-CSF (granulocyte-macrophage
colony- stimulating factor)
G-CSF (granulocyte colony- stimulating
factor):
•Filgrastim: Granulokine, Neupogen
•Lenograstim (glycosilated): Granocyte,
Myelostim, Refludan
•Pegfilgrastim (filgrastim pegilated):
Neulasta, Neupopeg
Bennett CL et al, NEJM 2013
G-CSF: Management
PRIMARY
PROPHYLAXIS
Post-CT, BEFORE
NEUTROPENIA
THERAPEUTIC
USE
SECONDARY
PROPHYLAXIS
Post-CT in patients with PREVIOUS
EVENT of NF in another CT cycle
Primary Prophylaxis with G-CSF
“Previous studies and guidelines have concluded that myeloid growth
factors are less effective if administered on the same day as
chemotherapy, delayed more than 4 days after chemotherapy, or
delayed until the onset of neutropenia”
G-CSF vs
NO G-CSF
RR
Risk and RR
reduction
p
Infections
related
mortality
0.55
1,5 vs 2.8 = <45%
p: 0.018
Early mortality
0.60
ONLY FOR FILGASTRIM
3,4 vs 5,7 = <40%
p: 0.002
FILGASTRIM and
PEGFILGASTRIM
NF risk
0.54
46%
p: <0.001
PEGFIGASTRIM (RR 0.08)
Relative doseintensity
pro G-CSF
p: <0.001
Bone and
muscolar pain
10.4% vs 19.6%
versus G-CSF
p: <0.001
DFS e OS
Kuderer, JCO 2007
NO DATA
Primary Prophylaxis with G-CSF:
WHEN?
RISK CATHEGORIES
CT with risk of expected FN
G-CSF
≥ 20%
ALWAYS
10-20%
USE IF OTHERS
RISK FACTORS
≤ 10%
NEVER
(only if complications)
NCCN 2009
EORTC 2006
ASCO 2006
AIOM 2009
GEPARTRIO study:
PEG-f plus Ciprofolxacin in Primary Prophylaxis
PROSPECTIVE TRIAL
1257 pazienti NACT
• Ciprofloxacin ( 500mgx2 ) 5-14 days
• Filgrastim ( 5-10 days)
• Pegfilgrastim (2 day)
• Ciprofloxacina + Pegfilgrastim
• Control
Ciproflox
(253 pts)
Filgrastim/ Lenograstim
(377 pts)
Peg-f
(305 pts)
Neutropenia G4 (%)
62
58
37
Febrile
Neutropenia(%)
22
18
7
1256 pts (T2-T4)
Studio non R
Von Mickvitz, Ann Oncol 2008
Patients with febrile neutropenia
Time of recovery
HR=0.32 p<0.001
Hospital stay
HR=0.63p<0.001
Clark, JCO 2005
Patients with febrile neutropenia
CSFs in FN CT-induced reduces the amount of hospitalization and the neutrophil recovery period.
Influence on infection-related mortality requires further investigation.
Infection related mortality
Mortality
Clark, JCO 2005
Guidelines
Primary prophylaxis is recommended in chemotherapy regimens
with > 20% of FN risk.
 Secondary prophylaxis is reccomended in patients with previous
complicated FN
Therapeutic use is indicated in patients with G4 neutropenia and
it is not recommended in apiretic patients and not necessary with
antibiotics association.
NAUSEA
The prevalence of Chemotherapy induced nausea and Vomiting (CINV) varies
but has been estimated at between 60 and 72%.
(King C, Oncol Nurs Forum 1997)
Nausea and vomiting is referred to as “chronic” if it is present for more than a few days,
and the median duration in palliative care has been reported as seven days. These
symptoms occur in 16%–68% of patients.
However, the three most frequent symptoms in term of life-limiting illnesses were pain,
breathlessness, and fatigue.
Glare P et al Clin Invest Aging 2011
Pathophysiology of Chemotherapy-Induced Emesis
Grunberg SM et al. NEJM 1993
Nausea and Vomiting (N&V) in Oncologic patients
Classification
 Acute N&V: during the first 24-hour period after chemotherapy administration.
 Delayed N&V: more than 24 hours after chemotherapy administration. It is
associated with cisplatin, cyclophosphamide, and other drugs (e.g., doxorubicin and
ifosfamide) given at high doses or on 2 or more consecutive days.
 Anticipatory nausea and vomiting (ANV): ANV is nausea and/or vomiting that occurs
prior to the beginning of a new cycle of chemotherapy in response to conditioned
stimuli such as the smells, sights, and sounds of the treatment room. ANV is a classically
conditioned response that typically occurs after three or four prior chemotherapy
treatments, following which the person experienced acute or delayed N&V.
 Chronic N&V in advanced cancer patients: Chronic N&V in the advanced cancer
patient is N&V associated with a variety of potential etiologies. A definitive
understanding of cause is neither well known nor well researched, but potential causal
factors include gastrointestinal, cranial, metabolic, drug-induced (e.g., morphine),
cytotoxic chemotherapy, and radiation-induced mechanisms.
Chemotherapy induced Nausea and Vomiting
Vomiting
Nausea
Grade
Description
Grade
Description
1
Loss of appetite without
alteration in eating habits
1
1–2 episodes (separated by 5
min) in 24 h
2
Oral intake decreased
without significant weight
loss, dehydration, or
malnutrition
2
3–5 episodes (separated by 5
min) in 24 h
3
≥6 episodes (separated by 5
min) in 24 h; tube feeding,
TPN, or hospitalization
indicated
4
Life-threatening
consequences; urgent
intervention indicated
5
Death
3
Inadequate oral caloric or
fluid intake; tube feeding,
TPN, or hospitalization
indicated
4
Grade not available
5
Grade not available
NAUSEA
Mean number of days in hospital per cycle of chemotherapy
according to incidence of emesis
Neymark N et al, Support Care Cancer, 2005
NAUSEA
The lung cancer trial
P 0,71
Survival according to whether the patients
experienced emesis (vomiting, bold line) or
not (thin line).
Neymark N et al, Support Care Cancer, 2005
p=0.0004
Survival for separating patients that
completed the full protocol treatment
(bold line) with those who stopped
treatment before having received six
cycles.
Inadequate control of CINV has
consistently been shown to reduce
patients’ QOL and functional status
and jeopardize the delivery of
optimal treatment.
Lindley CM et al. Quality of Life Research , 1992
Emetic risk
Anthracyclines-cyclophosphamide
combinations are reclassified
as highly emetogenic.
Basch E et al, JCO 2011
5-HT3 Antagonists
Palononsetron is preferred
effectiveness significantly
increased in delayed phase
Aapro MS et al, Ann Onc 2006
Saito M et al, Lancet Oncol 2009
NK1 Antagonists
Aprepitant e Fosaprepitant
Compared with standard dual therapy,
addition of aprepitant was generally
well tolerated and provided consistently
superior protection against CINV in
patients receiving highly emetogenic
cisplatin-based chemotherapy.
Hesketh PJ et al, JCO 2003
866 patients
The aprepitant regimen was more effective
than the control regimen for prevention of
CINV in patients receiving both an
anthracycline and cyclophosphamide
Warr DG et al, JCO 2009
Benzodiazepines
Benzodiazepines such as lorazepam, midazolam, and alprazolam have become recognized
as valuable adjuncts in the prevention and treatment of anxiety and the symptoms of
anticipatory nausea and vomiting (ANV) associated with chemotherapy, especially with
the highly emetogenic regimens given to children.
Better subjective evaluations,
and the combination using the
highest lorazepam dose tested
showed superior patient
satisfaction and less anxiety
during therapy.
Guidelines
For highly emetogenic agents (including also AC regimen) NK1
antagonists plus 5-HT3 antagonists and dexamethasone are
recommended.
For moderate emetogenic agents 5-HT3 antagonists (mainly
palonosetron) and dexamethasone are recommended.
For low emetogenic agents 8 mg of dexamethasone alone is
recommended.
Benzodiazepine should be used as adjunctive but not as single
agents.
Do not forget……
Correct diet
Lifestyle
“Un’isola che ha saputo rimanere un’isola.
Un microcosmo a sé.
Ponza è scontrosa e bellissima.
Ritrosa, diffidente e mai prevedibile.
Tra fichi d’India, bouganville e esplosioni di ginestre,
mi perdo nella bellezza dei suoi tramonti
e trovo sulla terra il mio paradiso”
E. Montale