Oncology best supportive care in

the management of cancer

patients
A.Harryanto Reksodiputro

Div of Hematology – Medical Oncology

Dept of Internal Medicine,
School of Medicine, Univ of Indonesia/
Dr.Cipto Mangunkusumo General Hospital / Dharmais Cancer Center
Hospital

1
AHR
 Extent of weight loss in cancer patients
at the time of initial diagnosis and its effect on
survival after antineoplastic thera
Type of cancer No of % of Survival of Survival of
(diagnosis) patients patients patients patients
with weight with weight without weight
loss at loss (wk) loss (wk)
diagnosis
Breast 289 36 45 70*
Colon 307 54 21 43*
Prostate 78 56 24 46*
Sarcoma 189 39 25 46*
Lung 590 61 14 20*
Small cell 436 60 27 34
(lung)
stomach 179 83 27 41*
2
* p<0.05 versus patients with weight loss AHR
Metabolic Changes During Cancer

• Hypermetabolism (may depend on

cancer type)
• Increased resting energy expenditure
• Increased muscle atrophy
• Decreased protein synthesis
• Insulin resistance & glucose
intolerance
• Increased glucose production
3
AHR
Muscle Atrophy During Cancer

Decreased protein synthesis

(hypoanabolism)
+
Increased protein catabolism
(hypercatabolism)
=
worst muscle atrophy
4
AHR
Muscle Atrophy During Cancer
• Hypoanabolism
– Failure of normal stimuli for muscle protein
synthesis
– &/or lack of substrate (amino acids & energy) for
net muscle protein synthesis
• Hypercatabolism
– Involves catabolic stimuli & activation of
intracellular proteolytic enyzmes

Cancer Treatment Differs

5
AHR
What is Cancer-Associated Cachexia?

• Clinical wasting syndrome

• Syndrome of progressive wasting of
adipose tissue & skeletal muscle
• Occurs in majority of advanced cancer
patients
• Associated with extreme fatigue (due
to extensive loss of muscle mass)
6
AHR
 Cancer-Associated
Cachexia
• Most common in advanced cancers of:
– Stomach
– Pancreas
– Lung
– Colon

• Breast cancer per se is rarely associated with

cachexia

7
AHR
 Starvation vs Cachexia?
• Starvation:
– Adaptations to reduce energy expenditure,
– conserve protein, utilize fatty acids/ketones

• Cachexia:
– Adaptations are attenuated or absent!
– Energy expenditure is increased!
– Muscle protein loss continues!

8
AHR
 Mediators of Cachexia

Proinflammatory cytokines

Acute-phase proteins

Produced by Host or Tumour – or both?

9
AHR
 TNF-a
• A cytokine associated with:
– Anorexia
– Weight loss
– Acute-phase protein response
– Protein & fat breakdown
– Decreased insulin, insulin resistance
– Anemia, fever
– Increased energy expenditure

10
AHR
 IL-6
• Directly induces acute phase protein
response
• Likely works with other mediators, such
as TNFa
• Different tumours = different responses
• Elevated levels in some weight-losing
cancer patients
11
AHR
 Tumour-derived Products
Proteolysis-inducing factor (PIF)
• 1st factor of tumour origin thought to
participate in regulation of muscle protein
turnover
• Potent stimulus of protein catabolism in skeletal
muscle in vitro & in vivo
• Not present in cancer patients without
weight loss
• Not present with weight loss in non-cancer
disease
12
AHR
 Tumour-derived Products
Lipid-mobilizing factor (LMF)
• Identified in urine of weight-losing
cancer patients
• Increases lipolysis

13
AHR
 Nutritional support?
• Cancer cachexia seems resistant to
intervention with enteral or parenteral
nutrition
• Likely due to metabolic changes – increased
tumour or host production of proinflammatory
cytokines
• Need to overcome metabolic changes
• What about specific dietary nutrients?

14
AHR
 Nutrition & the Cancer Patient

Good Nutrition Important for :

• Improved immune function
• Better tolerance to therapies
• Increased “quality of life”

15
AHR
 Cancer-Related Fatigue

• Up to 70% of patients during chemo &

radiation
• Long-lasting problem for 30% of
survivors
• Can interfere with normal daily activities
or work
• Economic & social consequences

16
AHR
 Diagnosis of anaemia:
Symptoms
• Symptoms of anaemia include
– fatigue
– lethargy
– inability to concentrate
– dizziness and breathlessness on exertion
– headache
– paraesthesia of the extremities

17
AHR
 Prevalence of anaemia in
cancer
• Anaemia is the most common haematological
disorder in patients with cancer
– approximately 20%–60% of patients with cancer will
have anaemia at presentation

• Treatment for cancer can induce or exacerbate

anaemia: the extent of this varies according to the
type of tumour and treatment

18
AHR
Cancer-related anaemia in Europe:
Most patients diagnosed as anaemic
had Hb <10 g/dL
Mild anaemia is very often unrecognised

6%
(n = 69)

Serum Hb
46% 48%
(n = 501) <10 g/dL
(n = 476)
10–12 g/dL
>12 g/dL

19
AHR
 Causes of anaemia in patients with
cancer: Disease-related factors
• Anaemia of chronic disease
• Bone marrow involvement of malignancy
• Haemolysis (RBC destruction)
• Tumour-associated blood loss – particularly with
gastro-intestinal or uterine tumours
• Nutritional deficiences –  iron, folate or vitamin
B12
• Renal insufficiency
• Hypersplenism 20
AHR
 Factors involved in the cause and development
of anaemia in patients with cancer

Tumour cells

Activated
immune system
RBCs Erythrophagocytosis
TNF Macrophages
Dyserythropoiesis

Shortened
survival IFN-,IFN-IFN-
IL-1 IL-1 IL-1
TNF TNF TNF
1-antitrypsin

Reduced Impaired Suppressed

Anaemia EPO iron BFU-e
production utilisation CFU-e
TNF = tumour necrosis factor; IFN = interferon;
IL-1 = interleukin-1;BFU-e = erythroid burst-forming unit;
CFU-e = erythroid colony-forming unit Nowrousian M. Med Oncol. 21
1998;15(suppl 1):S19–S28 AHR
 Signs and symptoms of
anaemia
 Central nervous system  Immune system
 Debilitating fatigue  Impaired T-cell and
 Dizziness, vertigo macrophage function
 Depression
 Cardiorespiratory system
 Impaired cognitive function
 Exertional dyspnoea
 Tachycardia, palpitations
 Gastro-intestinal system  Cardiac enlargement,
 Anorexia hypertrophy
 Nausea  Increased pulse pressure,
systolic ejection murmur
 Vascular system  Risk of life-threatening cardiac
 Low skin temperature failure
 Pallor of skin, mucous
membranes and conjunctivae  Genital tract
 Menstrual problems
 Loss of libido

Adapted from Ludwig H. Semin Oncol. 1998;25(suppl 7):2-6. 22

AHR
 Anaemia adversely affects
quality of life (QOL)
• Fatigue is the most commonly reported clinical
manifestation of anaemia in patients with cancer
– 78% of patients with cancer suffer fatigue1

• Fatigue is not relieved by sleep or rest

• At Hb levels <12 g/dL, fatigue increases

significantly

  Hb and  fatigue   QOL2

Vogelzang N, et al. Semin Hematol. 1997;34 (suppl 2):4-12.

1 23
2
Cella D. Semin Hematol. 1997;34 (suppl 2):13-19. AHR
 Tumour hypoxia potentiates
tumour progression
• The impact of anaemia on the survival of patients with
cancer may be due to low tumour levels of oxygen

• Experimental data show that tumour hypoxia leads to

  tumour invasiveness
  metastatic potential
  resistance to cancer therapy1

• Hypoxia may also promote the selection of aggressive

tumour phenotypes with reduced apoptotic potential

1
Höckel M, et al. Cancer Res. 1999;59:4525-4528. 24
AHR
Increasing serum Hb levels may
improve survival in patients with cancer
• In a placebo-controlled trial of 375 anaemic patients receiving
non-platinum–based chemotherapy for a variety of malignancies,
administration of recombinant EPO (rHuEPO) led to a:

– significant increase in Hb levels (P <0.001)

– significant decrease in transfusion requirements (P = 0.0057)

– significant improvement in QOL (P <0.01)

– trend towards an increase in survival (12-month estimated

rates: 60% vs 49% for placebo)*
NB: This study was not powered for
*

survival as an endpoint 25
Littlewood T, et al. J Clin Oncol. 2001;11:2865-2874. AHR
 rHuEPO and survival in cancer patients with
anaemia: 26-month median follow-up

*
NB: This study was not powered 26
for survival as an endpoint AHR
Littlewood T, et al. J Clin Oncol. 2001;19:2865-2874.
 Summary
• Anaemia is common in patients with cancer

• Incidence and severity of anaemia varies according to

– tumour type
– cancer treatment

• Anaemia has effects on most body organs and can

lead to potentially serious consequences, eg,
cardiovascular complications
• Anaemia increases the need for RBC transfusions,
which are associated with serious risks, eg,
transmission of infection
27
AHR
 Table Infections During Granulocytopenia
Common sites :
Alimentary canal
Periodontitis / gingivitis
Pharyngitis
Esophagitis
Perianal lesions
Pneumonia
Skin lesions
Vascular access-related

Common Organisms :
Gram-negative
Escheria coli
Pseudomonas aeruginosa
Gram-positive
staphylococcus epidermidis
staphylococcus aureus
-hemolytic Streptococcus spp.
Yeast
Candida spp
Fungi
Aspergillus flavus and Aspergillus fumigatus
Virus
Herpes simplex

The sites and organism listed account for about 80% of infections
during granulocytopenia
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AHR
Infections in the setting of cellular
immune dysfunction
• Bacteria
– Listeria monocytogenes
– Salmonella spp
– Mycobacterium spp
– Nocardia asteroides
– Legionella pneumophilia
• Viruses
– Varicella-zoster
– Herpes simplex
– Cytomegalovirus
• Fungi
– Cryptococcus neoformans
– Histoplasma capsulaturn
– Coccidiodes immitis
• Protozoa
– Pneumocystis carinii
– Toxoplasma gondii
• Helminth
– Strongyloides stercoralis
29
AHR
 Nature of Febrile Episodes in
Neutropenic Patients

Unexplained Neoplastic fever

fever
•Tumor fever
(FUO)
•Tumor lysis syndrome
(40%-60%)
(4%-8%)

Documented fever
Other causes
•Clinically documented
•Tranfusion reaction
•Microbiologically
•Drug fever
Documented
(25%-40%) 30
AHR
Changing Spectrum of Infection in
Neutropenic Patients

Number (%)
Type of episode 1975-77 1986-89 1994-95
Unexpleined fever 481 (47) 644 (53) 373 (56)
Clinically documented 227 (22) 248 (20) 107 (16)
Micribiologically documented 318 (31) 334 (27) 189 (28)
Gram positive 65 (21) 170 (51) 86 (46)
Gram negative 201 (63) 110 (33) 54 (28)
Polymicrobial 42 (13) 54 (16) 49 (26)

Data from UT-M.D. Anderson Cancer Center febrile neutropenia antibiotic trials

31
AHR
 Spectrum of Infection in
Neutropenic Patients
Gram Positive Gram Negative
Coagulase-negative Eschericia coli
staphylococci
Klebsiella spp
Staphylococcus aureus
Pseudomonas aeruginosa
Viridans streptococci
Enterococcus spp Enterobacter spp
Baccilus spp Citrobacter spp
Corynebacterium jeikeium Proteus spp
Streptococcus spp Acinetobacter spp
Stenotrophomonas
maltophilia
Micrococcus spp
Stomatococcus spp

32
AHR
 Spectrum of Infection in
Neutropenic Patients (cont’d)

Number (%) of Isolates

Organism 1985 1986 1993 1996 Total
E coli 294 (31) 248 (29) 194 (29) 203 (37) 939 (29)
P aeruginosa 169 (18) 171 (20) 92 (14) 143 (19) 575 (18)
Klebsiella spp 144 (15) 129 (15) 111 (16) 115 (15) 499 (16)
Enterobacter spp 78 (8) 94 (11) 75 (11) 101 (13) 348 (11)
Proteus spp 100 (11) 59 (7) 63 (9) 42 (6) 264 (8)

Rolston et al. Clin Infect Dis. 1999;29 :463-464

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AHR
 34
AHR
 Current Treatment Options
for Febrile Neutropenia
Standard (one size fits all) options
• Combination regimens (duotherapy)
– Aminoglycoside +  -lactam
– Teicoplanin + -lactam
– Quinolone + -lactam
– Double -lactam regimens
• Single-agent regimens (monotherapy)
- extended-spectrum cephalosporin
- third generation
- fourth generation
- carbapenem
• Hospital-based therapy for all patients

Hughes et al. Clin Infect Dis. 1997;25:551-573 35

AHR
Hepatic Metabolism
• Reduced blood flow to liver
• Decreased liver size
• Age related changes in P450
microsomal systems
– 32% decline after age 70
• Polypharmacy
– P450 inhibitors, eg, grapefruit juice
– P450 inducers, eg, phenobarbital
36
AHR
Renal Excretion
• Decline in glomerular filtration rate
(GFR) is one of most predictable age-
related changes
• Renal function may also be affected by
comorbidity

37
AHR
 Adjusting Chemotherapy Dose To
Account for Reduced Renal Function

Kintzel-Dorr Formula

Adjusted dose = standard dose x adjustment factor

120-GFR
Adjustment factor = 1 - [renal excretion fraction x
120

38
Kintzel and Door. Cancer Treat Rev. 1995 AHR
PERBEDAAN “FEBRILE NEUTROPENIA”

ANTARA KANKER DAN NONKANKER

Kanker Non
Kanker
Gangguan integritas kulit + -
Gangguan integritas mukosa + -
Gangguan fungsi limfosit T + -
Gangguan fungsi limfosit B + -
Febrile neutropenia + +

39
AHR
 40
AHR
 41
AHR
 Distribution
• Doubled fat content
• Decreased intracellular water
• Increased volume of distribution (Vd)
• Lowered peak concentration and prolonged
terminal t½
• Reduced albumin concentrations (etoposide,
taxanes are highly protein bound)
• Displacement of protein-bound drugs by
other medications may occur
42
AHR
Absorption
• Factors that may affect absorption
– Reduced gastric secretion
– Reduced gastric emptying time
– Reduced gastrointestinal motility
– Diminished splanchnic blood flow
– Decreased absorption surface
– Concomitant medication, ie. H2
blockers, antacids
43
AHR
 Chemotherapy Protectors
Drug Toxicity Protector
paclitaxel myelosuppresion Growth factors
methotrexate Myelosuppression, Folinic acid
mucositis
doxorubicin cardiac Dexrazoxane
vincristine neuropathy Glutamic acid
cisplatin anemia Erythropoietin
cisplatin Renal,neuropathy, Amifostine
myelosuppresion
5-FU diarrhea Octreotide
irinotecan diarrhea loperamide
44
AHR
NOSISEPTOR :
• RESEPTOR SENSORIK NYERI
• UJUNG SYARAF TELANJANG
ANTARA SEL-SEL JARINGAN
NOSISEPTOR :
• SOMATIK : SUPERFISIAL
– KULIT
– SUB-KUTAN
– MUKOSA
• VASERIAL :
– MUKOSKELETAL
– KORNEA
– PULPA GIGI
– SISTIM PERNAFASAN
– SISTEM KARDIOVASKULAR
– SISTIM PENCERNAAN
– SISTIM UROGENITAL
SISTIM NOSISEPTIF
TRANSDUKSI

TRANSMISI

MODULASI

PERSEPSI
 TRANSDUKSI

DEPOLARISASI MEMBRAN

IMPULS

TRANSMISI

MODULASI

PERSEPSI
 UJUNG SYARAF
KERUSAKAN JARINGAN

UJUNG SYARAF

SUBSTANSI KIMIA

VASODILATOR VASOKONSTRIKSI PERMEABILITAS KAPILER

SUBSTANSI NEUROAKTIF
+
VASOAKTIF
NYERI KANKER

1. NYERI NEUROGENIK
2. NYERI SOMATIK
3. NYERI VISERAL
Step Ladder WHO
 52
AHR
 53
AHR
 54
AHR
 55
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