content of this slide is regarding cancer cachexia- pathophysiology, stages and management

1. Cancer Cachexia
NOVEMBER 23,2017
DR. MEHAK CHAWLA

2. Content
Definition
Causes of Anorexia
Pathophysiology
Stages of Cancer Cachexia
Management
1
2
3
4
5

3. Definition.
“Cachexia” comes from Greek word. Kakos (bad), and hexis (condition).
An international consensus defined cancer anorexia-cachexia as a
multifactorial syndrome with weight loss greater than 5% over the past 6
months or weight loss greater than 2% in individuals already showing
depletion according to current body weight and height (body-mass index
[BMI] <20 kg/m2) or skeletal muscle mass

4. CHRONIC ILLNESS
e.g. Chronic heart failure, Chronic obstructive pulmonary disease,
Chronic kidney disease, Chronic infection & Sepsis, Cancer
Anorexia Inflammation Insulin resistance Hypogonadism Anemia
FAT LOSS MUSCLE WASTING
Weight Loss
Weakness & Fatigue
Reduced muscle strength, VO2 max, and physical
activity
CACHEXIA DIAGNOSIS
Weight loss of at least 5% in 6
months or more
(or BMI < 20 kg/m2)
• Decreased muscle strength
• Fatigue
• Anorexia
• Low fat-free mass index
• Abnormal biochemistry:
• Increased inflammatory markers (CRP, IL-6)
• Anemia (Hb <12 g/dL
• Low serum albumin (<3.2 g/dL)
3 of 5
Chronic Illness

5. Causes of Cancer related Anorexia
Cause of Anorexia: Central and Peripheral
Peripheral causes:
1. Tumor causing dysphagia.
2. Tumors producing substances that alter food intake like lactate,
tryptophan and parathormone related peptide.
3. Tumor leading to alteration of nutrients (Zn)
4. Tumor producing inflammation cytokine release.

6. Central Causes
 Includes Depression (changes in serotonin and CRF levels), pain and changes in
neurotransmitters.
 Anorexia in head & neck cancer patients  can be due to hypoxia
 Central anorectic effects of chemotherapy  Ghrelin
Methrotrexate  decrease POMC (proopiomelanocortin) mRNA (decrease opiod mediated
feeding) & activation of brain pathways associated with dehydration.
Tamoxifen  Inhibits fatty acid synthesis in hypothalamus accumulation of malonyl CoA.

7. Activation of CTZ (contains 5HT3) activation of
neurokinin-1 receptor  emesis

8. IL-1; LIF
POMC
NPY/AgRP
+
-
PEPTIDES
nNOS
NPY, Ghrelin, Oxerin A
-
+
Cytokines
VAGUS
Tryptophan
Melanocortin
CRF
Serotonin
CRF
NPY
+
+
+
+
-
+
+
Blood-Brain Barrier
LACTATE
AMP Kinase
Acetyl CoA Carboxylase
Acetyl CoA
Via MCT4
Malonyl CoA
ANOREXIA
-
- -
-
+
+
Pathophysiology of anorexia

9. PVN
MC4R
Neuron
CRH
LHA
MCH
Orexin
ARC
POMC
CART
NPY
AgRP
Hypothalamus
Blood-Brain Barrier
Starvation
• Food Intake ↑
• Energy Expenditure ↓
Anorexigenic Orexigenic
Leptin Ghrelin
CNS
cytokines
Cytokines
PVN
MC4R
Neuron
CRH
LHA
MCH
Orexin
ARC
POMC
CART
NPY
AgRP
Hypothalamus
Blood-Brain Barrier
Cancer Cachexia
• Food Intake ↓
• Energy Expenditure ↑
Leptin Ghrelin
CNS
cytokines?
?
Hypothalamic Neuropeptide Circuitry in response to Starvation
and Cancer Cachexia/ Neuropeptide

10. Cytokines
1. TNF-Alpha
Causes cachexia by:
1. Muscle breakdown through ubiquitin-proteasome pathway and NO synthase expression
2. Fat depletion that occurs by increased lipolysis through increased HSL activation (Hormone
sensitive lipase).
3. Decreased lipogenesis and anorexia.
2. Interferon- gamma has action similar to TNF-Alpha
3. IL-1 and IL-6 are proinflammatory cytokines.
IL-1 increases anorexia, increases peripheral breakdown of muscle, and promotes release of IL-6
IL-6 elevates rate of hepatic gluconeogenesis and peripheral proteolysis, can result in more profound
wasting than TNF.

11. Tumor Factors
 In animals,PIF signals via NFκB and STAT3 pathways. Induces proteolysis in muscles via the
ubiquitin-proteasome pathway and in hepatocytes, results in production of IL-6, IL-8 and CRP
These mechanisms of PIF have not yet been validated in humans.
 Parathyroid hormone-related peptide (PTHrP),another tumor-derived circulating factor, is
associated with higher soluble TNF receptor levels and with lower albumin and transferrin levels
 It is thought that LMF (Lipid mobilizing factor) sensitizes adipocytes to lipolytic stimuli by
increasing cyclic AMP production.
 LMF may bind to beta adrenergic receptors and causes either increased receptor number or
increased G protein expression.

12. Tumour Factors

13. Summary of Pathophysiology of Cancer Cachexia
TUMOR
Digestive factors Humoral factors Tumor factors
• Dysguesia
• Early satiety
• Nausea, dysphagia
• Odynopahgia
• Mucositis
• Gastric infiltration
• constipation
• Cytokines
• Neuropeptides
• Hormones like insulin
• Increased proteolysis
• Lipolysis
• Gluconeogenesis
• Glucose turnover
• Insulin resistance
• Proteolysis inducing factor(PIF)
• Lipid mobilizing factor (LMF)

14. Stages of Cancer Cachexia

15. Management of Cancer Cachexia

16. Managing Cancer Related Cachexia
 Best management is to cure cancer as this will reverse the cachexia syndrome but
unfortunately this is an infrequent achievement in adults with advanced solid tumor.
 A second option would be to increase nutritional intake, but a large number of
randomized controlled trials of nutritional intervention did not show a significant
benefit.
 These results have led to attempts to manipulate the process of cachexia with a variety
of pharmacological agents, with the main purpose of providing symptomatic
improvement.

17. Pharmacological options for Management of Cachexia
Drugs commonly used:
1. Progestagens: megestrol acetate/Medroxyprogesterone acetate
2. Corticosteroids
Drugs with a strong rationale that failed or did not show univocal results in
clinical trials:
1. Omega-3 fatty acids—EPA
2. Cannabinoids (dronabinol)
3. Bortezomib

18. Emerging drugs with some effective results but still under clinical evaluation
Pharmacological options for Management of Cachexia
(contd.)
1. Melanocortin antagonists
2. β2 agonists (formoterol)
3. Anti-myostatin peptibody
4. Anti-IL-6
5. SARMs
1. Thalidomide
2. Ghrelin
3. COX-2 inhibitors
4. Insulin
5. BCAA
6. Oxandrolone
Future trends :

19. Effective Drugs: Progestagens
 Progestagens, that is, Medroxyprogesterone Acetate (MPA) and Megestrol Acetate (MA) are currently
considered the best available treatment option for CACS, and they are approved in Europe for treatment
of cancer- and AIDS-related cachexia.
 Fewer than 30% of patients treated with MA experience short-term appetite stimulation and although
weight and appetite improve, there is no demonstrated improvement in quality of life or survival.
Mechanism of action: Improve appetite, calorie intake and weight.
 There is a hypothetical mechanism of action that medroxyprogestrone acetate may stimulate appetite
the release of neuropeptide Y in the CNS (ventromedial hypothalamus)
 Downregulation of synthesis and release of proinflammatory cytokines.

20. Progestagens (contd…)
Dose:
Dose ranges between 160 to 1280 mg per day.
It follows that it might be acceptable from a clinical point of view to start with lower doses of
megestrol acetate (160 mg/day), reserving higher doses for resistant patients.
All data in the literature indicate that high doses of progestagens are usually safe, and serious
side-effects are not frequent in clinical practice.
Side effects:
Increases risk of thromboembolic events, peripheral oedema, breakthrough bleeding,
hyperglycaemia, hypertension and Cushing's syndrome.

21. RESULTS:
Compared with placebo, 12 weeks of MPA led to an increase in energy intake (between-group
difference, 426 kcal/day; P = 0.01) that was significantly associated (r = 0.68, P = 0.003) with an
increase in fat mass (between-group difference, 2.5 kg; P = 0.009). Fat-free mass was not significantly
influenced. REE increased during MPA treatment: at 6 weeks, the between-group difference in
change was 135 kcal/day (P = 0.009); after 12 weeks, this difference was 93 kcal/ day (P = 0.07).

22. Megestrol acetate Nanocrystal Oral Suspension
• It improves bioavailability by enhancing the performance of drug
with poor water solubilityrapid increase in plasma MA
concentration more rapid clinical response.
• It was approved by FDA for the treatment of AIDS- related cachexia
and it is under evaluation for approval in cancer cachexia.

23. Effective Treatment: Corticosteroids.
 Among orexigenic agents, corticosteroids are widely used. In
randomized controlled studies, they have been shown to improve
appetite and quality of life compared with placebo.
 MA and corticosteroids seem equally effective
 Long-term use of corticosteroids have more side effects like
protein breakdown, insulin resistance, water retention, and
adrenal suppression
 Therefore, corticosteroids are not suitable for long-term use and
should be used during the pre-terminal phase of cachexia.

24. Drugs with a strong rationale that have failed or have not
shown univocal results in clinical trials so far
Drugs capable of inhibiting:
 Synthesis and/or release of cytokines(i.e. eicosapentaenoic acid (EPA),
melatonin, etc.)
 The cytokine action (i.e. anti-cytokine antibodies, anti-inflammatory cytokines
interleukin (IL)-12, and IL- 15)
 Proteasome activity (i.e. bortezomib)
Unfortunately, most clinical trials in humans have provided limited or
disappointing results.

25. OMEGA-3- FATTY ACIDS (N-3-FA),
EICOSAPENTAENOIC ACID
Mechanism of action:
 EPA down-regulates the production of pro-inflammatory cytokines
 Furthermore, the effects of proteolysis inducing factor (PIF) are also
inhibited by EPA.

26. EPA (Contd…)
Mazzotta et al[150] systematically reviewed several databases including
publications until 2006 in order to identify the clinical efficacy of EPA and DHA
for the management of cachexia in cancer patients. They analyzed 10 studies
and 7 RCTs and found no clear advantage of either EPA or DHA
(docosahexaenoic acid) on weight, lean muscle mass, symptoms, quality of life,
or survival. No significant differences was found on use of EPA or DHA alone as a
treatment option.
However, it does seem clear that multidimensional treatments represent the
most useful approach for cachexia in advanced cancer.

27. Cannabinoids
 Cannabinoids have a definite effect on weight gain and, bearing this in mind,
have been used to increase food intake in cancer patients.
 The main effective constituent of cannabis is delta-9-tetrahydrocannabinol.
 It has been postulated that they may act via endorphin receptors, through
inhibition of prostaglandin synthesis, or by inhibiting IL-1 secretion.
 Two separate randomized clinical trials carried out by Jatoi et al and Strasser
et al have failed to show benefit as compared to MA or placebo, respectively.

28. Bortezomib
 It is a NF-kB and ubiquitin-proteasome inhibitor.
 Although potentially promising, in preliminary results published by Jatoi showed negligible
favorable effects on cancer-associated weight loss in patients with metastatic pancreatic
cancer.
 The authors concluded that further study of bortezomib specifically in this setting and for
this indication were not warranted.
Anti-TNF-alpha MoAb (infliximab):
A clinical study carried out by Wiedenmann et al.,[21] showed that the addition of infliximab
to gemcitabine to treat cachexia in advanced pancreatic cancer patients was not associated
with statistically significant differences in safety or efficacy when compared to placebo.

29. Emerging drugs with some effective results but still
under clinical evaluation
Thalidomide
 Its inhibitory effect on TNF-α and IL-6 production may be responsible for its
apparent anticachectic activity.
 Gordon et al. undertook a randomized placebo-controlled study to assess the
safety and efficacy of thalidomide in attenuating weight loss in patients with
cachexia secondary to advanced pancreatic cancer and concluded that
thalidomide was well tolerated but it was only able to attenuate loss of weight
and LBM in patients with cachexia due to advanced pancreatic cancer.

30. Selective COX-2 inhibitors
 There are four studies investigating the relationship between non-steroidal
anti-inflammatory drugs (NSAIDs) and cancer cachexia. These studies
demonstrated improved quality of life, performance status, inflammatory
markers, weight gain and survival.
 However, two reports concluded data were insufficient for interpreting their
widespread use of NSAIDs in practice.

31. β2-adrenergic agonists
Formoterol exerts a selective, powerful protective action on heart and skeletal
muscle by antagonizing the enhanced protein degradation, which is a
characteristic of cancer cachexia. β2-agonists are also proposed to have a
protective action against the apoptosis of skeletal muscle. Formoterol may be
potential therapeutic tool in pathologic states

32. Ghrelin Mimetic with Orexigenic and Anabolic Activity
 Ghrelin is a 28 amino acid peptide produced by the P/D1 cells of the stomach.
 The functions of ghrelin include food intake regulation, gastrointestinal (GI) motility, and
acid secretion in the GI tract.
 Synthetic human ghrelin has been shown to improve muscle wasting and functional
capacity in patients with cardiopulmonary-associated cachexia and to improve energy
intake in anorexic cancer patients.
 Significant questions remain to be answered, however, before its widespread use, most
prominently whether the gains produced by GHS R agonists maintain safety and efficacy
with long-term use in human diseases.

33. Emergence of ghrelin as a treatment for cachexia
syndrome
 Strasser et al. conducted a study on Safety, tolerability and pharmacokinetics of intravenous
ghrelin for cancer-related anorexia/cachexia: The author concluded that nutritional intake and
eating-related symptoms, measured to explore preliminary efficacy, did not differ between ghrelin
and placebo. Ghrelin is well tolerated and safe in patients with advanced cancer.
 Neary et al,carried out an acute, randomized, placebo-controlled, cross-over clinical trial to
determine whether ghrelin (5 pmol/kg/min for 180 min i.c.) stimulates appetite in cancer patients
with anorexia . A marked increase in energy intake was observed with ghrelin infusion compared
with saline control, and every patient reported food intake increase. No side effects were observed
 Further controlled randomized studies are warranted before the use of ghrelin can be translated
into clinical practice

34. Insulin
• Insulin treatment significantly stimulates carbohydrate intake, decreased
serum-free fatty acids, and increased whole body fat, particularly in trunk and
leg compartments, whereas fat-free lean tissue mass was unaffected.
• Insulin treatment improved metabolic efficiency during exercise, but did not
increase maximum exercise capacity and spontaneous physical activity.
• Insulin is a significant metabolic treatment in multimodal palliation of weight-
losing cancer patients.

35. Oxandrolone
 Xandrolone is an agonist of the androgen receptor
 Recently, a prospective, randomized, phase III trial comparing the effects of oxandrolone (10
mg bid) and MA (800 mg q.d.) on weight, body composition, and quality of life (QOL) in 155
adult patients with solid tumors and weight loss receiving chemotherapy demonstrated that
patients treated with oxandrolone experienced an increase in LBM, a reduction in fat mass, and
reduced self-reported anorectic symptoms.
Olanzapine
 It is an atypical neuroleptic with safe therapeutic window for several psychotic diseases,
induces significant weight gain and positive metabolic effects.
 Preliminary data from a phase I pilot study by Braiteh et al suggest that lower doses of OAZ are
very well tolerated with promising clinical activity on weight, nutrition, and function in
advanced cancer patients with cachexia. The trial is ongoing.

36. Herbal Medicine (kampo)
 Kampo is the Japanese herbal medical practice.
 Fujitsuka et al reported that Rikkunshito, a Kampo formula, improved anorexia,
gastrointestinal dysmotility, muscle wasting, and anxiety-related behavior.
 Rikkunshito significantly prolonged median survival of pancreatic cancer
patients with ascites who were treated with gemcitabine. These studies
suggest that Rikkunshito may be useful in clinical practice for cachectic cancer
patients but its mechanism of action is unclear and needed further studies.

37. Combined Approach
 From all the data presented, one can speculate that one single therapy may not be completely
successful in the treatment of cachexia.
 Cerchietti LC et al. studied the effects of celecoxib, medroxyprogesterone, and dietary intervention
on systemic syndromes in patients with advanced lung adenocarcinoma: a pilot study and
concluded that patients with advanced lung adenocarcinoma, treated with MPA, celecoxib and
dietary intervention, might have considerable improvement. This multitargeted symptomatic
approach deserves further study.
 Cerchietti LC et al. studied the effects of eicosapentaenoic and docosahexaenoic n-3 fatty acids
from fish oil and preferential Cox-2 inhibition on systemic syndromes in patients with advanced
lung cancer. Cohort of 22 patients with advanced lung cancer were randomly assigned to receive
either fish oil, 2 g tid, plus placebo capsules bid (n=12) or fish oil, 2 g tid, plus celecoxib 200 mg bid
(n=10). All patients in both groups received oral food supplementation.

38.  After 6 weeks of treatment, patients receiving fish oil+placebo or fish oil + celecoxib showed
significantly more appetite, less fatigue, and lower C reactive protein (C-RP) values than their
respective baselines values (P<0.02 for all the comparisons). Additionally, patients in the fish
oil+celecoxib group also improved their body weight and muscle strength compared to
baseline values (P<0.02 for all the comparisons).
 Comparing both groups, patients receiving fish oil + celecoxib showed significantly lower C-RP
levels (P = 0.005, t-test) and higher muscle strength (P=0.002, t-test), and body weight (P=0.05,
t-test) than patients receiving fish oil+placebo.
 The addition of celecoxib improved the control of the acute-phase protein response, total body
weight, and muscle strength.
 Overall, these trials based on a combined approach, although supported by a good rationale,
are all phase II studies enrolling a small number of patients and hence are to be considered
preliminary and warrant further confirmation in phase III studies
Combined Approach (contd.)

39. Dietary Treatment
 Since cancer cachexia differs from starvation, at the present time no single modality therapies
using traditionally applied nutritional regimens has succeeded in demonstrate any efficacy in
improving weight gain, including gain in lean body mass, in patients diagnosed with cancer
cachexia
 The average calorie deficit in weight-losing patient is reported to be approximately 200 kcal per
day in the setting of advanced cancer and 250-400 kcals/d in those patients with cancer
cachexia. The average protein intake in patients with cancer cachexia is about 0.7-1.0 g/kg per
day.
 Food energy intake needs to increase by 300-400 kcal per day and protein intake to increase by
up to 50% to have an effect on anabolic resistance (recommended intake 1.0-1.5 g/kg per day).

40.  The analysis of a randomized trial found that in addition to oral nutritional support, the use of
parenteral nutrition resulted in a short (6-8 wk) prolongation of survival when nutritional goals
were achieved.
 A meta-analysis of oral nutritional interventions in malnourished patients with cancer suggests
that oral nutritional interventions have no effect on survival and that the effect on body weight
and energy intake is inconsistent, though statistically significant improvements in some aspects
of QOL may be achieved.
Dietary Treatment (contd.)

41. Physical Exercise
 Physical exercise has been suggested as a promising countermeasure for
preventing cachexia.
 Since it is reported that exercise increases insulin sensitivity, protein synthesis
rate, and anti-oxidative enzyme activity it may lead to a suppression of the
inflammatory response and enhancement of immune function.
 A randomized trial has also reported that, in patients with advanced-stage
cancer, exercise is feasible and that although fatigue is not reduced, physical
performance is improved significantly.

42. Future Trends
 Anti-IL-6 humanized monoclonal antibody which in murine models appear to inhibit cancer
cachexia
 IL-15, a cytokine expressed in skeletal muscle, is able to suppress the increased DNA
fragmentation associated with muscle wasting in tumor-bearing rats[57] and also to have
muscle anabolic effects in vitro and slow muscle wasting in rats with cancer cachexia.
 Selective androgen receptor modulators (SARMs), which claim to preferentially act on skeletal
muscle. They bind to the androgen receptor (AR) with high affinity and exert strong
pharmacological activity in selective tissues, although the mechanism is not well understood.

43.  SARMs are designed to have predominantly anabolic activity in muscle and bone with minimal
androgenic effects in most other tissues.
 Evans et al.,[60] carried out a randomized phase II proof of concept study of Ostarine, the first-
in-class SARM, in healthy postmenopausal women and elderly men prior to initiating a phase II
study in cancer patients. The primary end point was change from baseline to 3 months in total
LBM measured by dual energy X-ray absorptiometry. Ostarine was shown to improve LBM and
physical performance in healthy older men and women. Ostarine had no unwanted androgenic
side effects.
 Blockade of melanocortin signaling using antagonists to the melanocortin MC4 receptor
attenuates disease-associated anorexia and wasting in rodent models of cancer and renal
failure.
Future Trends (contd.)

44. Rationale for Agent selection
1. Polyphenols have high antioxidant activity.
2. The oral dietary supplement has objective to integrate energetic / protein intake
with supplementation of n-3 PUFA, which are able to inhibit cytokine production
(TNF alpha)
3. Medroxyprogestrone acetate inhibits cytokine production.
4. The selected antioxidant treatment has demonstrated effective in reducing blood
levels of ROS and increasing blood levels of physiological antioxidant enzymes in
series of published papers.
5. The COX-2 selective inhibitors like celecoxib has been chosen for its ability,
demonstrated both in experimental and in clinical studies, to inhibit cancer –related
inflammatory mediators (PGE2), angiogenesis and therefore cancer progression as
well as CACS casual factor.

45. Summary
1. Wasting is a predictable event in many cancer patients, readily diagnosed by assessment of
weight, change in appetite, and food intake. Often these patients will also have anemia and low
albumin, with a concomitant increase in C-reactive protein. The above simple assessments
should form a consistent part of the record of all advanced cancer patients.
2. At the onset and throughout the course of illness, offer patients nutritional counseling and
consider the use of specific pharmacologic interventions.
3. Follow-up visits should not only note careful evaluation of antitumor therapy and tumor
volume, but also regular assessment of symptom control, weight, appetite, and function.
4. Take careful note of the full medication profile and assess amy secondary cause of wasting.
Drugs that could favorable effect on cachexia like, cardiac agents such as the statins, ACE
inhibitors must be assessed .
5. Patients must be assured of a reasonable intake of amino acids. Protein-containing foods are
indicated and rich sources of both essential and nonessential amino acids will support any
anabolic potential.