ASCO 2006
Supportive Care
John Glaspy, MD
Sanders Chair in Cancer Research
Jonsson Comprehensive Cancer Center
Professor of Medicine
UCLA School of Medicine
Supportive Care Overview
UCLA
• Integrative Medicine (diet, exercise, etc.)
– Fresh Start
– HBEX
– Yoga
• Bone health
– Focusing zoledronic acid rx
– Denosumab
– Aromatase inhibitors and bone loss (#511)
• Hematopoietic growth factors
– Thrombocytopenia
– Anemia
Supportive Care Overview (2)
UCLA
• GI Toxicities
– Octreotide ineffective for pelvic RT (#8506)
– Chlorhexidine or cryotherapy for prevention of
chemotherapy mucositis
• Cachexia/Inanition/Depression
– Etanercept (TNF inhibitor) is ineffective for the treatment
of cancer cachexia (#8534)
– Pain, depression and fatigue do not cluster in advanced
cancer (#8522)
– Depressive symptoms are a strong predictor of short
survival in lung cancer (#8511)
– Depression is common in older men with prostate
cancer (#8510)
Supportive Care Overview (3)
UCLA
• Chemotherapy-induced nausea and
vomiting (CINV)
– Severity of nausea and not presence of vomiting is the
main driver of QOL in CINV (#8514)
– Neurokinin-1 (NK-1 RA) receptor antagonists
Fresh Start (#8503)
UCLA
• Prostate or breast cancer
• RCT of tailored, iteratively customized
print materials vs. standardized materials
• N = 270/group, 2 years of follow up
• Excluded
– Disabled
– Contraindication to fruits and vegetables or
exercise
– Already exercising 150 min/w or low fat high F
+ V diet
Demark-Wahnefried, et. al.
Results
UCLA
HBEX (#8504)
UCLA
• Prostate or breast cancer undergoing RT
• RCT of home-based exercise (HBEX), aerobic +
resistance vs. standard of care
• N = 38, endpoints FACT-F, aerobic capacity (AC)
and strength (S)
• HBEX decreased fatigue and increased AC,
standard care was associated with increased
fatigue and decline in AC (p < .05). Strength
declined less with HBEX
• Some of the fatigue and functional impairment
in that we treat with EPO may preventable
Mustian, et. al.
Yoga (#8505)
UCLA
• Breast cancer undergoing RT
• RCT of Yoga (2X/wk X 6 weeks) vs. “wait
list”
• N = 71, endpoints SF36, depression, fatigue,
sleep, impact of events, perceived benefit
• Yoga well tolerated, viewed as beneficial
• Yoga associated with improvements in
SF36, PSQI (sleep) and fatigue
Cohen, et. al.
Yoga Results
UCLA
• Change from baseline
at one week follow up
• Preliminary, but
change scores
compare favorably to
ESAs, the major
QOL/fatigue treatment
administered in
oncology
Predictors of Benefit from Bisphosphonates
(#8529)
UCLA
• Retrospective review of 3 large, RCT
• Stratified on the # of bone mets at baseline
• Greater # of bone mets associated with higher
risk of SRE and greater benefit from therapy
Shirina et. al.
Denosumab
UCLA
• RANK-ligand,
acting through
RANK on
osteoclast
progenitors is the
primary regulator
of osteoclast
formation and
survival
• Ratio of RANKL to decoy receptor (osteoprogerin)
determines the level of osteoclastogenesis
• Denosumab (AMG 162) is a human monoclonal antibody to
RANKL
Roodman: NEJM 350:1655, 2004
Active-Control RCT of Denosumab in
Bisphosphonate-Naïve Breast Cancer (#512)
UCLA
• Endpoints: Changes in urinary N-telopeptide (uNTx) and
skeletal-related events (SRE) at week 16
Lipton, et al
Results
UCLA
• Safety profiles excellent (no ONJ)
• Dose chosen for phase III is 120 mg SQ q
4w
Lipton, et al
UCLA
TPO is the Primary Regulator of Platelet
Production
• Levels correlate inversely with platelet count in humans
• Regulated primarily though clearance by platelets and precursors
• Knockout results in severe thrombocytopenia
Kaushansky: Blood 86(2) 419, 1995
AMG 531: TPO-R Agonist “Peptibody”
UCLA
• A peptide TPO-R binding domain that has no
sequence homology to endogenous
thrombopoietin
• An antibody Fc domain that increases serum
half life
Eltrombopag: Small Molecule TPO-R Agonist
UCLA
• Small molecule TPO-R agonist
(mw=442)
• Interacts with TPO-R differently
than endogenous TPO
• Stimulates megakaryocyte
proliferation and differentiation
• Orally bioavailable
• Does not prime platelets for
activation
Rationale for TPO-R Agonists in ITP
UCLA
• Endogenous TPO
levels relatively
low in ITP
• Platelet
production is
reduced or normal
in 2/3 of ITP
patients (based
upon I125 labeling
studies)
• Auto-antibodies
bind and induce
apoptosis of
platelet precursors
Nichol J, Stem Cells 16(suppl2):165-175, 1998
Future Applications
UCLA
• Both drugs are safe and raise platelet counts in ITP
Bussel, #8602
• Likely to find a role in chemotherapy-induced
thrombocytopenia
– Incidence is not trivial and increasing (see Kuderer,
#8616)
– Results in dose delays and reductions, as well as txns
and bleeding
Parenteral Iron and Darbepoetin in CIA (#8612)
UCLA
• Darbepoetin, 50 mcg q3w +/- parenteral iron
• Parenteral iron was given at a dose of 200 mg
every 3 weeks; held for ferritin > 1,000 ng/mL
• N = 196 of planned 400, interim analysis
Vandebroek, et. al.
Iron/Darbepoetin: Outcomes, Interim Analysis
UCLA
Epoetin q2w (#8624)
UCLA
• Open-label, randomized trial of epoetin alfa
40,000U/week vs. 80,000/2 weeks for CIA
• No dose escalation in q2w group; crossover
allowed for hb decline in q2w group
• Duration = 12 weeks, endpoint: hb change from
baseline, N = 198
• No difference in toxicity or clinically relevant TVE
Henry, et. al.
Epoetin q2w (#8624): Results
UCLA
Primary Endpoint
Transfusions
AMG 114 for CIA (#8626)
UCLA
• Hyperglycosylated rhuEPO; 10 aa difference, 4
additional carbohydrate chains
• Efficacy q3w, no antibodies reported
Österborg , et. al.
UCLA
Chlorhexidine or Cryotherapy for
Chemotherapy Mucositis (#8508)
• Patients with GI cancer undergoing
FU+LV chemotherapy
• RCT of chlorhexidine mouthwash vs.
cryotherapy (crushed ice in mouth 10
min before to 35 min after
chemotherapy) vs. placebo
mouthwash
• N = 206, endpoint: self-reporting
questionnaire
Sorensen, et. al.
Results (#8508)
UCLA
Grading of Mucositis
Incidence of Mucositis
Duration of Mucositis
Sorensen, et. al.
NK-1 RA (#8512)
UCLA
• RCT of ondansetron + dex +/- casopitant for CINV due to
moderately emetogenic chemotherapy; 6 arms, N=719
• Casopitant groups better than control (p < .05). Single
day dosing of particular interest.
OND
8 mg BID
d 1-3
8 mg BID
d 1-3
8 mg BID
d 1-3
8 mg BID
d 1-3
8 mg BID
d 1-3
16 mg/d
d 1-3
DEX
8 mg BID
d1
8 mg BID
d1
8 mg BID
d1
8 mg BID
d1
8 mg BID
d1
8 mg BID
d1
CAS
-
50 mg/d
d 1-3
100 mg/d
d 1-3
150 mg/d
d 1-3
150 mg/d
d1
150 mg/d
d 1-3
70%
81%
79%
85%
80%
84%
CR
120 h
Arpornwirat et. al.
NK-1 RA (#8513)
UCLA
• RCT of ondansetron + dex +/- casopitant for CINV due to
highly emetogenic chemotherapy; 6 arms, N=493
• Casopitant groups better than control (p < .05). Single
day dosing of particular interest.
OND
32 mg IV
d1
32 mg IV
d1
32 mg IV
d1
32 mg IV
d1
32 mg IV
d1
32 mg IV
d1
DEX
PO
d1-14
PO
d1-14
PO
d1-14
PO
d1-14
PO
d1-14
PO
d1-14
CAS placebo
CR
60%
50 mg/d
d 1-3
76%
100 mg/d 150 mg/d 150 mg/d
d 1-3
d 1-3
d1
86%
77%
75%
Aprepitant
125 mg d1,
80 mg d 2-3
72%
120 h
Rolski et. al.
Olanzapine (Zyprexa) for CINV (#8608)
UCLA
• A thienobenzodiazepine anti-psychotic useful in bipolar
disorders and schizophrenia
• Phase II trial of olanzapine + palonosetron
– Olanzapine, 10 mg PO day 1-4
– Palonosetron, .25 mg IV day 1
– Dexamethasone, d1, 20 mg (HEC) or 8 mg (MEC)
• N=40, well tolerated
Acute (d1)
Delayed (d2-5)
HEC
100%
97%
MEC
75%
75%
CR Rates
Navari et. al.