ASCO 2006 Supportive Care John Glaspy, MD Sanders Chair in Cancer Research Jonsson Comprehensive...
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Transcript of ASCO 2006 Supportive Care John Glaspy, MD Sanders Chair in Cancer Research Jonsson Comprehensive...
ASCO 2006Supportive Care
John Glaspy, MDSanders Chair in Cancer ResearchJonsson Comprehensive Cancer CenterProfessor of MedicineUCLA School of Medicine
UCLA
Supportive Care Overview
• 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
UCLA
Supportive Care Overview (2)
• 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)
UCLA
Supportive Care Overview (3)
• 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
UCLA
Fresh Start (#8503)
• 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 dietDemark-Wahnefried, et. al.
UCLA
Results
UCLA
HBEX (#8504)
• 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.
UCLA
Yoga (#8505)
• 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.
UCLA
Yoga Results
• Change from baseline at one week follow up
• Preliminary, but change scores compare favorably to ESAs, the major QOL/fatigue treatment administered in oncology
UCLA
Predictors of Benefit from Bisphosphonates (#8529)
• 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.
UCLA
Denosumab
• 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
• RANK-ligand, acting through RANK on osteoclast progenitors is the primary regulator of osteoclast formation and survival
UCLA
Active-Control RCT of Denosumab in Bisphosphonate-Naïve Breast Cancer (#512)
• Endpoints: Changes in urinary N-telopeptide (uNTx) and skeletal-related events (SRE) at week 16
Lipton, et al
UCLA
Results
• 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
UCLA
AMG 531: TPO-R Agonist “Peptibody”
• A peptide TPO-R binding domain that has no sequence homology to endogenous thrombopoietin
• An antibody Fc domain that increases serum half life
UCLA
Eltrombopag: Small Molecule TPO-R Agonist
• 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
UCLA
Rationale for TPO-R Agonists in ITP
• 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
UCLA
Future Applications
• Both drugs are safe and raise platelet counts in ITP
• 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
Bussel, #8602
UCLA
Parenteral Iron and Darbepoetin in CIA (#8612)
• 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.
UCLA
Iron/Darbepoetin: Outcomes, Interim Analysis
UCLA
Epoetin q2w (#8624)
• 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.
UCLA
Epoetin q2w (#8624): Results
Primary Endpoint
Transfusions
UCLA
AMG 114 for CIA (#8626)
• 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.
UCLA
Results (#8508)
Sorensen, et. al.
Duration of Mucositis
Incidence of Mucositis
Grading of Mucositis
UCLA
NK-1 RA (#8512)
• 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
d 1
8 mg BID
d 1
8 mg BID
d 1
8 mg BID
d 1
8 mg BID
d 1
8 mg BID
d 1
CAS - 50 mg/d
d 1-3
100 mg/d
d 1-3
150 mg/d
d 1-3
150 mg/d
d 1
150 mg/d
d 1-3
CR120 h
70% 81% 79% 85% 80% 84%
Arpornwirat et. al.
UCLA
NK-1 RA (#8513)
• 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
d 1
32 mg IV
d 1
32 mg IV
d 1
32 mg IV
d 1
32 mg IV
d 1
32 mg IV
d 1
DEX PO
d1-14
PO
d1-14
PO
d1-14
PO
d1-14
PO
d1-14
PO
d1-14
CAS placebo 50 mg/d
d 1-3
100 mg/d
d 1-3
150 mg/d
d 1-3
150 mg/d
d 1
Aprepitant
125 mg d1, 80 mg d 2-3
CR120 h
60% 76% 86% 77% 75% 72%
Rolski et. al.
UCLA
Olanzapine (Zyprexa) for CINV (#8608)
• 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
Navari et. al.
CR Rates Acute (d1) Delayed (d2-5)
HEC 100% 97%
MEC 75% 75%