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

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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

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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

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AMG 114 for CIA (#8626)

• Hyperglycosylated rhuEPO; 10 aa difference, 4 additional carbohydrate chains

• Efficacy q3w, no antibodies reported

Österborg , et. al.

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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%