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ASCO 2006 Supportive Care

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. Integrative Medicine (diet, exercise, etc.) Fresh Start HBEX Yoga Bone health

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ASCO 2006 Supportive Care

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  1. ASCO 2006Supportive Care John Glaspy, MD Sanders Chair in Cancer Research Jonsson Comprehensive Cancer Center Professor of Medicine UCLA School of Medicine

  2. 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

  3. 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)

  4. 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

  5. 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 diet Demark-Wahnefried, et. al.

  6. Results

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. Denosumab • 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

  12. 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

  13. Results • Safety profiles excellent (no ONJ) • Dose chosen for phase III is 120 mg SQ q 4w Lipton, et al

  14. 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

  15. 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

  16. 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

  17. 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

  18. Future Applications • 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

  19. 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.

  20. Iron/Darbepoetin: Outcomes, Interim Analysis

  21. 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.

  22. Epoetin q2w (#8624): Results Primary Endpoint Transfusions

  23. AMG 114 for CIA (#8626) • Hyperglycosylated rhuEPO; 10 aa difference, 4 additional carbohydrate chains • Efficacy q3w, no antibodies reported Österborg , et. al.

  24. 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.

  25. Results (#8508) Grading of Mucositis Incidence of Mucositis Duration of Mucositis Sorensen, et. al.

  26. 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. Arpornwirat et. al.

  27. 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. Rolski et. al.

  28. 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.

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