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MCO 2011 - Slide 11 - M. Aapro - Antiemetics, growth factors, bone health
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  • Slide 9 In a prospective survey study, 80 patients from 6 oncology practices received a 5-HT 3 receptor antagonist with 84% also receiving a corticosteroid prior to receipt of chemotherapy (90% received moderately emetogenic regimens). Physicians and nurses consistently overestimated the efficacy of antiemetic treatment. The greatest discrepancy between predicted and actual nausea and emesis occurred for the delayed period, with physicians and nurses underestimating the presence of nausea/vomiting by approximately 30%. Of interest, even with treatment with a 5-HT 3 receptor antagonist, 47% of patients experienced acute nausea and 57% experienced delayed nausea. 1 1. Grunberg SM, Hansen M, Deuson R et al. Incidence and impact of nausea/vomiting with modern antiemetics: perception vs. reality. Proc Am Soc Clin Oncol. 2002:21(part 1);250a. Abstract #996.
  • Multiple neurotransmitters are involved in emesis. Three 5-HT3 receptor antagonists were approved for use in the United States for chemotherapy-induced emesis prior to the approval of palonosetron (Aloxi®): ondansetron (Zofran®), dolasetron (Anzemet®), and granisetron (Kytril®). 5-HT3 antagonists are first-line treatments for emesis associated with chemotherapy.1 Prior to the use of 5-HT3 receptor antagonists, dopamine antagonists (especially metoclopramide) were used to treat emesis from highly emetogenic chemotherapy regimens. Use of dopamine antagonists is limited by antidopaminergic side effects,2 including extrapyramidal reactions, anxiety, and depression. The effectiveness of metoclopramide, which is due to both antidopaminergic and antiserotonergic actions, led to the development of 5-HT3 receptor antagonists specifically for the treatment of emesis.2 Cannabinoids are effective in patients receiving moderately emetogenic chemotherapy, although serious side effects (including dysphoria, hallucinations, sedation, and disorientation) limit their use.2 A relatively new treatment option are the NK-1 antagonists, with aprepitant as the only agent in this class with FDA approval. As single agents, NK-1 antagonists are less effective than serotonin receptor antagonists in preventing acute emesis. However, when combined with serotonin receptor antagonists, they appear to be effective in delayed emesis.3 Gralla RJ, Osoba D, Kris MG et al. Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. J Clin Oncol. 1999;17:2971-2994. 2. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med. 1993;329: 1790-1796. 3. Hesketh PJ. Potential role of NK1 receptor antagonists in chemotherapy-induced nausea and vomiting. Support Care Cancer . 2001;9:350-354.
  • Emend is a moderate CYP3A4 inhibitor and should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride.Inhibition of cytochrome CYP450 isoenzyme 3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. Due to the small number of patients in clinical studies who received the CYP3A4 substrates docetaxel, vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied. Coadministration of Emend with warfarin may result in a clinically significant decrease in INR or prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of Emend with each chemotherapy cycle. Oral dexamethasone doses should be reduced by approximately 50% when coadministered with Emend, to achieve exposures of dexamethasone similar to those obtained when it is given without Emend. Reference 1. Emend ® (aprepitant) [package insert]. Whitehouse Station, NJ; Merck & Co, Inc: March 2003.
  • ITT populationP value comparing two groups calculated by one-sided Cochran-Mantel-Haenszel test stratifed by centres P values P overall 0.478 Acute 0.573 Delayed 0.250
  • Overall p 0.429 Acute 0.583 Delayed 0.077
  • Currently, guidance is emerging for women with early-stage breast cancer receiving aromatase inhibitor (AI) therapy A recent publication by Moy et al (2007) recommends Treatment for patients with T-score < –2.0 Consideration of bisphosphonate therapy for patients with T-score –1.5 to –2.0 (osteopenic) based on additional risk factors Annual bone mineral density (BMD) screening for patients with T-score –1.0 to –1.5 A recent abstract by Aapro et al (2007) Presented a literature review study to identify factors contributing the increased fracture risk Using an evidence-based medicine approach, among patients with breast cancer, risk factors were assessed to identify patients who may benefit from bisphosphonate therapy Risk assessments were recommended for patients with or without BMD T-scores

Transcript

  • 1. Sunday, 3 April
    • Supportive care
    • Chair: Lena Sharp
    • 15:00-15:45
    • Fatigue management
    • Agnes Glaus
    • 15:45-16:30
    • Antiemetics, growth factors, bone health
    • Matti Aapro
  • 2. Matti S. Aapro IMO Clinique de Genolier 1272 Genolier Switzerland Joint medics and nurses spotlight session ERMATINGEN ESO MASTERCLASS April 3, 2011, 15:00-16:30 Supportive care around cases Antiemetics, growth factors, bone health
  • 3. COI Dr Aapro is a consultant for Amgen, BMS, Celgene, GSK, Helsinn, Novartis, Merck, Merck Serono, Pfizer, Pierre Fabre, Roche, Sandoz, Vifor and has received honoraria for lectures at symposia of Amgen, Bayer Schering, Cephalon, GSK, Helsinn, Hospira, JnJ OrthoBiotech, Merck, Merck Serono, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, Sanofi Aventis, Vifor
  • 4. COI Dr Aapro is a consultant for Amgen, BMS, Celgene, GSK, Helsinn, Novartis, Merck, Merck Serono, Pfizer, Pierre Fabre, Roche, Sandoz, Vifor and has received honoraria for lectures at symposia of Amgen, Bayer Schering, Cephalon, GSK, Helsinn, Hospira, JnJ OrthoBiotech, Merck, Merck Serono, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, Sanofi Aventis, Vifor
  • 5. FOR MORE INFORMATION www.mascc.org www.afsos.org
  • 6.
    • Supportive Care is the prevention and management of the adverse effects of cancer and its treatment.
    • This includes physical and psychosocial symptoms and side effects across the entire continuum of the cancer experience including the enhancement of rehabilitation and survivorship.
    Definition of Supportive Care
  • 7. Importance of Supportive Care
    • Allows patients to tolerate and benefit from active therapy more easily
    • Alleviates symptoms and complications of cancer
    • Reduces or prevents toxicities of treatment
    • Supports communication with patients about their
    • disease and prognosis
    • Eases emotional burden of patients and care givers
    • Helps cancer survivors with psychological and social
    • problems
  • 8. SOME AREAS OF SUPPORT
    • Febrile N… : but are MASCC guidelines applied?
    • Hairloss : remains an issue
    • Depression : underdiagnosed
    • Nausea/V : MASCC guidelines
    • Wbc’s : EORTC guidelines
    • Anemia : EORTC guidelines
    • Diarrhea : guidelines exist
    • Mucositis : MASCC guidelines
    • AIBL /CTIBL : Expert opinions 2011
    • Pain : « WHO guidelines »: but morphine is still not available worldwide!
    • etc etc ( elderly; palmo-plantar dysesthesia; skin toxicity )
  • 9. Chosen chapters in Supportive Care G-CSF Antiemetics Bone Health
  • 10. The Facts
    • and my thoughts…
  • 11. CASE ANNA
    • Anna is a healthy 68 years old patient with a history of recurrrent urinary tract infections. She is diagnosed with triple-negative breast cancer T2 N1(3/17)MO. Adjuvant therapy with docetaxel / cyclophosphamide is planned. What do you suggest?
      • Pegfilgrastim prophylaxis of FN
      • Filgrastim/lenograstim prophylaxis
      • Either one combined with a fluoroquinolone
      • No primary prophylaxis
      • Other choice
  • 12. G-CSF
    • Chemotherapy for cancer causes febrile neutropenia (FN ) in rare or frequent cases
    • FN is a high-risk situation for some and specially elderly patients
    • Elderly patients are at higher risk of FN
  • 13. Updated Guidelines: 2011
  • 14. PROPHYLACTIC APPROACH, NOT A REACTIVE ONE 2010 additions
  • 15.
    • Pegfilgrastim + Ciprofloxacin
    • for TAC chemotherapy
    3 cases of typhlitis with G/Peg, none on peg+cip
  • 16. Impact of prophylactic G-CSF in chemotherapy induced toxicity (TARGET 0) Martin M et al. Ann Oncol. 2006 Aug;17(8):1205-12 . Prophylactic G-CSF Febrile neutropenia Grade 3 – 4 asthenia Grade 3 – 4 mucositis Grade 3 – 4 diarrhoea NO 23.9% 21.1% 6.4% 6.4% YES 3.5% 3.5% 2.6% 0.9%
  • 17. CAN WE DO BETTER?
  • 18. G-CSF supportive therapy reduces mortality: HR: 0.897 (95% CI, 0.8 57 to 0.9 38 ; p < 0 .001) Lyman GH et al. J Clin Oncol 2010;28:2914–2924
    • Greater mortality
    • reduction in:
    • larger trials
    • greater RDI
    • dose-dense chemo
    • More secondary
    • AML and MDS
    • RR: 1.92
    • AR: 0.41%
  • 19. And if FN hits?
  • 20. CASE ANNA
    • Anna is a healthy 68 years old patient with a history of recurrrent urinary tract infections. She is diagnosed with triple-negative breast cancer T2 N1(3/17) MO. Adjuvant therapy with docetaxel / cyclophosphamide is planned. What do you suggest?
      • Pegfilgrastim prophylaxis of FN
      • Filgrastim / lenograstim prophylaxis
      • Either one combined with a fluoroquinolone
      • No primary prophylaxis
      • Other choice
  • 21. CASE BIRGIT
    • Birgit is a 46 years old patient diagnosed with endocrine-responsive ( ER 50% PgR 30) G3 Ki 67 30% HEr-2 neg (FISH) breast cancer T2 N0 MO. Adjuvant therapy with doxorubicin / cyclophosphamide followed by a taxane is planned. What do you USE as an acute-phase antiemetic
      • Aprepitant + setron + corticosteroid
      • Palonosetron + corticosteroid
      • Setron + corticosteroid
      • Metoclopramide ( or similar ) + corticosteroid
      • Other choice
  • 22. ANTIEMETICS
    • Nausea and vomiting (N/V) due to chemotherapy are unacceptablen in the XXI century
    • Patients are at risk of renal and other complications in case of N/V
  • 23. Perceptions and Reality - Underestimation of emesis with chemotherapy - 34 17 24 15 35 13 52 28 0 20 40 60 80 100 Acute Nausea Acute Vomiting Delayed Nausea Delayed Vomiting Percent of Patients MD/RN prediction Patient experience
    • Physicians and nurses from 14 oncology practices in 6 countries
    • Patients: 75% women; 78% Mod emetic chemo; 50% breast cancer; 18% lung cancer
    Grunberg et al. (2004). Cancer, 100, 261-268
  • 24. Neurotransmitters/Treatments Associated With Emesis Emetic reflex GABA Histamine Endorphins Acetylcholine Dopamine/ DA RAs Serotonin/ 5-HT 3 RAs Cannabinoids Substance P/ NK-1 RAs DA = dopamine; GABA = gamma-aminobutyric acid; NK = neurokinin; RAs = receptor antagonists.
  • 25.  
  • 26. ANTIEMETIC GUIDELINE CONSENSUS - Official Process Subscribed to by many International Oncology Groups - www.mascc.org Updated 2010 corrections to come AND Ann Oncol 2010; Supplt 5: v232-v243 AND JSCC 2011
  • 27. ACUTE NAUSEA AND VOMITING / MODIFIED AAPRO 5HT3 DEX APR 5HT3 DEX APR PALO DEX DEX + + + + + 5HT3 = serotonin receptor antagonist DEX = DEXAMETHASONE APR= APREPITANT PALO = PALONOSETRON 5HT3 DEX APR 5HT3 DEX APR PALO DEX DEX NB: IF APREPITANT IS NOT USED IN AC CHEMO, PALO IS THE PREFERRED 5HT3RA The Antiemetic Subcommittee of The Multinational Association of Supportive Care in Cancer. Ann Oncol 2010; www.mascc.org. EMETIC RISK GROUP ANTIEMETICS High + + Anthracycline + Cyclophosphamide (AC) + + Moderate (other than AC) + Low Minimal No routine prophylaxis
  • 28. SUMMARY DELAYED NAUSEA AND VOMITING 5HT3 DEX APR 5HT3 DEX APR PALO DEX DEX + + + + + DEX = DEXAMETHASONE APR= APREPITANT DEX APR APR DEX *or dex if aprepitant not used in acute phase. The Antiemetic Subcommittee of The Multinational Association of Supportive Care in Cancer. Ann Oncol 2010; www.mascc.org. DEX EMETIC RISK GROUP ANTIEMETICS High + Anthracycline + Cyclophosphamide (AC) or* Moderate (other than AC) Low No routine prophylaxis Minimal No routine prophylaxis
  • 29. Aprepitant Drug Interactions
    • Should not be used
    • concomitantly with
    • Pimozide
    • Terfenadine
    • Astemizole
    • Cisapride
    • Caution with
    • Docetaxel
    • Vinblastine
    • Vincristine
    • Ifosfamide
    • other chemotherapy agents metabolized primarily by CYP3A4 that were not studied: oral vinorelbine; trabectedin
    Based on nd modifying Aprepitant package insert 2008
    • Oral dexamethasone dose should be decreased by 50% when administered with aprepitant
    • Prothrombin time and INR may be decreased when warfarin is administered concomitantly with aprepitant
    Not far from grapefruit juice or clarithromycin Review by Aapro and Walko, Annals of Oncology, 2010
  • 30. Potential Side Effects of Dexamethasone
  • 31. M. Aapro, A. Fabi, F. Nolè, M. Medici, G. Steger, C. Bachmann, S. Roncoroni, and F. Roila Double-blind, randomised, controlled study of the efficacy and tolerability of palonosetron plus dexamethasone for 1 day with or without dexamethasone on days 2 and 3 in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy Ann Oncol (2010) 21(5): 1083-1088 See also Celio et al, J Supp Care, 2010
  • 32. Study Design Study description: Non-inferiority, double-blind, randomized, multicenter trial Patients: Na ï ve breast cancer patients scheduled to receive AC/EC (n=300, ITT) Treatment scheme: Aapro M et al. Annals of Oncology 2010 Day 1 Day 2 Day 3 PALO Palo 0.25mg IV + Dex 8 mg IV Placebo Placebo PALO + DEX Palo 0.25mg IV + Dex 8 mg IV Dex 4 mg po bid Dex 4 mg po bid
  • 33. Results: Complete Response (No emesis, no rescue medication) Complete Response (% of Patients) ns 53.6 69.5 62.3 53.7 68.5 65.8 0 10 20 30 40 50 60 70 80 90 Overall (0-120 hrs) Acute (0-24 hrs) Delayed (24-120hrs) Primary endpoint ns ns PALO+DEX d1+placebo (d2-3) PALO+DEX d1-3 Aapro M et al. Annals of Oncology 2010
  • 34. Quality of Life… impact of CINV on daily life Mean FLIE score (Range 18-126) 119.4 105.1 20 30 40 50 60 70 Pre-treatment 120.0 105.8 Overall (Day 1-5) Functional Living Index (FLIE) – questions 1-18, score range 18-126 high score indicates better functional situation 80 90 100 110 120 130 PALO+DEX d1+placebo (d2-3) PALO+DEX d1-3 Aapro M et al. Annals of Oncology 2010
  • 35. A LOOK INTO THE FUTURE THIS IS NOT (YET?) A RECOMMENDED USE OF THE AGENTS….
  • 36. Evaluation of Fosaprepitant in Single Dose Schedule (NCT00619359)
    • Experimental Arm
      • Fosaprepitant 150 mg Day 1 IV
      • Ondansetron 32 mg Day 1 IV
      • Dexamethasone 12 mg Day1, 8 mg Day 2, 8 mg bid Days 3-4 PO
    • Active Comparator
      • Aprepitant 125 mg Day 1, 80 mg Days 2-3 PO
      • Ondansetron 32 mg Day 1 IV
      • Dexamethasone 12 mg Day 1, 8 mg Days 2-4 PO
    Grunberg, Proc ASCO 2010, Abst 9021
  • 37. Ondansetron/Dexamethasone + NK-1 Antagonist for Cisplatin-Induced Emesis Grunberg, Proc ASCO 2010, Abst 9021 in press Warr et al JCO 2011
  • 38. CASE BIRGIT
    • Birgit is a 46 years old patient diagnosed with endocrine-responsive ( ER 50% PgR 30) G3 Ki 67 30% HEr-2 neg (FISH) breast cancer T2 N0 MO. Adjuvant therapy with doxorubicin / cyclophosphamide followed by a taxane is planned. What WOULD YOU USE PER GUIDELINES as an acute-phase antiemetic ( assume all agents are available )
      • Aprepitant + setron + corticosteroid
      • Palonosetron + corticosteroid
      • Setron + corticosteroid
      • Metoclopramide ( or similar ) + corticosteroid
      • Other choice
  • 39. CASE CHIARA
    • Chiara is a 71 years old patient who exercises daily AND smokes a pack/day. She has endocrine-responsive ( ER 50% PgR 30) G2 Ki 67 15% HEr-2 neg (FISH) breast cancer T1 N0 MO. Adjuvant therapy with an aromatase inhibitor is planned and her BMD score is T-1.8. What would you suggest (assume there is no restriction)
      • Calcium + vitD + bisphosphonate / denosumab
      • Calcium + vitD
      • Calcium + vitD + zoledronic acid every 6 months
      • Use tamoxifen
      • Tamoxifen +Calcium + vitD + oral bisphosphonate
  • 40. UPDATE PLANNED FOR 2010
  • 41. BONE
    • Osteopenia/osteoporosis is prevalent among many male and femal cancer patients
    • Bisphosphonates (BPs) and denosumab are established agents for supportive care in case of bone metastases
    • BPs might be more than supportive care?
    • ( on going studies with denosumab )
  • 42. ABCSG-12 (62 mo) Time since randomization, months Disease-free survival, % ZOL vs no ZOL First event per patient, n ZOL NO-ZOL HR = 0.68 P = 0.008 Median follow-up = 62 mo Gnant M, et al. J Clin Oncol 28:15s, 2010 (suppl; abstr 533). No-ZOL (110 events) vs. ZOL (76 events) Absolute Difference = 34 56 7 16 2 29 (n = 903) No ZOL (n = 900) ZOL Death without prior recurrence Secondary malignancy Contralateral breast cancer Distant recurrence Locoregional recurrence 100 90 80 70 60 50 40 30 20 10 0 12 24 36 48 60 72 84 96 108 0 120 100 80 60 40 20 0 44 6 11 0 15
  • 43. ZO-FAST: Disease-free Survival 9.2 Eidtmann H, et al. Presented at: 31st Annual SABCS; December 10-14, 2008; San Antonio, TX. Abstract 44. Coleman RE, et al. Presented at 32 nd Annual SABCS; December 9 - 13, 2009; San Antonio, TX. Abstract 4082. – 13% – 35% – 40% P = .0314 – 41% P = .0175 2.8 3.9 4.9 5.5 3.2 6 8.1 0 1 2 3 4 5 6 7 8 9 10 12 months 24 months 36 months 48 months Patients with DFS events, % Immediate ZOL Delayed ZOL
  • 44. Evolving Treatment Strategies for Hormone-Responsive Breast Cancer Note that these are cross-trial comparisons of disease recurrence risks. TAM, tamoxifen; LET, letrozole; ZOL, zoledronic acid. 1. EBCTCG. Lancet. 1998;351:1451-1467; 2. Coates A, et al. J Clin Oncol . 2007;25:486-492; 3. Coleman R, et al. Presented at: SABCS 2009. Abstract 4083. EBCTCG meta-analysis of adjuvant TAM trials 10-yr data 1 BIG 1-98 Monotherapy analysis 51-mo data 2 ZO-FAST Uncensored analysis 48-mo data 3 Risk of breast cancer recurrence, % 47% risk reduction with 5 years of TAM Additional 18% risk reduction with LET Additional 41% risk reduction with ZOL No adjuvant therapy TAM for 5 years P < .00001 P = .007 P = .0175 N = 30,000 N = 4,922 N = 1,060 0 10 20 30 40 LET for 5 years LET + upfront ZOL
  • 45. Myeloma IX (MRC) – ZOL Improved OS and PFS vs CLO a
    • ZOL significantly reduced the relative risk of death by 16% vs CLO (HR = 0.842; 95% CI = 0.736, 0.963; P = .0118)
    • Median survival improved by 5.5 months (50 vs 44.5 months)
    Abbreviations: CLO, clodronate; OS, overall survival; PFS, progression-free survival; ZOL, zoledronic acid. a Cox model adjusted for chemotherapy, and minimization factors. Risk reduction Hazard ratio (ZOL versus CLO) 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 P value .0118 0.842 16% In favor of ZOL In favor of CLO OS .0179 12% 0.883 PFS Morgan GJ, et al. J Clin Oncol 28:15s, 2010 (suppl; abstr 8021).
  • 46. AZURE: Adjuvant Zoledronic Acid RedUces REcurrence in Breast Cancer
    • Primary endpoint : Disease-free survival
    • Secondary endpoints : Bone-metastases-free survival (BMFS), SREs, overall survival (OS), predictive biomarkers
    Standard therapy Standard therapy Zoledronic acid 4 mg 6 doses (q 3-4 weeks) 8 doses (q 3 months) 5 doses (q 6 months)
    • 3,360 patients Breast cancer Stage II/III Stratification:
    • N + /N –
    • T-score
    • ER status
    • Adj. Syst. Therapy
    • Pre- / Postmenopausal
    • Statins
    R Follow-up without treatment: 5 years for recurrence and survival Treatment duration 5 years SREs = Skeletal-related events; R = Randomization; ER = Estrogen receptor. ClinicalTrials.gov Identifier NCT00072020.
  • 47. Neoadjuvant AZURE: Exploratory Analysis of Residual Invasive Tumor Size Adjusted Median RITS ( mm) P = 0.006 Patients achieving pCR, % CT CT CT + ZOL CT + ZOL Relative  44%  ~ 2 Fold 0 5 10 15 20 25 0 5 10 15 20 25 30 CT alone CT + ZOL 15.5 Multivariate analysis N = 205. RITS, residual invasive tumor size; CT, chemotherapy; ZOL, zoledronic acid; pCR, pathologic complete response Coleman, RE, et al. Br J Cancer . 2010 Mar 30;102(7):1099-105. 6.9 11.7 27.4
  • 48. AZURE: Disease (DFS) and Invasive Disease Free Survival (IDFS) DFS 100 0 IDFS % % 100 0 ZOL: CONT: ZOL: CONT: 0 1 2 3 4 5 6 7 20 40 60 80 TIME (YEARS) Zoledronic acid: N= 1681 No. at risk: 1681 1591 1465 1354 1243 580 83 1678 1583 1445 1344 1252 561 71 Control: N= 1678 Adjusted HR = 0.98 95% CI [0.85,1.13] p=0.79 1 2 3 4 5 6 7 20 40 60 80 TIME (YEARS) Zoledronic acid N= 1681 No. at risk: 1681 1578 1443 1337 1224 570 82 1678 1574 1426 1316 1221 544 68 Control N= 1678 Adjusted HR = 0.98 95% CI [0.85,1.12] p=0.73
  • 49. AZURE Treatment Effect* on DFS By Menopausal Status Typical Odds Ratio Menopausal Group Description Pre + < 5 years post + unknown <60 years >5 years postmenopausal + >60 years Total: 0% +/- 7% Z = .07; P = .95  2 1 (heterogeneity) = 10.23; P = .001 Odds Reduction (+/- S.D)
    • 1.2 1.4 1.6 1.8 2.0
    0.2 0.4 0.6 0.8 *Adjusted For Imbalances In ER, Lymph Node Status and T Stage) N = 1101 263 events N = 2258 489 events
  • 50. AZURE: Overall Survival by Menopausal Status Pre, peri and unknown menopausal status % Surviving 100 0 0 ZOL: CONT: >5 years post-menopausal or age > 60 ZOL: CONT: 0 0 1 2 3 4 5 6 7 20 40 60 80 TIME (YEARS) Zoledronic acid N= 1131 No. at risk: 1131 1101 1051 993 932 454 70 1127 1096 1049 1007 940 432 58 Control N= 1127 Adjusted HR = 1.01 95% CI [0.81,1.26] p=0.93 157 vs 156 deaths 1 2 3 4 5 6 7 20 40 60 80 TIME (YEARS) Zoledronic acid N= 550 No. at risk: 550 532 509 475 448 202 30 551 536 502 466 424 191 28 Control N= 551 Adjusted HR = 0.71 95% CI [0.54,0.94] p=0.017 86 vs 120 deaths
  • 51. Denosumab in Early Adjuvant BC: ABCSG-18 & D-CARE Trials
    • ABCSG-18 :
    • Primary Endpoint : Rate of 1 st clinical fracture
    • Secondary Endpoints : Bone metastasis-free survival (B MFS), DFS, OS
    Placebo SC q6 mo Dmab 60 mg SC q6 mo 3,460 EBC pts R Study duration: 96 months
    • D-CARE:
    • Primary Endpoint : Bone metastasis-free survival
    Placebo 120mg SC monthly x 6 mo, q 3 mo for 4.5 yrs Dmab 120mg SC monthly x 6 mo, q 3 mo for 4.5 yrs 4,500 EBC pts R Treatment duration 5 yrs http://www.abcsg.org/trials/trial18.html, http://clinicaltrials.gov/ct2/show/NCT01077154?term=d-care&rank=1
  • 52. Published Guidance UPDATE TO APPEAR 2011 discusses limitations of FRAX, BPs and SURVIVAL and data on other agents than BPs
  • 53. T-score < –2.0
    • Any 2 of the following risk factors:
    • T-score < –1.5
    • Age > 65 years
    • Low BMI (< 20 kg/m 2 )
    • Family history of hip fracture
    • Personal history of fragility fracture after age 50
    • Oral corticosteroid use of > 6 months
    • Smoking (current and history of)
    T-score ≥ –2.0, No risk factors Monitor risk status and BMD at 1 year Bisphosphonate* calcium and vitamin D supplements EXERCISE Monitor BMD …every 1-2 years if oral BPs Calcium and vitamin D supplements EXERCISE *≥ 10% drop in BMD (4-5% if osteorotic ) should trigger treatment. Use lowest T-score from 3 sites. Adapted from Hadji P, et al. in press Annals of Oncology 2011 Recommendations for Women With Breast Cancer Initiating AI Therapy (updated in press 2011 )
    • *DENOSUMAB is a potential option for some patients. Oral health precautions needed for BPs and denosumab
  • 54. CASE CHIARA
    • Chiara is a 71 years old patient who exercises daily AND smokes a pack/day. She has endocrine-responsive ( ER 50% PgR 30) G2 Ki 67 15% HEr-2 neg (FISH) breast cancer T1 N0 MO. Adjuvant therapy with an aromatase inhibitor is planned and her BMD score is T-1.8. What would you suggest (assume there is no restriction)
      • Calcium + vitD + bisphosphonate / denosumab
      • Calcium + vitD
      • Calcium + vitD + zoledronic acid every 6 months
      • Use tamoxifen
      • Tamoxifen +Calcium + vitD + oral bisphosphonate
  • 55. SUPPORTIVE CARE IN CANCER 24th International Symposium MASCC/ISOO AVEC SÉANCE AFSOS June 23-25, 2011 ATHENS Greece www.mascc.org
  • 56.