Supportive Care Spotlight - Antiemetics, Growth Factors, Bone Health
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Supportive Care Spotlight - Antiemetics, Growth Factors, Bone Health
- 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
- 9. Chosen chapters in Supportive Care G-CSF Antiemetics Bone Health
- 14. PROPHYLACTIC APPROACH, NOT A REACTIVE ONE 2010 additions
- 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?
- 19. And if FN hits?
- 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.
- 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
- 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….
- 37. Ondansetron/Dexamethasone + NK-1 Antagonist for Cisplatin-Induced Emesis Grunberg, Proc ASCO 2010, Abst 9021 in press Warr et al JCO 2011
- 40. UPDATE PLANNED FOR 2010
- 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
- 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
- 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
- 52. Published Guidance UPDATE TO APPEAR 2011 discusses limitations of FRAX, BPs and SURVIVAL and data on other agents than BPs
- 55. SUPPORTIVE CARE IN CANCER 24th International Symposium MASCC/ISOO AVEC SÉANCE AFSOS June 23-25, 2011 ATHENS Greece www.mascc.org
Notes de l'éditeur
- 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