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Le emergenze oncologiche, la terapia di supporto e la qualità di vita

L’ASSISTENZA ONCOLOGICA NELLE PICCOLE ISOLE ATTESE, RISORSE, CRITICITÀ . Le emergenze oncologiche, la terapia di supporto e la qualità di vita La gestione dei sintomi ( anemia, neutropenia , nausea ) . F. Tomao Università Sapienza –Roma-. Supportive Care. 1960.

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Le emergenze oncologiche, la terapia di supporto e la qualità di vita

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  1. L’ASSISTENZA ONCOLOGICA NELLE PICCOLE ISOLE ATTESE, RISORSE, CRITICITÀ Le emergenze oncologiche, la terapia di supporto e la qualità di vita La gestione dei sintomi (anemia, neutropenia, nausea) F. Tomao UniversitàSapienza –Roma-

  2. Supportive Care 1960 Dott. Cecily Sanders “Treatment administered with the intent to maximize quality of life without a specific antineoplastic regimen,” (antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, nutritionalsupport, and focal external-beam radiation for control of pain, cough, dyspnea, or hemoptysis) Jassem et al. J Clin Oncol 2008

  3. Supportive Care Toxicity Targets • Neurologic • Peripheral neuropathy • Cognitive • Pulmonary • Renal • Cutaneous • Alopecia • Rash • Hematologic • Myelosuppression • Gastrointestinal • Nausea/vomiting • Constipation/diarrhea • Mucositis • Cardiovascular • Thrombosis • Cardiac

  4. Anemia Hgb < 14g/dl Hgb < 12g/dl

  5. Anemia in cancerpatients: the ECAS study Prospectivestudy 15.367 pts 748 cancer centres, 24 countries Hgb <12.0 g/dl=49.1% Ludwig et al. Eur.J.Cancer 2004

  6. Causes and Effects of Cancer – related Anemia Causes Effects • Disease – relatedfactors1 • Folate, Vit B12, Iron deficiency1 • Anemia of chronic disease1 • Chemotherapy1 • Decrease in QOL2,3,4 • Increase in transfusion rates5 • Probabledecrease in survival6,7,8 1- Grotto, MedOncol, 2008; 2- Gabrilove, JCO 2001; 3- Littlewood, JCO 2001; 4- Cella D. AnnOncol, 2003; 5-Benoist S., Surgery, 2001; 6- Caro, Cancer2001; 7- Waters, JCO 2002; 8- Fuso L. GynecolOncol 2005

  7. Incidence of anemia associated with chemotherapeutic agents and regimens

  8. Treatments for Anemia • Transfusions • ESAs • Non ESAs: • - Fe++ • - Lattoferrina • Dietarysupplementation

  9. Benefits and Risks of RBC Transfusions Quick enhancement of HB level: 1 U of RBC (circa 300 cc) 1/g/dLicrease in 1 hour • Graft-versus-host disease • Transfusion Related • Acute Lung Injury (TRALI) • Non emolitic fever related • Reactions • Acute Emolisis • Allergy • Anafilaxis • More peri-operative infections • Infectious (HIV, HBV, HCV, HTLV West Nile, Bacteria) • More relapses • Worst prognosis Upile, T, et al. Clinical Advances in Hematology & Oncology, 2009

  10. Use of ESAs in cancerpatients BLOOD TRASFUSION RATE: ESAs significantly reduced the RR of RBC transfusions (RR 0.64; 95% CI 0.60 to 0.68, 42 trials, n = 6,510). Pubmed Bohlius J et al. Cochrane Database Syst Rev, 2006

  11. rHuEPOs Bunn H.F., Blood, 2007; DeicherR. et al., Drugs, 2004; Osterborg, bjh, 2007; Llop E. et al., AnalyticalBiochemistry, 2008

  12. Use of ESAs in cancerpatients Epo 12 Transfusion 10 Hb (g/dl) 8 6 transfusions 4 0 30 60 90 120 150 180 210 Österborg. MedOncol 1998; 15 (Suppl 1): S47–9 Ludwig et al. N Engl J Med 1990; 322: 1693–9

  13. ESAs: improvement in CRF. Studies with FACT F. Haemopoetic growth factors versus no intervention. Minton O et al. Cochrane Database Syst Rev 2008

  14. “Isitall over for erythropoietin?” • The role of erythropoietinreceptors on the tumourcell surface • Risk of Thromboembolicevents Burton A., Lancet Oncology, 2007; Murat O. Arcasoy, ClinCancer Res, 2008

  15. ESAs and prognosis Survival, Tumor Progression, TVE* BEST 2005‡ ENHANCE 2003‡ EPO-CAN-20 2007‡ PREPARE 11/07† 20000161 4/05, 4/07† 20010103 1/07† GOG-191 2007† DAHANCA 12/06† *8 trials selected by FDA for label inclusion out of 57 total, ‡ publication date, † = date data reported to FDA HR for mortality significantly higher for patients with cancer who were treated with ESA vs the control (placebo) group (HR, 1.10; 95% CI, 1.01-1.20;P=.03) Bennett CL et al, JAMA, 2008

  16. ESA treatment in cancer patients increased on study mortality and worsened overall survival. • For patients undergoing chemotherapy the increase was less pronounced, but an adverse effect could not be excluded. cHRfor on study mortality for OS: 1.17 (95% CI 1.06-1.30) 1.10 (95% CI 0.98-1.24) and 1.04; 95% CI 0.97-1.11) in ptsreceiving CT. 53 trials BohliusJ et al., Cochrane Database SystRev, 2010

  17. 91 trials 20102 patients • ESAs increase mortality HR1.17 (CI 1.06 to 1.29) • ESAs decrease overall survival HR 1.05 (CI 1.00 to 1.11) • ESAsIncreaseRisk ratio for thromboembolicomplications RR 1.52(CI 1.34 to 1.74) • ESAs may also increase risk for hypertension RR 1.30 (CI 1.08 to 1.56) and thrombocytopenia/haemorrhage RR 1.21 (CI 1.04 to 1.42) • Insufficient evidence to support an effect of ESA on tumour response Bohlius J et al., Cochrane Database Syst Rev, 2012

  18. 91 trials 20102 patients • BIAS • Tumorsetherogemeity • Hb <8 g/dl ~ 6% • Hb 8-9.9 g/dL~ 30% • Hb 10-11.9 g/dL~ 40% • Hb 12-14g/dL~ 22% • Hb > 14 g/dl ~ 6% • 65% studiesonly CT (10 % no RT • no CT) • Doses and times of administration • outlabel • ESAs increase mortality HR1.17 (CI 1.06 to 1.29) • ESAs decrease overall survival HR 1.05 (CI 1.00 to 1.11) • ESAsIncreaseRisk ratio for thromboembolicomplications RR 1.52(CI 1.34 to 1.74) • ESAs may also increase risk for hypertension RR 1.30 (CI 1.08 to 1.56) and thrombocytopenia/haemorrhage RR 1.21 (CI 1.04 to 1.42) • Insufficient evidence to support an effect of ESA on tumour response Bohlius J et al., Cochrane Database Syst Rev, 2012

  19. 2010 • - 60 studiesanalized, 15323 patients • - SETTING: chemotherapy/radiochemotherapy, radiotherapy only treatment or • anemia for cancer • MORTALITY : OR 1.06 • DISEASE PROGRESSION : OR 1.01 • RISK OF VENOUS TROMBOEMBOLIC EVENTS: OR: 1.48 No significant effect of ESAs on survival or disease progression Glapsy J et al, Br J Cancer. 2010

  20. GOG STUDY Citokine use and survival in the first line treatment of ovariancancer 1864 pts This study do not support existing literature which suggests that ESA or G-CSF use may be associated with adverse ovarian cancer progression and death

  21. Study-levelmeta-analysis - 9 studies - 2342 ptsreceving CT Mortality OR 0,87 (CI 0.63-1.09) Mortalityriskdifference-0,02 ( CI -0,06-0,04) Diseaseprogression0,84 (CI 0,65-1.09) Trasfusionincidence0,34 (CI 0,28-0.41) J. Vansteenkiste et al. / Lung Cancer 76 (2012)

  22. …and what about iron supplementation? Not rigorously applied because…. False perception that cancer patients do not have decreased iron stores(as measured by serum ferritin) and thus the belief that they do not to require iron supplementation also during ESA therapy; Failure to appreciate the relative blockade in access to storage iron pools or dietary iron that frequently exists in patients with chronic inflammatory illnesses such as cancer; Misinformationand misinterpretation of the incidence and clinical nature of serious adverse events of iv iron. Pedrazzoli P et al, Cancer 2009

  23. Ironi.v.: another way to treat cancer-related anemia Cervicalcancerpatients undergoingconcurrentChemoradiotherapy P = 0.04 P = 0.04 Kim YT et al., GynecolOncol, 2007

  24. ESAs-Ironsupplementation • Hb105 g/L, • Serum ferritin 450 pmol/L or 675 pmol/L • Transferrin saturation 19% 157 PTS No-iron Oral iron 325 mg twice daily Iron dextran repeated 100mg IV bolus Iron dextran total dose infusion (TDI). rHuEPO 40,000 U once weekly to > Hb level < Non responders Auerbach M et al, JCO 2004

  25. Ironsupplementation: oral vs iv Plus Darbopoetin 502 Pts Addition of IV ferric gluconateto darbepoetinfailed to provide additional benefitcompared with oral iron or oral placebo. Steensma DP et al, JCO 2011

  26. 149 Pts P = .0033 In patients with chemotherapy-related anemia and no iron deficiency, IV iron supplementation significantly reduces treatment failures to darbepoetin without additional toxicity. PedrazzoliP et al., JCO 2008

  27. Functionalirondeficiency (FID)or Absolute irondeficiency 30-50 % pts treated by ESAs are non-responders: Dysregulationof iron metabolism TSAT:10-20%; Ferritin < 800 ng/ml FID: imbalance between iron needs in the erythropoietic bone marrow and iron supply (ESAs) Absolute iron deficiency: lower absorption, constitutional defects TSAT<10%; Ferritin < NV IRON STATUS Pedrazzoli P et al, Cancer 2009

  28. Guidelines • ESA treatment may improve fatigue or QOL • Goalof ESA therapy for patients with CIA is to reduce RBC transfusion requirements. • In patients treated with chemotherapy and an Hb level of <10 g/dl, with target Hb ≤12 g/dl. • ESAs should notbe given to patients who are being treated for cancer when the goal is to curethe patients (of cancer). • ESAs have been found to shorten overall survivaland cause thromboembolism (always informed consent). • ESAs should not be given in patients who are not receiving CT o who are receiving RT

  29. Guidelines • IV iron products alone (without an ESA) are recommended for iron repletion in patients with cancer with absolute iron deficiency (ferritin < 30 ng/mL, transferrin saturation < 15%). • ESAsshould be used in addition to iv iron for patients with CIA and functional iron deficiency (no data about IV iron alone) • There are no evidences about a real efficacy of oral iron supplementation. • There are no data about the effects of adequate diet on anemia and prognosis of cancer patients.

  30. NEUTROPENIA Rarely neutropenia isassociated with fever…. NF • Absoluteneutrophilcountoflessthan 500 cells per cubicmillimeter and a temperature of more than 38.5° C. • More than 60,000 pts are admittedfor the treatment of FN annually, or 8cases per 1000 patientsreceivingcancer CT. Overall, in-hospital mortality was 9.5%. Mean (median) length of stay was 11.5 days, and the mean (median) cost was $19,110 ($8,376) per episode of FN. ASCO 2006/ AIOM 2009 Guidelines

  31. Fever in Neutropenicpatients ETIOLOGY IN CANCER 21% 39% 35% 5% Picazo J, Int J Hematol 1998

  32. Neutropenia in CT regimens Review of Literature

  33. STIMULATING FACTOR GM-CSF (granulocyte-macrophagecolony- stimulatingfactor) G-CSF (granulocytecolony- stimulatingfactor): • Filgrastim: Granulokine, Neupogen • Lenograstim(glycosilated): Granocyte, Myelostim, Refludan • Pegfilgrastim (filgrastimpegilated): Neulasta, Neupopeg Bennett CL et al, NEJM 2013

  34. G-CSF: Management PRIMARY PROPHYLAXIS THERAPEUTIC USE SECONDARY PROPHYLAXIS Post-CT, BEFORE NEUTROPENIA Post-CT in patients with PREVIOUS EVENT of NF in another CT cycle

  35. PrimaryProphylaxis with G-CSF 17 RCT 3.493 Pts “Previousstudies and guidelineshaveconcludedthatmyeloidgrowthfactors are lesseffectiveifadministered on the samedayaschemotherapy, delayed more than 4 daysafterchemotherapy, or delayeduntil the onset of neutropenia” Kuderer, JCO 2007

  36. Primary Prophylaxis with G-CSF: WHEN? RISK CATHEGORIES G-CSF CT with risk of expected FN ≥ 20% ALWAYS USE IF OTHERS RISK FACTORS 10-20% ≤ 10% NEVER (onlyifcomplications) NCCN 2009 EORTC 2006 ASCO 2006 AIOM 2009

  37. GEPARTRIO study: PEG-f plus Ciprofolxacin in PrimaryProphylaxis PROSPECTIVE TRIAL 1257 pazienti NACT • Ciprofloxacin ( 500mgx2 ) 5-14 days • Filgrastim ( 5-10 days) • Pegfilgrastim (2 day) • Ciprofloxacina + Pegfilgrastim • Control p<0,01 p<0,001 Von Mickvitz, AnnOncol2008

  38. Patients with febrile neutropenia HR=0.32 p<0.001 Time of recovery HR=0.63p<0.001 Hospital stay Clark, JCO 2005

  39. Patients with febrile neutropenia • CSFs in FN CT-inducedreduces the amountofhospitalization and the neutrophilrecoveryperiod. • Influence on infection-relatedmortalityrequiresfurtherinvestigation. Infectionrelatedmortality Mortality Clark, JCO 2005

  40. Guidelines • Primary prophylaxis is recommended in chemotherapy regimens with > 20% of FN risk. • Secondary prophylaxis is reccomended in patients with previous complicated FN • Therapeutic use is indicated in patients with G4 neutropenia and • it is not recommended in apiretic patients and not necessary with antibiotics association.

  41. NAUSEA The prevalence of Chemotherapy induced nausea and Vomiting (CINV) varies but has been estimated at between 60 and 72%. (King C, OncolNurs Forum 1997) Nausea and vomiting is referred to as “chronic” if it is present for more than a few days, and the median duration in palliative care has been reported as seven days. These symptoms occur in 16%–68% of patients. However, the three most frequent symptoms in term of life-limiting illnesses were pain, breathlessness, and fatigue. Glare P et al Clin Invest Aging 2011

  42. Pathophysiology of Chemotherapy-Induced Emesis Grunberg SM et al. NEJM 1993

  43. Nausea and Vomiting (N&V) in Oncologicpatients • Classification • Acute N&V:during the first 24-hour period after chemotherapy administration. • Delayed N&V:more than 24 hours after chemotherapy administration. It is associated with cisplatin, cyclophosphamide, and other drugs (e.g., doxorubicin and ifosfamide) given at high doses or on 2 or more consecutive days. • Anticipatory nausea and vomiting (ANV): ANV is nausea and/or vomiting that occurs prior to the beginning of a new cycle of chemotherapy in response to conditioned stimuli such as the smells, sights, and sounds of the treatment room. ANV is a classically conditioned response that typically occurs after three or four prior chemotherapy treatments, following which the person experienced acute or delayed N&V. • Chronic N&V in advanced cancer patients: Chronic N&V in the advanced cancer patient is N&V associated with a variety of potential etiologies. A definitive understanding of cause is neither well known nor well researched, but potential causal factors include gastrointestinal, cranial, metabolic, drug-induced (e.g., morphine), cytotoxic chemotherapy, and radiation-induced mechanisms.

  44. Chemotherapyinduced Nausea and Vomiting Vomiting Nausea

  45. NAUSEA Mean number of days in hospital per cycle of chemotherapy according to incidence of emesis Neymark N et al, SupportCareCancer, 2005

  46. NAUSEA The lung cancer trial P 0,71 p=0.0004 Survival according to whether the patients experienced emesis (vomiting, bold line) or not (thin line). Survival for separating patients that completed the full protocol treatment (bold line) with those who stopped treatment before having received six cycles. Neymark N et al, SupportCareCancer, 2005

  47. Inadequate control of CINV has consistently been shown to reduce patients’ QOL and functional status and jeopardize the delivery of optimal treatment. Lindley CM et al. Quality of Life Research , 1992

  48. Emeticrisk Anthracyclines-cyclophosphamide combinations are reclassified as highly emetogenic. Basch E et al, JCO 2011

  49. 5-HT3 Antagonists Palononsetron is preferred effectiveness significantly increased in delayed phase Aapro MS et al, Ann Onc 2006 Saito M et al, Lancet Oncol 2009

  50. NK1 Antagonists Aprepitant e Fosaprepitant Compared with standard dual therapy, addition of aprepitant was generally well tolerated and provided consistently superior protection against CINV in patients receiving highly emetogeniccisplatin-based chemotherapy. HeskethPJ et al, JCO 2003

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