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Le emergenze oncologiche, la terapia di supporto e la qualità di vita La gestione dei sintomi (anemia, neutropenia, nausea) L’ASSISTENZA ONCOLOGICA NELLE.

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Presentation on theme: "Le emergenze oncologiche, la terapia di supporto e la qualità di vita La gestione dei sintomi (anemia, neutropenia, nausea) L’ASSISTENZA ONCOLOGICA NELLE."— Presentation transcript:

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

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

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

4 Anemia Hgb < 14g/dl Hgb < 12g/dl GradeToxicityNCI ScoreWHO Score 0None12-16 g/dL>11 1Mild10g/dL-LLN g/dL 2Moderate8-10 g/dL8-9.4 g/dL 3Severe g/dL 4life-threatening or disabling<6.5 g/dL

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

6  Disease – related factors 1  Folate, Vit B12, Iron deficiency 1  Anemia of chronic disease 1  Chemotherapy 1  Decrease in QOL 2,3,4  Increase in transfusion rates 5  Probable decrease in survival 6,7,8 1- Grotto, Med Oncol, 2008; 2- Gabrilove, JCO 2001; 3- Littlewood, JCO 2001; 4- Cella D. Ann Oncol, 2003; 5-Benoist S., Surgery, 2001; 6- Caro, Cancer 2001; 7- Waters, JCO 2002; 8- Fuso L. Gynecol Oncol 2005 Causes and Effects of Cancer – related Anemia Causes Effects

7 AgentGrade 1-2 (%)Grade 3-4 (%)Cancer CisplatinNR11H&N Docetaxel NSCLC Ovarian 5-FUNR H&N Colorectal Paclitaxel937Breast TopotecanNR SCLC Ovarian Vinorelbine Breast RegimenGrade 1-2 (%)Grade 3-4 (%)Cancer Cisplatin-Ciclophosphamide439Ovarian Cisplatin-Etoposide NSCLC VIPNR52SCLC 5-FU-Carboplatin937H&N CHOP4917NHL Paclitaxel-Doxorubicin Breast Paclitaxel-Carboplatin NSCLC Incidence of anemia associated with chemotherapeutic agents and regimens

8  Transfusions  ESAs  Non ESAs: - Fe++ - Lattoferrina  Dietary supplementation Treatments for Anemia

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

10 Use of ESAs in cancer patients Pubmed 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). Bohlius J et al. Cochrane Database Syst Rev, 2006

11 rHuEPOs TYPE OF SYNTETIC ERYTHROPOIETIN COMMERCIAL NAME MOLECULARE STRUCTURE HALF - LIFE EPOETIN α Eprex®Epogen®Procrit® aa sequence identical to endogenous Epo. aa sequence identical to endogenous Epo. Different composition and arrangements of the sugar moieties. Different composition and arrangements of the sugar moieties. 7 – 8 h EPOETIN β NeoRecormon® Higher MW than Epoetin α Higher MW than Epoetin α Lower number of sialylated glycan residues Lower number of sialylated glycan residues 4 – 12 h DARBEPOETIN α Aranesp® 2 N- lynked glycosylation sites, above and beyond the 3 normally present in endogenous Epo 2 N- lynked glycosylation sites, above and beyond the 3 normally present in endogenous Epo 24 h EPOETIN δ Dynepo® Human- type glycosylation profile (engineered in human fibrosarcoma cell line HT ) Human- type glycosylation profile (engineered in human fibrosarcoma cell line HT ) 9 – 13 h C.E.R.A. (Continuous Erythropoietin Receptor Activator) MIRCERA® Integration of amide bonds between amino group Integration of amide bonds between amino group Integration of MPGBA Integration of MPGBA 135 h Bunn H.F., Blood, 2007; Deicher R. et al., Drugs, 2004; Osterborg, bjh, 2007; Llop E. et al., Analytical Biochemistry, 2008

12 Österborg. Med Oncol 1998; 15 (Suppl 1): S47–9 Ludwig et al. N Engl J Med 1990; 322: 1693– Hb (g/dl) Epo Transfusion transfusions Use of ESAs in cancer patients

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

14 “Is it all over for erythropoietin?” Burton A., Lancet Oncology, 2007; Murat O. Arcasoy, Clin Cancer Res, 2008  The role of erythropoietin receptors on the tumour cell surface  Risk of Thromboembolic events

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

16 Bohlius J et al., Cochrane Database Syst Rev, 2010  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. 53 trials cHR for on study mortality for OS: 1.17 (95% CI ) 1.10 (95% CI ) and 1.04; 95% CI ) in pts receiving CT.

17  ESAs increase mortality HR1.17 (CI 1.06 to 1.29)  ESAs decrease overall survival HR 1.05 (CI 1.00 to 1.11)  ESAs Increase Risk ratio for thromboembolic omplications 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 91 trials patients 91 trials patients Bohlius J et al., Cochrane Database Syst Rev, 2012

18  ESAs increase mortality HR1.17 (CI 1.06 to 1.29)  ESAs decrease overall survival HR 1.05 (CI 1.00 to 1.11)  ESAs Increase Risk ratio for thromboembolic omplications 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 91 trials patients 91 trials patients Bohlius J et al., Cochrane Database Syst Rev, 2012 BIAS  Tumors etherogemeity  Hb <8 g/dl ~ 6% Hb g/dL ~ 30% Hb g/dL ~ 40% Hb 12-14g/dL ~ 22% Hb > 14 g/dl ~ 6%  65% studies only CT (10 % no RT no CT) Doses and times of administration outlabel

19 No significant effect of ESAs on survival or disease progression - 60 studies analized, 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: Glapsy J et al, Br J Cancer. 2010

20 GOG STUDY Citokine use and survival in the first line treatment of ovarian cancer 1864 pts MEDIAN SURVIVAL PTS RECEIVING ESA PTS NOT RECEVING ESAP=NS 34 MO 38 MO MEDIAN SURVIVAL PTS RECEIVING G-CSF PTS NOT RECEVING G-CSFP=NS 40 MO 37 MO 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 J. Vansteenkiste et al. / Lung Cancer 76 (2012) Study-level meta-analysis - 9 studies pts receving CT Study-level meta-analysis - 9 studies pts receving CT Mortality OR 0,87 (CI ) Mortality risk difference -0,02 ( CI -0,06-0,04) Disease progression 0,84 (CI 0, ) Trasfusion incidence 0,34 (CI 0, )

22 1)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; 2) 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; 3)Misinformation and misinterpretation of the incidence and clinical nature of serious adverse events of iv iron. …and what about iron supplementation? Not rigorously applied because…. Pedrazzoli P et al, Cancer 2009

23 Iron i.v.: another way to treat cancer-related anemia Kim YT et al., Gynecol Oncol, 2007 Patients (n = 75) Patients (n = 75) Study Group 200 mg of iron sucrose Control group n = 30 n = 45 Cervical cancer patients undergoing concurrent Chemoradiotherapy P = 0.04

24 ESAs-Iron supplementation No-iron Oral iron 325 mg twice daily Iron dextran repeated 100mg IV bolus Iron dextran total dose infusion (TDI). 157 PTS Hb 105 g/L, Serum ferritin 450 pmol/L or 675 pmol/L Transferrin saturation 19% rHuEPO 40,000 U once weekly to > Hb level < Non responders Auerbach M et al, JCO 2004

25 Iron supplementation: oral vs iv Addition of IV ferric gluconate to darbepoetin failed to provide additional benefit compared with oral iron or oral placebo. 502 Pts Steensma DP et al, JCO 2011 Plus Darbopoetin

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

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

28 Guidelines  ESA treatment may improve fatigue or QOL  Goal of 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 not be given to patients who are being treated for cancer when the goal is to cure the patients (of cancer).  ESAs have been found to shorten overall survival and 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%).  ESAs should 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 Rarely neutropenia is associated with fever…. NF GRADESEVERITYNATIONAL CANCER INSTITUTE GUIDELINES WHO GUIDELINES 0Absent>2000>1500 1Light Mild Severe Risk for Life< 500 NEUTROPENIA ASCO 2006/ AIOM 2009 Guidelines 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.  Absolute neutrophil count of less than 500 cells per cubic millimeter and a temperature of more than 38.5° C.  More than 60,000 pts are admitted for the treatment of FN annually, or 8 cases per 1000 patients receiving cancer CT.

31 Fever in Neutropenic patients ETIOLOGY IN CANCER 39% 35% 5% 21%

32 Neutropenia in CT regimens REGIMENNeutropenia WHO Classification FEC 10025% TAC66% PEB59% CMF78% GemOx20% FOLFOX-441% FOLFOXIRI50% EOX28% DCF82% M-VAC82% Caelyx37% Carboplatino and Paclitaxel37% CDDP85% Topotecan89% Review of Literature

33 GM-CSF (granulocyte-macrophage colony- stimulating factor) G-CSF (granulocyte colony- stimulating factor): Filgrastim: Granulokine, Neupogen Lenograstim (glycosilated): Granocyte, Myelostim, Refludan Pegfilgrastim (filgrastim pegilated): Neulasta, Neupopeg STIMULATING FACTOR Bennett CL et al, NEJM 2013

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

35 Kuderer, JCO 2007 Primary Prophylaxis with G-CSF “Previous studies and guidelines have concluded that myeloid growth factors are less effective if administered on the same day as chemotherapy, delayed more than 4 days after chemotherapy, or delayed until the onset of neutropenia” G-CSF vs NO G-CSF RR Risk and RR reduction p Infections related mortality 0.551,5 vs 2.8 = <45% ONLY FOR FILGASTRIM p: Early mortality0.603,4 vs 5,7 = <40% FILGASTRIM and PEGFILGASTRIM p: NF risk0.5446% PEGFIGASTRIM (RR 0.08) p: <0.001 Relative dose- intensity pro G-CSFp: <0.001 Bone and muscolar pain 10.4% vs 19.6% versus G-CSF p: <0.001 DFS e OSNO DATA 17 RCT Pts

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

37 PROSPECTIVE TRIAL 1257 pazienti NACT Ciprofloxacin ( 500mgx2 ) 5-14 days Filgrastim ( 5-10 days) Pegfilgrastim (2 day) Ciprofloxacina + Pegfilgrastim Control Von Mickvitz, Ann Oncol pts (T2-T4) Studio non R Ciproflox (253 pts) Filgrastim/ Lenograstim (377 pts) Peg-f (305 pts) Neutropenia G4 (%) Febrile Neutropenia(%) p<0,001 p<0,01 GEPARTRIO study: PEG-f plus Ciprofolxacin in Primary Prophylaxis

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

39 Infection related mortality Clark, JCO 2005 Mortality Patients with febrile neutropenia  CSFs in FN CT-induced reduces the amount of hospitalization and the neutrophil recovery period.  Influence on infection-related mortality requires further investigation.

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, Oncol Nurs 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 Oncologic patients 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 Chemotherapy induced Nausea and Vomiting GradeDescription 1Loss of appetite without alteration in eating habits 2Oral intake decreased without significant weight loss, dehydration, or malnutrition 3Inadequate oral caloric or fluid intake; tube feeding, TPN, or hospitalization indicated 4Grade not available 5 Nausea Vomiting GradeDescription 11–2 episodes (separated by 5 min) in 24 h 23–5 episodes (separated by 5 min) in 24 h 3≥6 episodes (separated by 5 min) in 24 h; tube feeding, TPN, or hospitalization indicated 4Life-threatening consequences; urgent intervention indicated 5Death

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

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

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

48 Emetic risk 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 emetogenic cisplatin-based chemotherapy. Hesketh PJ et al, JCO 2003

51 866 patients The aprepitant regimen was more effective than the control regimen for prevention of CINV in patients receiving both an anthracycline and cyclophosphamide Warr DG et al, JCO 2009

52 Benzodiazepines Benzodiazepines such as lorazepam, midazolam, and alprazolam have become recognized as valuable adjuncts in the prevention and treatment of anxiety and the symptoms of anticipatory nausea and vomiting (ANV) associated with chemotherapy, especially with the highly emetogenic regimens given to children. Better subjective evaluations, and the combination using the highest lorazepam dose tested showed superior patient satisfaction and less anxiety during therapy.

53 Guidelines  For highly emetogenic agents (including also AC regimen) NK1 antagonists plus 5-HT3 antagonists and dexamethasone are recommended.  For moderate emetogenic agents 5-HT3 antagonists (mainly palonosetron) and dexamethasone are recommended.  For low emetogenic agents 8 mg of dexamethasone alone is recommended.  Benzodiazepine should be used as adjunctive but not as single agents.

54 Do not forget…… Correct dietLifestyle

55 “Un’isola che ha saputo rimanere un’isola. Un microcosmo a sé. Ponza è scontrosa e bellissima. Ritrosa, diffidente e mai prevedibile. Tra fichi d’India, bouganville e esplosioni di ginestre, mi perdo nella bellezza dei suoi tramonti e trovo sulla terra il mio paradiso” E. Montale

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