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GUIDELINES WORKING GROUP Chair: Andrés Cervantes; Co-Chair: George Pentheroudakis; Editorial Board: Enriqueta Felip, Nicholas Pavlidis, Rolf A Stahel; Subject Editors: Dirk Arnold, Christian Buske, Paolo G Casali, Fatima Cardoso, Nathan Cherny, Jørn Herrstedt, Alan Horwich, Ulrich Keilholz, Marco Ladetto, Lisa Licitra, Solange Peters, Philippe Rougier, Cristiana Sessa; Deputy Subject Editors: Nicoletta Colombo, Elzbieta Senkus-Konefka; Staff: Keith H McGregor, Claire Bramley, Jennifer Lamarre, Svetlana Jezdic. ESMO CLINICAL PRACTICE GUIDELINES Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapyinduced nausea and vomiting: Results of the Perugia consensus conference Roila F, Herrstedt J, Aapro M, Gralla RJ, Einhorn LH, Ballatori E, Bria E, Clark-Snow RA, Espersen BT, Feyer P, Grunberg SM, Hesketh PJ, Jordan K, Kris MG, Maranzano E, Molassiotis A, Morrow G, Olver I, Rapoport BL, Rittenberg C, Saito M, Tonato M and Warr D, on behalf of the ESMO/MASCC Guidelines Working Group Ann Oncol 2010;21(Suppl 5):v232–43 http://annonc.oxfordjournals.org/content/21/suppl_5/v232.full.pdf+html Erythropoiesis-stimulating agents in the treatment of anaemia in cancer patients: ESMO Clinical Practice Guidelines for use Schrijvers D, De Samblanx H and Roila F, on behalf of the ESMO Guidelines Working Group Ann Oncol 2010;21(Suppl 5):v244–7 http://annonc.oxfordjournals.org/content/21/suppl_5/v244.full.pdf+html Hematopoietic growth factors: ESMO Clinical Practice Guidelines for the applications Crawford J, Caserta C and Roila F, on behalf of the ESMO Guidelines Working Group Ann Oncol 2010;21(Suppl 5):v248–51 http://annonc.oxfordjournals.org/content/21/suppl_5/v248.full.pdf+html Management of febrile neutropenia: ESMO Clinical Practice Guidelines De Naurois J, Novitzky-Basso I, Gill MJ, Marti Marti F, Cullen MH and Roila F, on behalf of the ESMO Guidelines Working Group Ann Oncol 2010;21(Suppl 5):v252–6 http://annonc.oxfordjournals.org/content/21/suppl_5/v252.full.pdf+html Management of cancer pain: ESMO Clinical Practice Guidelines Ripamonti CI, Santini D, Maranzano E, Berti M and Roila F, on behalf of the ESMO Guidelines Working Group Ann Oncol 2012;23(Suppl 7):vii139–154 http://annonc.oxfordjournals.org/content/23/suppl_7/vii139.full.pdf+html Distributed with support by an educational grant from Grünenthal Grünenthal has not influenced the content of this publication 2 Management of oral and gastrointestinal mucositis: ESMO Clinical Practice Guidelines Peterson DE, Bensadoun RJ and Roila F, on behalf of the ESMO Guidelines Working Group Ann Oncol 2011;22(Suppl 6):vi78–84 http://annonc.oxfordjournals.org/content/22/suppl_6/vi78.full.pdf+html Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Peccatori FA, Azim Jr HA, Orecchia R, Hoekstra HJ, Pavlidis N, Kesic V and Pentheroudakis G, on behalf of the ESMO Guidelines Working Group Ann Oncol 2013;24(Suppl 6):vi160–70 http://annonc.oxfordjournals.org/content/24/suppl_6/vi160.full.pdf.html Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines Mandalà M, Falanga A and Roila F, on behalf of the ESMO Guidelines Working Group Ann Oncol 2011;22(Suppl 6):vi85–92 http://annonc.oxfordjournals.org/content/22/suppl_6/vi85.full.pdf+html Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines Curigliano G, Cardinale D, Suter T, Plataniotis G, de Azambuja E, Sandri MT, Criscitiello C, Goldhirsch A, Cipolla C and Roila F, on behalf of the ESMO Guidelines Working Group Ann Oncol 2012;23(Suppl 7):vii155–66 http://annonc.oxfordjournals.org/content/23/suppl_7/vii155.full.pdf+html Management of chemotherapy extravasation: ESMO-EONS Clinical Practice Guidelines Pérez Fidalgo JA, García Fabregat L, Cervantes A, Marguiles A, Vidall C and Roila F, on behalf of the ESMO Guidelines Working Group Ann Oncol 2012;23(Suppl 7):vii167–73 http://annonc.oxfordjournals.org/content/23/suppl_7/vii167.full.pdf+html 3 ESMO POCKET GUIDELINES PROVIDE YOU WITH A CONCISE SUMMARY OF THE FUNDAMENTAL RECOMMENDATIONS MADE IN THE PARENT GUIDELINES IN AN EASILY ACCESSIBLE FORMAT. This quick reference booklet provides you with the most important content of the full ESMO Clinical Practice Guidelines (CPG) and consensus statements on various aspects of supportive care for your patients. Key content includes prevention of chemotherapy- and radiotherapy-induced nausea and vomiting; the use of erythropoiesis-stimulating agents in patients with anaemia; management of febrile neutropenia, cancer pain, mucositis, venous thromboembolism, extravasation associated with the administration of chemotherapeutic agents and of the cardiotoxic effects of chemotherapy and radiotherapy; and fertility and pregnancy in patients with cancer. The ESMO CPG and consensus statements covered in this booklet are intended to provide you with a set of recommendations for the best standards of supportive care, using evidence-based medicine. Implementation of ESMO CPG and consensus statements facilitates knowledge uptake and helps you to deliver an appropriate quality of focused care to your patients. The approval and licensed indication of drugs mentioned in this pocket guideline may vary in different countries. Please consult your local prescribing information. This booklet can be used as a quick reference guide to access key content on evidence-based management of upper GI tumours. Please visit http://www.esmo.org or http://oncologypro.esmo.org to view the full guidelines. 4 10–19 PREVENTION OF CHEMOTHERAPY- AND RADIOTHERAPY-INDUCED NAUSEA AND VOMITING DEFINITIONS: ACUTE AND DELAYED NAUSEA AND VOMITING.............................10 THE EMETOGENIC POTENTIAL OF ANTINEOPLASTIC AGENTS..............................10 PREVENTION OF NAUSEA AND VOMITING DUE TO HIGHLY EMETOGENIC CHEMOTHERAPY.............................................................................12 Prevention of nausea and vomiting induced by multiple-day cisplatin chemotherapy.........................................................................................................14 PREVENTION OF NAUSEA AND VOMITING DUE TO MODERATELY EMETOGENIC CHEMOTHERAPY....................................................................................................14 PREVENTION OF NAUSEA AND VOMITING DUE TO LOW/MINIMALLY EMETOGENIC CHEMOTHERAPY.............................................................................16 REFRACTORY NAUSEA AND VOMITING AND RESCUE ANTIEMETIC THERAPY.....17 PREVENTION OF ANTICIPATORY NAUSEA AND VOMITING...................................17 PREVENTION OF NAUSEA AND VOMITING INDUCED BY HIGH-DOSE CHEMOTHERAPY..........................................................................17 PREVENTION OF RADIOTHERAPY-INDUCED NAUSEA AND VOMITING.................18 ANTIEMETICS FOR CHILDREN RECEIVING CHEMOTHERAPY...............................19 20–23 ERYTHROPOIESIS-STIMULATING AGENTS IN THE TREATMENT OF ANAEMIA DEFINITION OF ANAEMIA.......................................................................................20 EVALUATION...........................................................................................................20 Grading...................................................................................................................20 Assessments...........................................................................................................20 THE USE OF ERYTHROPOIESIS-STIMULATING AGENTS IN PATIENTS WITH NON-HAEMATOLOGICAL MALIGNANCIES..............................................................21 THE USE OF ERYTHROPOIESIS-STIMULATING AGENTS IN PATIENTS WITH HAEMATOLOGICAL MALIGNANCIES......................................................................22 Myelodysplastic syndrome (MDS)..........................................................................22 Bone marrow transplantation..................................................................................22 SAFETY AND TOLERABILITY..................................................................................22 CANCER THERAPY OUTCOME................................................................................23 5 24–27 HAEMATOPOIETIC GROWTH FACTORS DEFINITION OF FEBRILE NEUTROPENIA (FN)........................................................24 INDICATION FOR PROPHYLAXIS OF FEBRILE NEUTROPENIA (FN) WITH HEMATOPOIETIC GROWTH FACTORS (HGFS)..............................................24 Primary prophylaxis of chemotherapy-induced neutropenia...................................24 Secondary prophylaxis of chemotherapy-induced neutropenia...............................26 Dosing and administration......................................................................................26 USE OF HAEMATOPOIETIC GROWTH FACTORS IN HIGH-RISK SITUATIONS.........26 Autologous stem-cell transplant.............................................................................26 Allogeneic stem-cell transplant...............................................................................26 Mobilisation of peripheral blood stem-cells (PBSCs)..............................................26 Graft failure.............................................................................................................27 Patients with leukaemia..........................................................................................27 TREATMENT OF FEBRILE NEUTROPENIA WITH HEMATOPOIETIC GROWTH FACTORS................................................................................................27 TREATMENT WITH HEMATOPOIETIC GROWTH FACTORS FOR RADIATION INJURY........................................................................................27 28–34 MANAGEMENT OF FEBRILE NEUTROPENIA DEFINITION OF FEBRILE NEUTROPENIA (FN)........................................................28 ASSESSMENT.........................................................................................................28 RISK ASSESSMENT................................................................................................28 MANAGEMENT OF FEBRILE NEUTROPENIA...........................................................29 Low-risk patients....................................................................................................30 High-risk patients....................................................................................................30 Indications for alternative therapy...........................................................................30 ASSESSMENT OF RESPONSE.................................................................................32 DURATION OF THERAPY........................................................................................34 PATIENT EDUCATION AND LOCAL POLICIES.........................................................34 35–51 MANAGEMENT OF CANCER PAIN ASSESSMENTS.......................................................................................................35 PRINCIPLES OF PAIN MANAGEMENT....................................................................36 6 PAIN MANAGEMENT...............................................................................................37 Treatment of mild pain............................................................................................39 Treatment of mild-to-moderate pain.......................................................................39 Treatment of moderate-to-severe pain....................................................................40 Scheduling and titration..........................................................................................41 MANAGEMENT OF OPIOID ADVERSE EFFECTS......................................................42 BREAKTHROUGH PAIN (BTP).................................................................................43 BONE PAIN..............................................................................................................43 Radiotherapy...........................................................................................................44 Metastatic spinal cord compression (MSCC)..........................................................45 Targeted therapy.....................................................................................................45 NEUROPATHIC PAIN...............................................................................................46 INVASIVE MANAGEMENT OF REFRACTORY PAIN..................................................48 Spinal drug delivery................................................................................................48 Peripheral nerve block............................................................................................50 Neurolytic blockade.................................................................................................50 END-OF-LIFE PAIN..................................................................................................50 52–55 MANAGEMENT OF ORAL AND GASTROINTESTINAL MUCOSITIS DEFINITION.............................................................................................................52 RISK FACTORS.......................................................................................................52 GRADING................................................................................................................52 MANAGEMENT OF MUCOSITIS..............................................................................53 Oral mucositis.........................................................................................................53 Gastrointestinal mucositis.......................................................................................54 56–66 CANCER, PREGNANCY AND FERTILITY DIAGNOSIS.............................................................................................................56 STAGING AND RISK ASSESSMENT........................................................................56 OBSTETRIC CARE AND FOETAL FOLLOW-UP.........................................................57 LOCAL TREATMENTS.............................................................................................57 General concepts: Surgery......................................................................................57 General concepts: Radiotherapy.............................................................................58 Breast cancer..........................................................................................................58 Cervical cancer........................................................................................................58 SYSTEMIC TREATMENTS.......................................................................................60 7 General concepts on the use of chemotherapy during pregnancy...........................60 Breast cancer..........................................................................................................60 Lymphoma..............................................................................................................62 Leukaemia...............................................................................................................62 Other tumours.........................................................................................................63 MANAGING PREGNANCIES DIAGNOSED WHILE UNDERGOING ANTICANCER THERAPY..........................................................................................64 PREGNANCY IN CANCER SURVIVORS...................................................................65 FERTILITY PRESERVATION METHODS IN CANCER PATIENTS...............................66 67–71 MANAGEMENT OF VENOUS THROMBOEMBOLISM RISK FACTORS FOR VENOUS THROMBOEMBOLISM (VTE)...................................67 DIAGNOSIS OF OCCULT CANCER IN PATIENTS WITH IDIOPATHIC VENOUS THROMBOEMBOLISM (VTE)..................................................................................68 PREVENTION OF VENOUS THROMBOEMBOLISM (VTE) IN PATIENTS WITH CANCER........................................................................................................68 Surgical patients.....................................................................................................68 Medical patients......................................................................................................68 TREATMENT OF VENOUS THROMBOEMBOLISM (VTE) IN PATIENTS WITH SOLID TUMOURS.........................................................................................69 Acute treatment: Low molecular-weight heparins (LMWH) and unfractionated heparin (UFH).........................................................................................................69 Acute treatment: Thrombolytic therapy...................................................................69 Long-term treatment...............................................................................................69 Duration of therapy to prevent recurrence of venous thromboembolism (VTE)......70 Treatment of recurrent venous thromboembolism (VTE)........................................70 Use of a vena cava filter..........................................................................................71 CONTRAINDICATIONS TO ANTICOAGULATION......................................................71 ANTICOAGULATION AND PROGNOSIS...................................................................71 72–83 CARDIOVACULAR TOXICITY INDUCED BY CHEMOTHERAPY, TARGETED AGENTS AND RADIOTHERAPY CARDIOVASCULAR EVALUATION BEFORE ANTICANCER TREATMENT WITH POTENTIAL IRREVERSABLE (TYPE I) OR REVERSIBLE (TYPE II) CARDIOTOXICITY...................................................................................................72 LEFT VENTRICULAR DYSFUNCTION......................................................................73 Anthracyclines and cytotoxics with cumulative dose-related cardiotoxicity (Type I agents)........................................................................................................74 8 Monoclonal antibodies and targeted agents not associated with cumulative dose-related cardiotoxicity (Type II agents)............................................................76 Management of trastuzumab cardiotoxicity............................................................77 CARDIAC ISCHEMIA...............................................................................................78 HYPERTENSION......................................................................................................78 QT PROLONGATION................................................................................................79 CARDIOVASCULAR MONITORING DURING AND AFTER ANTICANCER TREATMENT WITH POTENTIAL IRREVERSIBLE (TYPE I) OR REVERSIBLE (TYPE II) CARDIOTOXICITY....................................................................................79 TREATMENT OF LEFT VENTRICULAR DYSFUNCTION (LVD) INDUCED BY ANTICANCER TREATMENT WITH IRREVERSIBLE (TYPE I) OR REVERSIBLE (TYPE II) CARDIOTOXICITY....................................................................................80 CARDIAC TOXICITY INDUCED BY RADIOTHERAPY...............................................80 Recommendations to reduce cardiac toxicity in patients treated by radiotherapy...81 Treatment of radiotherapy-related cardiac complications........................................82 Monitoring of cardiac function after chest radiotherapy..........................................82 84–93 CHEMOTHERAPY EXTRAVASATION DEFINITION OF EXTRAVASATION...........................................................................84 POTENTIAL FOR ANTICANCER AGENTS TO CAUSE LOCAL DAMAGE AFTER EXTRAVASATION.........................................................................................84 RISK FACTORS FOR EXTRAVASATION...................................................................85 PREVENTION OF EXTRAVASATION.........................................................................86 DIAGNOSIS OF EXTRAVASATION...........................................................................86 Differential diagnosis..............................................................................................87 MANAGEMENT OF EXTRAVASATION......................................................................88 General measures...................................................................................................88 Specific measures...................................................................................................90 SURGICAL MANAGEMENT OF SEVERE TISSUE DAMAGE......................................90 CENTRAL VENOUS ACCESS DEVICE EXTRAVASATION..........................................91 DOCUMENTATION...................................................................................................93 FOLLOW-UP............................................................................................................93 94–96 GLOSSARY 9 DEFINITIONS: ACUTE AND DELAYED NAUSEA AND VOMITING •Delayed nausea and vomiting is arbitrarily defined as nausea and vomiting developing >24 hours after chemotherapy administration; therefore, acute nausea and vomiting occurs in the first 24 hours after chemotherapy administration •A number of predictive factors have been identified for the development of delayed nausea and vomiting The most important is the presence/absence of acute nausea and vomiting •Factors of prognostic importance include: Protection against nausea and vomiting in prior chemotherapy cycles, cisplatin dose, gender and age THE EMETOGENIC POTENTIAL OF ANTINEOPLASTIC AGENTS •A number of systems classifying the emetogenic potential of antineoplastic agents have been proposed; the following 4-level classification has been accepted by most major organisations producing recommendations on antiemetics •The emetogenic classification scheme should be used to describe single agents, since the potential variety of combination doses and schedules of even a few chemotherapeutic agents might defy meaningful classification The commonly used combination of the moderately emetogenic agents doxorubicin and cyclophosphamide (AC) is a particularly potent moderately emetogenic combination that commonly serves as the basis for antiemetic clinical trials and that might require more aggressive antiemetic regimens THE EMETOGENIC POTENTIAL OF COMMONLY USED INTRAVENOUS (IV) ANTINEOPLASTIC AGENTS 10 DEGREE OF EMETOGENICITY (INCIDENCE) AGENT High (>90%) Cisplatin Mechlorethamine Streptozotocin Cyclophosphamide ≥1500 mg/m2 Carmustine Dacarbazine DEGREE OF EMETOGENICITY (INCIDENCE) AGENT Moderate (30–90%) Oxaliplatin Cytarabine >1 gm/m2 Carboplatin Ifosfamide Cyclophosphamide <1500 mg/m2 Doxorubicin Daunorubicin Epirubicin Idarubicin Irinotecan Azacitidine Bendamustine Clofarabine Alemtuzumab Low (10–30%) Paclitaxel Docetaxel Mitoxantrone Doxorubicin HCl liposome injection Ixabepilone Topotecan Etoposide Pemetrexed Methotrexate Mitomycin Gemcitabine Cytarabine ≤1000 mg/m2 5-Fluorouracil Temsirolimus Bortezomib Cetuximab Trastuzumab Panitumumab Catumaxumab Minimal (<10%) Bleomycin Busulfan 2-Chlorodeoxyadenosine Fludarabine Vinblastine Vincristine Vinorelbine Bevacizumab 11 •The emetogenic potential of oral agents (cytotoxics and biological agents) has generally been established based on the full course of therapy Chronic oral administration negates the distinction between acute and delayed emesis •Considerable uncertainty prevails regarding the emetogenic risk of oral agents THE EMETOGENIC POTENTIAL OF ORAL ANTINEOPLASTIC AGENTS DEGREE OF EMETOGENICITY (INCIDENCE) AGENT High (>90%) Hexamethylmelamine Procarbazine Moderate (30–90%) Cyclophosphamide Temozolomide Vinorelbine Imatinib Low (10–30%) Capecitabine Tegafur uracil Fludarabine Etoposide Sunitinib Everolimus Lapatinib Lenalidomide Thalidomide Minimal (<10%) Chlorambucil Hydroxyurea L-Phenylalanine mustard 6-Thioguanine Methotrexate Gefitinib Erlotinib Sorafenib PREVENTION OF NAUSEA AND VOMITING DUE TO HIGHLY EMETOGENIC CHEMOTHERAPY •A 3-drug regimen comprising a single dose of a 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, dexamethasone and aprepitant, a neurokinin (NK)1 neurotransmitter receptor antagonist, given before chemotherapy is recommended to prevent acute nausea and vomiting A single dose of IV fosaprepitant 115 mg can be used as an alternative to oral aprepitant 125 mg •The efficacy of dolasetron, granisetron, ondansetron and tropisetron are similar 12 More studies are required to determine if palonosetron should be recommended as the 5-HT3 receptor antagonist of choice for the prevention of cisplatin-induced nausea and vomiting ––Data from two studies suggest that palonosetron has similar efficacy to granisetron or ondansetron for prophylaxis of acute emesis, but offers more protection against delayed emesis than single dose granisetron before chemotherapy; however, in these studies, the doses of dexamethasone differed from those recommended, an NK1 antagonist was not given, and one study combined data for cisplatin- and anthracycline/cyclophosphamidetreated patients ANTIEMETIC AGENTS TO PREVENT ACUTE EMESIS INDUCED BY HIGHLY EMETOGENIC CHEMOTHERAPY IN ADULTS ANTIEMETICS SINGLE DAILY DOSE GIVEN BEFORE CHEMOTHERAPY 5-HT3 receptor antagonists Ondansetron Granisetron Oral: 24 mg IV: 8 mg or 0.15 mg/kg Oral: 2 mg IV: 1 mg or 0.01 mg/kg Tropisetron Oral or IV: 5 mg Dolasetron Oral: 100 mg IV: 100 mg or 0.18 mg/kg Palonosetron IV: 0.25 mg Oral: 0.50 mg Dexamethasone Oral or IV: 12 mg* Aprepitant Oral: 125 mg Fosaprepitant IV: 150 mg† *20 mg, if aprepitant is not available (i.e. when given without an NK1 antagonist or when given with fosaprepitant) If dexamethasone is not available, limited data suggest that prednisolone or methylprednisolone can be substituted at doses ~7 and 5 x higher, respectively †Findings from a recent randomised, double-blind non-inferiority study have shown that a single IV dose of fosaprepitant (150 mg) is not inferior to 3 days of aprepitant in terms of response rate among patients receiving cisplatin-based chemotherapy; fosaprepitant can therefore be recommended for the prevention of cisplatin-induced emesis 13 •All patients receiving cisplatin should receive antiemetics to prevent delayed nausea and vomiting •Given the dependence of delayed nausea and vomiting on acute antiemetic outcome, optimal acute antiemetic prophylaxis should be employed •For patients treated with cisplatin who received aprepitant plus a 5-HT3 receptor antagonist and dexamethasone on day 1 to prevent acute nausea and vomiting, the combination of dexamethasone and aprepitant on days 2 and 3 is suggested to prevent delayed nausea and vomiting based on its superiority to dexamethasone alone Aprepitant (80 mg single oral dose) should be given on days 2 and 3 after cisplatin administration The optimal dexamethasone dose for the prevention of delayed nausea and vomiting induced by cisplatin has not been determined Prevention of nausea and vomiting induced by multiple-day cisplatin chemotherapy •Patients receiving multiple-day cisplatin should receive a 5-HT3 receptor antagonist plus dexamethasone for acute nausea and vomiting and dexamethasone for delayed nausea and vomiting The optimal dose and schedule of both components of therapy are unknown Evidence for the efficacy of dexamethasone 20 mg, which is often used on every day of chemotherapy, is only available in patients receiving single-day, high-dose cisplatin-based chemotherapy (i.e. ≥50 mg/m2); it is unknown if a lower dose given on days 1–5 (in an attempt to decrease adverse events) would be as effective PREVENTION OF NAUSEA AND VOMITING DUE TO MODERATELY EMETOGENIC CHEMOTHERAPY •In patients receiving moderately emetogenic chemotherapy (not anthracycline/ cyclophosphamide), a combination of palonosetron plus dexamethasone is recommended as standard prophylaxis against acute nausea and vomiting •In patients receiving anthracycline/cyclophosphamide, a 3-drug regimen, including single doses of a 5-HT3 receptor antagonist, dexamethasone and aprepitant, given before chemotherapy is recommended for the prevention of acute nausea and vomiting If aprepitant is not available, patients should receive palonosetron plus dexamethasone •There are no clinically relevant differences in tolerability among the 5-HT3 receptor antagonists and no difference in the efficacy for oral and IV administration 14 ANTIEMETIC AGENTS TO PREVENT ACUTE EMESIS INDUCED BY MODERATELY EMETOGENIC CHEMOTHERAPY IN ADULTS ANTIEMETICS SINGLE DAILY DOSE GIVEN BEFORE CHEMOTHERAPY 5-HT3 receptor antagonists Ondansetron Oral: 16 mg (8 mg bid) IV: 8 mg or 0.15 mg/kg Granisetron Oral: 2 mg IV: 1 mg or 0.01 mg/kg Tropisetron Oral: 5 mg IV: 5 mg Dolasetron Oral: 100 mg IV: 100 mg or 1.8 mg/kg Palonosetron IV: 0.25 mg Oral: 0.5 mg Dexamethasone Oral or IV: 8 mg* Aprepitant Oral: 125 mg Fosaprepitant IV: 150 mg† bid, twice daily *If dexamethasone is not available, limited data suggest that prednisolone or methylprednisolone can be substituted at doses ~7 and 5 x higher, respectively † Findings from a recent randomised, double-blind non-inferiority study have shown that a single IV dose of fosaprepitant (150 mg) is not inferior to 3 days of aprepitant in terms of response rate among patients receiving cisplatin-based chemotherapy; fosaprepitant can therefore be recommended for the prevention of cisplatin-induced emesis •Patients who receive moderately emetogenic chemotherapy known to be associated with a significant incidence of delayed nausea and vomiting should receive antiemetic prophylaxis for delayed nausea and vomiting •In patients receiving moderately emetogenic chemotherapy (not anthracycline/ cyclophosphamide), multi-day oral dexamethasone is the preferred treatment for the prevention of delayed nausea and vomiting The optimal duration and dose of dexamethasone are unknown •In patients receiving anthracycline/cyclophosphamide, aprepitant should be used to prevent delayed nausea and vomiting It is unknown whether dexamethasone is as effective as aprepitant or if aprepitant plus dexamethasone is superior The recommended dose of aprepitant is 80 mg orally on days 2 and 3 15 PREVENTION OF NAUSEA AND VOMITING DUE TO LOW/MINIMALLY EMETOGENIC CHEMOTHERAPY •Patients who receive chemotherapy of low emetic potential as an intermittent schedule and who have no prior history of nausea and vomiting should receive a single antiemetic agent such as dexamethasone, a 5-HT3 receptor antagonist or a dopamine receptor antagonist as prophylaxis There is little evidence from clinical trials supporting the use of antiemetic prophylaxis in these patients •Patients who receive minimal emetogenic chemotherapy and who have no history of nausea and vomiting should not receive routine antiemetic therapy before chemotherapy •No prophylactic treatment should be administered for the prevention of delayed emesis induced by low or minimally emetogenic chemotherapy If nausea and vomiting occurs (acute or delayed), single agent antiemetics can be used in subsequent cycles (dexamethasone, a 5-HT3 receptor antagonist or a dopamine receptor antagonist) SUMMARY RECOMMENDATIONS FOR THE PREVENTION OF CHEMOTHERAPYINDUCED NAUSEA AND VOMITING RISK LEVEL CHEMOTHERAPY (SEE TABLES) High (>90%) Moderate (30–90%) ANTIEMETIC GUIDELINES Cisplatin and other highly emetogenic chemotherapies Day 1: 5-HT3 receptor antagonist + dexamethasone + (fos)aprepitant Day 2–3: Dexamethasone + aprepitant Day 4: Dexamethasone Anthracycline/ cyclophosphamide Day 1: 5-HT3 receptor antagonist + dexamethasone + (fos)aprepitant* Day 2–3: Aprepitant Non-anthracycline/cyclophosphamide moderately emetogenic chemotherapy Day 1: Palonosetron + dexamethasone Day 2–3: Dexamethasone Low (10–30%) Day 1: Dexamethasone, 5-HT3 receptor antagonist or dopamine antagonist Day 2–3: No routine prophylaxis Minimal (<10) Day 1: No routine prophylaxis Day 2–3: No routine prophylaxis (fos)aprepitant: Either intravenous or oral formulation of the NK1 receptor antagonist *If the NK1 receptor antagonist is not available, palonosetron is the preferred 5-HT3 receptor antagonist 16 REFRACTORY NAUSEA AND VOMITING AND RESCUE ANTIEMETIC THERAPY •Maximally effective antiemetics should be used as first-line therapy, rather than withholding them for use at the time of antiemetic failure Antiemetics are most effective when used prophylactically •Rescue antiemetic treatment is generally understood to be antiemetics given on demand to a patient with breakthrough emesis No randomised double-blind trials have investigated antiemetics in this setting •Refractory emesis is generally defined as emesis in the previous cycle of chemotherapy •A number of approaches have been utilised for treating refractory emesis: Switching to a different 5-HT3 receptor antagonist Adding other agents such as a dopamine antagonist or benzodiazepine Adding metopimazine (improved the efficacy of ondansetron and of ondansetron plus methylprednisolone) Cannabinoids and olanzapine, which act at multiple dopaminergic, serotonergic, muscarinic and histaminic receptor sites Non-pharmacological interventions, such as acupuncture NK1 receptor antagonists, which have shown efficacy in patients who did not achieve complete protection from emesis when treated with dexamethasone plus a serotonin receptor antagonist PREVENTION OF ANTICIPATORY NAUSEA AND VOMITING •Anticipatory nausea and vomiting is difficult to control pharmacologically Benzodiazepines are the only drugs that have been shown to reduce the occurrence of anticipatory nausea and vomiting, but their efficacy tends to decrease as chemotherapy continues •The best approach to the treatment of anticipatory emesis is to effectively control acute and delayed emesis •Behavioral therapies can effectively treat anticipatory nausea and vomiting, particularly progressive muscle relaxation training, systematic desensitisation and hypnosis Their use remains difficult to implement, as most patients are treated in settings where the required expertise is unavailable PREVENTION OF NAUSEA AND VOMITING INDUCED BY HIGH-DOSE CHEMOTHERAPY •Limited data exist on the effective use of antiemetics for patients treated with high-dose chemotherapy with stem cell support 17 In these patients, other contributing causes of emesis in addition to chemotherapy include prophylactic antibiotics, narcotic analgesics and, in some patients, the use of total body irradiation •Complete protection from nausea and vomiting is currently achieved in only a minority of these patients •The use of a 5-HT3 receptor antagonist plus dexamethasone represents the current standard of care. In randomised trials: Ondansetron was superior to metoclopramide and droperidol Granisetron had similar efficacy to standard antiemetic therapy Continuous infusion of chlorpromazine had similar efficacy to continuous infusion of ondansetron, but was more toxic •Randomised studies evaluating the efficacy of aprepitant plus standard therapy are required PREVENTION OF RADIOTHERAPY-INDUCED NAUSEA AND VOMITING •Current antiemetic guidelines vary when classifying radiation emetogenic risk categories and giving indications for the use of antiemetic drugs, reflecting the limited amount of high-level evidence available •New guidelines for the management of radiotherapy-induced emesis, proposed by ESMO/Multinational Association of Supportive Care in Cancer (MASCC), are provided in the table below RISK OF RADIOTHERAPY-INDUCED EMESIS AND NEW GUIDELINES* RISK LEVEL IRRADIATED AREA ANTIEMETIC GUIDELINES High (>90%) Total body, total nodal Prophylaxis with 5-HT3 receptor antagonists + dexamethasone Moderate (60–90%) Upper abdomen, half body, upper body Prophylaxis with 5-HT3 receptor antagonists + optional dexamethasone Low (30–60%) Cranium, cranio-spinal, head & neck, lower thorax region, pelvis Prophylaxis or rescue with 5-HT3 receptor antagonists Minimal (<30%) Extremities, breast Rescue with dopamine receptor antagonists or 5-HT3 receptor antagonists *In patients receiving chemoradiotherapy, antiemetic prophylaxis is given according to the chemotherapy-related antiemetic guidelines, unless the risk of emesis is higher with radiotherapy than chemotherapy 18 ANTIEMETICS FOR CHILDREN RECEIVING CHEMOTHERAPY •All pediatric patients receiving chemotherapy with high or moderate emetogenic potential should receive antiemetic prophylaxis with a 5-HT3 receptor antagonist plus dexamethasone A 5-HT3 receptor antagonist plus dexamethasone has been shown to be more efficacious than a 5-HT3 receptor antagonist alone •The optimal dose and scheduling of the 5-HT3 receptor antagonists has not been identified In clinical practice, established doses for ondansetron are 5 mg/m2 or 0.15 mg/kg and for granisetron are 0.01 mg/kg or 10 µg/kg once daily 19 DEFINITION OF ANAEMIA •The reduction of haemoglobin (Hb) concentration, red cell count or packed cell volume below normal levels – mild: Hb ≤11.9 g/dL and ≥10 g/dL; moderate: Hb ≤9.9 g/dL and ≥8 g/dL; severe: Hb <8 g/dL •Anaemia has a negative impact on quality of life, is an important factor in cancerrelated fatigue, and is a negative prognostic factor for overall survival in most types of cancer EVALUATION Grading •Treatment-related anaemia is graded according to the National Cancer Institute (NCI)Common Terminology Criteria of Adverse Events version 4 (CTCAE v4): Grade 1: Hb <lower normal limit to 10.0 g/dL Grade 2: Hb <10.0 to 8.0 g/dL Grade 3: Hb <8.0 to 6.5 g/dL; transfusion indicated Grade 4: Life-threatening consequences; urgent intervention indicated Grade 5: Death Assessments •Thorough history (emphasis on medication use); blood examination including reticulocyte count, iron, transferrin saturation (TFS) and ferritin levels, C-reactive protein (CRP), folate and vitamin B12 status and a peripheral blood smear; bone marrow examination, if indicated; assessment of occult blood loss in stool and urine; evaluation of renal function •Consider Coombs testing in patients with chronic lymphocytic leukaemia (CLL), non-Hodgkin’s lymphoma (NHL) and those with a history of autoimmune disease •Endogenous erythropoietin (EPO) levels may predict response to erythropoiesisstimulating agents (ESAs) in patients with myelodysplastic syndrome (MDS) •All causes of anaemia should be considered and corrected, if possible, before using ESAs. Possible causes of anaemia include: Patient-related: Hemoglobinopathies, thalassemia, diminished nutritional status with deficiencies Disease-related: Bone marrow infiltration, bleeding, hypersplenism, hemolysis, anaemia of chronic disease 20 Treatment-related: Extensive radiotherapy, bone marrow and renal toxicity secondary to chemotherapy, drug-induced hemolysis THE USE OF ERYTHROPOIESIS-STIMULATING AGENTS IN PATIENTS WITH NONHAEMATOLOGICAL MALIGNANCIES Treatment recommendations according to the European Medicines Agency (EMA) labels for ESAs are shown below. These recommendations can be followed if there is no suspicion of functional iron deficiency (ferritin >100 ng/mL and TFS saturation <20%) •ESAs are recommended in patients receiving chemotherapy with Hb ≤10 g/dL; treatment with ESAs may be considered in order to increase Hb by <2 g/dL or to prevent further decline in Hb •In patients not receiving chemotherapy, ESAs are not indicated; there may be an increased risk of death when ESAs are administered to a target Hb of 12–14 g/dL •In patients treated with curative therapy, ESAs should be used with caution •ESAs do not differ in terms of efficacy and safety DOSING RECOMMENDATIONS ACCORDING TO EMA LABELLING EPOETIN α EPOETIN β DARBEPOETIN Initial treatment 150 IU/kg SC tiw 450 IU/kg SC qw 30,000 IU SC qw 2.25 μg/kg SC qw 500 μg (6.75 μg/kg) SC q3w Dose increase 300 IU/kg SC tiw 60,000 IU SC qw Not recommended Dose reduction If result achieved: Reduce by 25–50% If Hb >12 g/dL: Reduce by 25–50% If Hb rise >2 g/dL/4 weeks: Reduce by 25–50% Dose withholding If Hb >13 g/dL: Withhold until Hb 12 g/dL sc, subcutaneous; tiw, thrice weekly; qw, once weekly; q3w, once every three weeks •If Hb increase is <1 g/dL above baseline, the dose of ESA should be increased If after an additional 4 weeks, the Hb increase is ≥1 g/dL, the dose can be kept the same or decreased by 25–50% If the Hb increase is <1 g/dL above baseline after 8–9 weeks of therapy, response to ESA therapy is unlikely; treatment should be discontinued 21 •If Hb increase is ≥1 g/dL above baseline after 4 weeks of treatment, the dose can be kept the same or decreased by 25–50% •If Hb increase is >2 g/dL during any 4 week period or if the Hb exceeds 12 g/dL, the dose should be reduced by ~25–50% •If Hb exceeds 13 g/dL, therapy should be discontinued until Hb is <12 g/dL and then resumed at a 25% lower dose •In those who respond, ESAs should be discontinued 4 weeks after the end of chemotherapy THE USE OF ERYTHROPOIESIS-STIMULATING AGENTS IN PATIENTS WITH HAEMATOLOGICAL MALIGNANCIES Myelodysplastic syndrome (MDS) •In patients with low-risk MDS (based on bone marrow blast percentage, number of cytopenias and cytopenic analysis), ESAs (± granulocyte colony-stimulating factor [G-CSF]) can be used to improve anaemia (off-label indication) •Treatment with ESAs should start at ~450 IU/kg/week for ≥8–10 weeks Predictors of response to ESAs include a normal karyotype, endogenous EPO levels <100–200 mU/mL and the refractory anaemia subtype Bone marrow transplantation •The response to EPO is reduced shortly after autologous transplantation; however, endogenous EPO is produced in appropriately increased amounts. Later, responsiveness of the transplanted marrow to EPO recovers, and transfusion requirements decrease •The response to EPO after allogeneic transplantation is faster. Thereafter, endogenous EPO production is reduced and there is a diminished response to EPO ESAs have demonstrated efficacy after allogeneic transplantation at higher doses (i.e. 75–200 IU/kg for epoetin α) SAFETY AND TOLERABILITY •ESAs should not be used in patients with a known hypersensitivity to ESAs or any of the excipients, or in patients with poorly controlled hypertension •ESAs should be used with caution in patients with liver disease •Due to an increased risk of thromboembolic events associated with ESAs, their use should be carefully reconsidered in: Patients at high risk of thromboembolic events, e.g. history of thrombosis, surgery, prolonged immobilisation, limited activity 22 Patients with multiple myeloma treated with thalidomide or lenalidomide in combination with doxorubicin and corticosteroids; consider low molecular weight heparins, aspirin or adjusted-dose warfarin (international normalised ratio [INR] ~1.5) •Other adverse events associated with ESAs include rare allergic reactions (including dyspnoea, skin rash and urticaria), arthralgia, peripheral oedema and mild and transient injection-site pain •Baseline and periodic monitoring of iron, CRP, TFS and ferritin levels are required In anaemic patients with iron deficiency, intravenous iron supplementation leads to higher Hb increment compared with oral or no iron substitution ––Iron supplementation may also reduce the numbers of patients requiring red blood cell transfusions CANCER THERAPY OUTCOME •The influence of ESAs on tumour response and overall survival in patients with cancer and anaemia remains unclear 23 DEFINITION OF FEBRILE NEUTROPENIA (FN) •A rise in axillary temperature to >38.5°C lasting >1 hour or two consecutive readings >38°C over 2 hours and an absolute neutrophil count (ANC) <0.5 x 109/L INDICATION FOR PROPHYLAXIS OF FEBRILE NEUTROPENIA (FN) WITH HEMATOPOIETIC GROWTH FACTORS (HGFs) Primary prophylaxis of chemotherapy-induced neutropenia •hGFs should only be used for primary prophylaxis of chemotherapy-induced 24 neutropenia when the risk of FN is ≥20%, in high-risk situations (see opposite) and in the following situations: Patients with reduced marrow reserve (e.g. ANC <1.5 x 109/L) due to radiotherapy of >20% marrow Patients with human immunodeficiency virus (HIV) Patients aged ≥65 years treated with curative regimens (cyclophosphamide/ doxorubicin/vincristine/prednisolone [CHOP] or more intensive regimens for patients with aggressive non-Hodgkin’s lymphoma [NHL]) When a reduction in the dose of chemotherapy is deemed detrimental to outcome EXAMPLES OF CHEMOTHERAPY REGIMENS ASSOCIATED WITH A RISK OF FN OF ≥20% MALIGNANCY CHEMOTHERAPY REGIMEN Bladder cancer MVAC (methotrexate/vinblastine/doxorubicin/cisplatin) TC (paclitaxel/cisplatin) Breast cancer TAC (docetaxel/doxorubicin/cyclophosphamide) Dose-dense AC/T (doxorubicin/cyclophosphamide/paclitaxel) Cervical cancer TC Gastric cancer DCF (docetaxel/cisplatin/fluorouracil) Head and neck cancer Paclitaxel/ifosfamide/mesna/cisplatin Non-Hodgkin's lymphoma CHOP-14 (cyclophosphamide/doxorubicin/vincristine/prednisolone every 14 days) ICE (ifosfamide/carboplatin/etoposide) R-ICE (rituximab/ifosfamide/carboplatin/etoposide) DHAP (dexamethasone/cisplatin/cytarabine) Non-small-cell lung cancer DP (docetaxel/carboplatin) Ovarian cancer Topotecan Sarcoma MAID (mesna/doxorubicin/ifosfamide/etoposide) Doxorubicin/ifosfamide Small-cell lung cancer CAE (cyclophosphamide/doxorubicin/etoposide) Topotecan Testicular cancer VIP (vinblastine/ifosfamide/cisplatin) •Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is not indicated during chemoradiotherapy to the chest due to the increased rate of bone marrow suppression associated with an increased risk of complications and death •There is a risk of worsening thrombocytopenia when hGFs are given immediately before, or simultaneously with, chemotherapy •There is a possible risk of subsequent acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in women receiving adjuvant chemotherapy for breast cancer and hGFs The benefits of hGFs outweigh the risk in this setting •hGFs should be avoided in patients who are not at risk of FN, such as those with infections not related to neutropenia (e.g. community- or hospital-acquired pneumonia) or neutropenic complications 25 Secondary prophylaxis of chemotherapy-induced neutropenia •hGFs can be used for secondary prophylaxis of FN in the following situations: When it is anticipated that further infections during the next treatment cycle could be life threatening When the reduction in chemotherapy dose required to avoid neutropenia is below the efficacy threshold When neutropenia would delay chemotherapy Due to a lack of protocol adherence that compromises cure rate, overall survival or disease-free survival Dosing and administration •G-CSF 5 μg/kg/day given subcutaneously (SC) initiated 24–72 hours after the last day of chemotherapy until sufficient/stable post-nadir ANC recovery (achieving a target ANC of >10 x 109/L is unnecessary) •Pegfilgrastim, given SC as a single dose of either 100 μg/kg (individualised) or a total dose of 6 mg (general approach), is considered as effective as G-CSF USE OF HAEMATOPOIETIC GROWTH FACTORS IN HIGH-RISK SITUATIONS Therapy of acute leukaemias and autologous and allogeneic stem cell transplantations are associated with high risk of FN and potentially lethal complications Autologous stem-cell transplant •Marrow: G-CSF 5 μg/kg/day is recommended; administration may be safely postponed for 5–7 days after transplant •Peripheral blood stem cell (PBSC): hGFs are recommended; they have been associated with reductions in the duration of hospitalisation and in overall medical costs Allogeneic stem-cell transplant •Marrow: The use of hGFs after allogeneic marrow transplant is reasonable; starting hGFs 5–7 days after transplant is sufficient •PBSC: hGFs are not recommended Mobilisation of peripheral blood stem-cells (PBSCs) •Autologous PBSC: G-CSF 10 μg/kg/day for 7–10 days before apheresis ± chemotherapy is recommended hGF-mobilised PBSCs are superior, in terms of recovery of ANC, to marrow stem cells + post-infusion hGFs •Allogeneic PBSC: G-CSF 10 μg/kg daily for 7–10 days before apheresis is recommended 26 ANC recovery is faster after PBSC compared with marrow stem cells Graft failure •hGFs are recommended in patients with graft failure Patients with leukaemia •AML: Not recommended outside clinical trials •MDS: Not recommended as mortality may be increased •Acute lymphoblastic leukaemia (ALL): The use of hGFs during induction chemotherapy for ALL is controversial TREATMENT OF FEBRILE NEUTROPENIA WITH HAEMATOPOIETIC GROWTH FACTORS •Recommended for the treatment of high-risk FN associated with increased mortality, such as when FN is protracted (>7 days), the patient has hypotension, sepsis, pneumonia or a fungal infection hGFs are not recommended for the treatment of afebrile neutropenia TREATMENT WITH HAEMATOPOIETIC GROWTH FACTORS FOR RADIATION INJURY •Recommendations for the use of hGFs to treat radiation injury (accidental or intentional) are shown below LETHAL DOSES OF TOTAL BODY RADIOTHERAPY AND RECOMMENDATIONS FOR THE USE OF HGFS FOR THE TREATMENT OF RADIATION INJURY RADIOTHERAPY DOSE CLINICAL OUTCOME USE OF HGFS 3–10 Gy Probable or certain death from bone marrow failure Yes <3 Gy Survival with excellent nursing care No >10 Gy Death due to injury to other organs such as gastrointestinal tract No 27 DEFINITION OF FEBRILE NEUTROPENIA (FN) •An oral temperature >38.5°C or two consecutive readings >38.0°C over 2 hours and an absolute neutrophil count (ANC) of, or expected to be, <0.5 x 109/L These guidelines are intended to be used alongside local antimicrobial policies ASSESSMENT •Detailed history, including chemotherapy given, prior prophylactic antibiotics, concomitant steroid use, recent surgical procedure and presence of allergies •Note the presence of an indwelling intravenous (IV) catheter •Initial assessment of respiratory and circulatory function, then careful examination of the respiratory system, gastrointestinal tract, skin, peripheral region/genitourinary discharges, oropharynx and central nervous system for signs and symptoms suggesting an infection focus Signs and symptoms may be minimal, particularly in those receiving corticosteroids Vigilance is required in patients at risk of FN who present as unwell, hypotensive, with a low grade fever or afebrile as they may be developing Gram-negative septicemia requiring prompt treatment •Check clinical records for past positive microbiology, including history of antibiotic-resistant organisms or bacteraemia •Routine investigations: Urgent blood tests to assess bone marrow, renal and liver function; coagulation screen; C-reactive protein (CRP); blood cultures (minimum two sets – peripheral vein and any indwelling catheter); chest radiograph Urinalysis and culture, sputum microscopy and culture, stool microscopy and culture and skin lesions (aspirate, biopsy swab), when clinically indicated •Further investigations (prolonged/profound neutropenia/following allografts): High resolution chest computed tomography (CT; if febrile despite 72 hours of appropriate antibiotics), broncho-alveolar lavage RISK ASSESSMENT •A number of instruments have been developed to predict FN cases at high-risk of complications; the Multinational Association of Supportive Care in Cancer (MASCC) index is the most widely used 28 MASCC SCORING INDEX FOR RISK ASSESSMENT IN PATIENTS WITH FN CHARACTERISTIC SCORE Burden of illness: No or mild symptoms 5 Burden of illness: Moderate symptoms Burden of illness: Severe symptoms No hypotension (systolic blood pressure >90 mmHg) No chronic obstructive pulmonary disease 3 0 5 4 Solid tumour/lymphoma with no previous fungal infection 4 No dehydration 3 Outpatient status (at onset of fever) 3 Age <60 years 2 Scores ≥21: Low risk of complications Points attributed to ‘burden of illness’ are not cumulative; maximum theoretical score = 26 MANAGEMENT OF FEBRILE NEUTROPENIA Initial Management of febrile neutropenia Temperature >38.5°C and ANC <0.5x109/L Prompt assessment and vigorous resuscitation if needed Calculate MASCC score High risk Low risk Inpatient broad spectrum IV antibiotics Inpatient oral antibiotics for some cases Hemodynamically stable; do not have acute leukaemia, evidence of organ failure, pneumonia, an indwelling venous catheter or severe soft tissue infection 29 Low-risk patients •Inpatient oral antibacterial therapy: Although single agent quinolones are not inferior to combination (quinolone + amoxicillin + clavulanic acid), the latter is preferred given the rise in Gram-positive FN episodes Oral quinolones should not be used in patients who have received quinolone prophylaxis An early change to oral combinations in patients who are afebrile after 48 hours of IV therapy is supported and preferred by many physicians •Outpatient management: Exclusive outpatient management with oral antibiotics for low-risk FN cases is unsupported by high-level evidence •Early discharge: Evidence supports early discharge in patients with low-risk FN who are clinically stable, with symptomatic improvement and evidence of fever lysis after ≥24 hours in hospital High-risk patients •High-risk patients should be admitted and started on broad spectrum IV antibiotics Local epidemiological bacterial isolate and resistance patterns are crucial to determine first-choice empirical therapy Monotherapy (e.g. an anti-pseudomonal cephalosporin or a carbapenem) is as effective as combination therapy in most patients ––In patients at high risk of prolonged neutropenia and those with bacteraemia, a β-lactam + aminoglycoside are preferred Indications for alternative therapy •A number of situations require a specific antibiotic regimen, rather than standard treatment with a broad-spectrum antibiotic Local antibacterial guidelines should be used to determine the duration of treatment •Central IV catheters: A differential time to positivity (DTTP; i.e. the difference between positivity of results between a catheter culture and peripheral blood culture) of ≥2 hours is a highly sensitive and specific indicator of catheter-related bacteraemia When a catheter-related infection (CRI) is suspected and the patient is stable, the catheter should not be removed without microbiological evidence of infection ––A glycopeptide e.g. vancomycin should be administered through the line, when possible, to cover Gram-positive organisms ––Teicoplanin administered once daily as a line lock is a useful alternative 30 In CRI due to coagulase-negative Staphylococcus, an attempt to retain the catheter can be made if the patient is stable •Catheter retention does not affect resolution of coagulase-negative Staphylococcus bacteraemia, but may be a significant risk factor for recurrence Removal of the catheter is indicated for tunnel infections, pocket infections (implanted port system), persistent bacteraemia despite adequate treatment, atypical mycobacterial infections and candidaemia ––For CRI caused by S. aureus, the literature is divided ––The desire to preserve the catheter must be balanced against the risk of metastatic spread by bloodstream seeding •Pneumonia: A macrolide should be added to a β-lactam antibiotic to increase cover to atypical organisms, e.g. Legionella and Mycoplasma Consider Pneumocystic jerovecii infection in patients who present with high respiratory rates and/or desaturate readily without oxygen or on minimal exertion •Suspected Pneumocystis infection should be treated with high-dose co-trimaxazole •Cellulitis: The addition of vancomycin broadens coverage against skin pathogens •Intra-abdominal or pelvic sepsis: Metronidazole should be initiated •Diarrhoea: Assessment for Clostridium difficile is required and treatment with metronidazole, if suspected •Disseminated candidiasis: Patients at risk are those with prolonged neutropenia e.g. those with haematological malignancies undergoing myeloablative therapy Treatment is usually started empirically in patients whose fever fails to respond to broad-spectrum antibiotics after 3–7 days A chest CT including liver and spleen is required before commencing antiCandida treatment First-line empirical treatment: ––In patients already exposed to an azole or known to be colonised with nonalbicans Candida, liposomal amphotericin B or an echinocandin antifungal (e.g. caspofungin) are appropriate ––In patients who have not received an azole, are at low risk of invasive aspergillosis and when local epidemiological data suggest low rates of azole-resistant isolates of Candida, fluconazole can be given Antifungal treatment should be continued until neutropenia has resolved, or for ≥14 days in patients with a demonstrated fungal infection 31 •Lung infiltrates: Frequent assessment of initial response to antibiotics is essential; in the absence of prompt improvement, further investigations are warranted For suspected invasive aspergillosis, an urgent high-resolution chest CT scan should be performed. If any infiltrate is found, broncho-alveolar lavage should be undertaken, if possible ––For presumed aspergillosis (cases with typical infiltrates on CT) treatment could include voriconazole or liposomal amphotericin B, combined with an echinocandin in unresponsive disease Advice from an infectious diseases specialist/clinical microbiologist should be sought and appropriate therapy against infection with fungi or Pneumocystis species started ––Choice of antifungal agents depends on centres, individual patients and use of prior prophylactic therapy •Vesicular lesions/suspected viral infection: Treatment with acyclovir should be initiated after appropriate samples have been taken Only replace with ganciclovir when there is high suspicion of invasive cytomegalovirus infection •Suspected meningitis or encephalitis: A lumbar puncture should be performed Bacterial meningitis should be treated with ceftazidime + amoxicillin or meropenem Viral encephalitis should be treated with high-dose acyclovir ASSESSMENT OF RESPONSE •The frequency of clinical assessment is determined by the severity of FN •Daily assessment of fever trends, bone marrow and renal function is indicated until the patient is afebrile with ANC ≥0.5 x 109/L 32 ASSESSMENT OF RESPONSE AND SUBSEQUENT MANAGEMENT REVIEW OF THERAPY AT 48 HOURS Patients apyrexial and ANC ≥0.5 x 109/L Pyrexia continues Patient stable: Continue same therapy Low risk On oral antibacterials: Continue therapy and consider early discharge On IV antibacterials: Consider continuing therapy with oral antibacterials Patient deteriorating: Seek expert advice from ID physician or clinical microbiologist High risk Pathogen not identified: Discontinue aminoglycoside, continue IV therapy Pathogen identified: Consider specific antibacterial therapy ID, infectious diseases •In patients who are afebrile with an ANC ≥0.5 x 109/L after 48 hours Low risk and no cause found: Consider changing to oral antibiotics High risk and no cause found: If receiving dual therapy, aminoglycoside may be discontinued Cause found: Continue appropriate specific therapy •In patients who remain febrile after 48 hours and are clinically unstable, antibacterial therapy should be rotated or cover broadened if clinically justified Some haematology units add a glycopeptide, others change the regimen to a carbapenem + glycopeptide Prompt advice from an infectious diseases specialist/clinical microbiologist should be sought due to high risk of serious complications 33 Unusual infections should be considered, particularly in the context of a rising CRP; imaging of the chest and upper abdomen can exclude probable fungal or yeast infection, or abscesses If pyrexia persists for >4–6 days, consider initiating antifungal therapy DURATION OF THERAPY •If ANC ≥0.5 x 109/L, the patient is asymptomatic, has been afebrile for 48 hours and has negative blood cultures, antibiotics can be discontinued •If ANC ≤0.5 x 109/L, the patient has had no complications and has been afebrile for 5–7 days, discontinue antibiotics, except in high-risk cases with acute leukaemia and following high-dose chemotherapy when antibiotics are often continued for up to 10 days or until ANC ≥0.5 x 109/L •Patients with persistent fever despite ANC recovery should be assessed by an infectious diseases specialist/clinical microbiologist and antifungal therapy considered PATIENT EDUCATION AND LOCAL POLICIES •The successful management of FN requires prompt recognition of, and reaction to, potential infections. Thus, it is vital to educate outpatients to monitor symptoms including body temperature, and to provide clear written instructions on when and how to contact the appropriate service •Clear protocols should be put in place to manage patients, including those presenting with FN at the Emergency Department 34 ASSESSMENTS GUIDELINES FOR THE ADEQUATE ASSESSMENT OF PATIENTS WITH PAIN AT ANY DISEASE STAGE 1. ASSESS AND REASSES THE PAIN • Causes, onset, type, site, absence/presence of radiating pain, duration, intensity, relief and temporal patterns of pain, number of breakthrough pain (BTP) episodes, pain syndrome, inferred pathophysiology, pain at rest and/or moving • Presence of trigger factors and signs and symptoms associated with pain • Presence of relieving factors • Use of analgesics and their efficacy and tolerability • Description of pain quality Aching, throbbing, pressure: Often associated with somatic pain Aching, cramping, gnawing, sharp: Often associated with visceral pain Shooting, sharp, stabbing, tingling, ringing: Often associated with neuropathic pain 2. ASSESS AND REASSES THE PATIENT • Clinical situation: By means of a complete/specific physical examination and the specific radiological and/or biochemical investigations • If pain interferes with the patient’s daily activities, work, social life, sleep patterns, appetite, sexual functioning, mood, well-being, coping • Impact of pain, the disease and therapy on physical, psychological and social conditions • The presence of a caregiver, psychological status, the degree of awareness of the disease, anxiety and depression and suicidal ideation, social environment, quality of life (QoL), spiritual concerns/needs, problems with communication and personality disorders • Presence and intensity of signs, physical and/or emotional symptoms associated with cancer pain syndromes • Presence of comorbidities (e.g. diabetes, renal and/or hepatic failure, etc.) • Functional status • Presence of opioidophobia or misconceptions related to pain treatment • Alcohol and/or substance abuse 3. ASSESS AND REASSES YOUR ABILITY TO INFORM AND TO COMMUNICATE WITH THE PATIENT AND THE FAMILY • Take time to spend with the patient and family to understand their needs 35 •Self assessment of pain intensity and treatment outcomes should be undertaken regularly using one of the following standardised scales: Visual analogue scale (VAS) Verbal rating scale (VRS) Numerical rating scale (NRS) VALIDATED ASSESSMENT TOOLS FOR THE ASSESSMENT OF PAIN INTENSITY VISUAL ANALOGUE SCALE 10 cm No pain Worst pain VERBAL RATING SCALE • No pain • Very mild • Mild • Moderate • Severe • Very severe 1 2 3 4 5 6 NUMERICAL RATING SCALE No pain 1 2 3 4 5 6 7 8 9 10 Worst pain •Older age, limited communicative skills, or cognitive impairment, such as during the last days of life, makes self-reporting pain more difficult In these patients, observation of pain-related behaviours and discomfort (i.e. facial expression, body movements, verbalisation or vocalisations, changes in interpersonal interactions, changes in routine activity) is an alternative strategy to assess the presence of pain •The assessment of all components of suffering, such as psychosocial distress, should be considered and evaluated Psychosocial distress is strongly associated with cancer pain and may amplify the perception of pain Inadequately controlled pain may cause substantial psychological distress PRINCIPLES OF PAIN MANAGEMENT •Patients should be informed about pain and its management and be encouraged to take an active role in their pain management 36 Patients should be encouraged to communicate with the physician and/or nurse about their suffering, the efficacy of therapy and adverse events and to not consider analgesic opioids as a therapeutic approach for dying patients Patients’ involvement in pain management improves communication and has a beneficial effect on their pain experience •Analgesics for chronic pain should be prescribed on a regular basis not on an ‘as required’ schedule •Oral analgesics should be advocated first line •For BTP episodes, rescue doses of medications (as required) in addition to regular basal therapy must be prescribed Assess and treat BTP, defined as ‘a transitory flare of pain that occurs on a background of relatively well-controlled baseline pain’ Typical BTP episodes are of moderate-to-severe intensity, rapid onset (minutes) and relatively short duration (median 30 minutes) •Tailor the dosage, type and route of drugs administered according to the patient’s needs An alternative route for opioid administration should be considered when oral administration is not possible (due to severe vomiting, bowel obstruction, severe dysphagia or severe confusion), in the presence of poor pain control requiring rapid dose escalation and/or in the presence of oral opioid-related adverse effects PAIN MANAGEMENT •Analgesic treatment should start with drugs indicated in the World Health Organisation (WHO) analgesic ladder, appropriate for the severity of pain The WHO ladder is a sequential 3-step analgesic ladder: Non-opioids, weak opioids, strong opioids •Opioid analgesics are the mainstay of analgesic therapy and are classified according to their ability to control pain: Mild, mild-to-moderate, moderate-tosevere intensity •Opioid analgesics may be combined with non-opioid drugs, such as paracetamol, or with non-steroidal anti-inflammatory drugs (NSAIDs) and adjuvant drugs 37 ALGORITHM 1: THE TREATMENT OF CANCER PAIN STRONG RECOMMENDATION MILD PAIN Step 1 NRS 1–3 NSAIDS – paracetamol Periodical reassessment of cancer pain Use rescue medications If pain not controlled, go to the next step Step 2 NRS 4–6 Weak opioids ± NSAIDS – paracetamol Periodical reassessment of cancer pain Use rescue medications If pain not controlled, go to the next step WEAK RECOMMENDATION MILD– MODERATE PAIN STRONG RECOMMENDATION MODERATE– SEVERE PAIN Strong opioids ± NSAIDS – paracetamol Step 3 NRS 7–10 Increase the dose of opioid every day, considering the number of opioid rescue doses used, until pain control or side effects Side effects Persisting pain Go on or, if necessary, opioid or route of opioid adminstration switching, using an equianalgesic dose of the same or different opioid: • Symptomatic treatment Team decision • Reasses the pain intensity and its causes • Consider the type and/or doses of adjuvants • Consider opioid or route of opioid adminstration switching • Consider invasive interventions Always use rescue doses to treat BTP Adjuvant drugs such as corticosteroids, anticonvulsants and antidepressants should be considered at any step, when necessary 38 Treatment of mild pain •Paracetamol (acetaminophen) and/or an NSAID are indicated for treating mild pain •Paracetamol and NSAIDs are universally accepted as part of the treatment of cancer pain of all intensities at any step in the WHO analgesic scale, unless contraindicated Paracetamol improves pain and well-being in patients with cancer receiving a strong opioid regimen The addition of an NSAID to WHO step 3 opioids can improve analgesia or reduce opioid dose requirement ––There is no evidence to support superior safety or efficacy of one NSAID over another •Long-term use of NSAIDs or a cyclo-oxygenase-2 (COX-2) selective inhibitor should be periodically monitored and revised They can induce severe toxicity such as gastrointestinal bleeding, platelet dysfunction and renal failure and may increase the risk of thrombotic cardiovascular adverse reactions (COX-2 inhibitors) Treatment of mild-to-moderate pain •Weak opioids such as codeine, tramadol and dihydrocodeine should be given in combination with non-opioid analgesics Traditionally, patients with mild-to-moderate pain have been treated with a combination product containing acetaminophen, aspirin or NSAID plus a weak immediate-release opioid such as codeine, dihydrocodeine, tramadol or propoxyphene •The use of drugs in step 2 of the WHO ladder is controversial due to the absence of definitive evidence for the efficacy of weak opioids over non-opioids Uncontrolled studies also show that the efficacy of drugs in step 2 of the WHO ladder have a time limit of 30–40 days in most patients, and that the shift to step 3 is mainly due to insufficient analgesia, rather than adverse effects The use of weak opioids is also associated with a ‘ceiling effect’ above which increasing the dose does not improve efficacy but is associated with increased adverse effects •As an alternative to weak opioids, low doses of strong opioids in combination with non-opioid analgesics should be considered Many authors have proposed the abolition of step 2 of the WHO analgesic ladder in favour of the early use of low-dose morphine ––Until now the few studies designed to evaluate this specific topic have reported inconclusive results due to the small number of patients enrolled 39 Treatment of moderate-to-severe pain •Strong opioids are the mainstay of analgesic therapy in treating moderate-tosevere cancer-related pain •Oral morphine is the opioid of choice There is no evidence that other opioids are superior to morphine in terms of efficacy and tolerability The efficacy of tapentadol prolonged release is superior to placebo during maintenance and not inferior to oral controlled release morphine during the titration phase Oral morphine is effective, well tolerated, simple to administer and inexpensive Morphine is the only opioid analgesic considered in the WHO essential drug list for adults and children with pain •Oral hydromorphone or oxycodone (immediate-release and modified-release) and oral methadone are effective alternatives to oral morphine •Although the oral route is advocated, patients presenting with severe pain who require urgent relief should be treated with titrated parenteral opioids, usually administered by the subcutaneous (SC) or intravenous (IV) route When converting from oral to parenteral morphine, the dose should be divided by two or three to get an approximately equianalgesic effect; upward or downward dose adjustment may be required ––The average relative potency ratio of oral to IV or SC morphine is between 1:2 and 1:3 •Transdermal fentanyl and buprenorphine are usually the treatment of choice for patients who are unable to swallow, those with poor tolerance of morphine and those with poor compliance They are best reserved for patients whose opioid requirements are stable •In patients with renal impairment, all opioids should be used with caution and at reduced doses and frequency Fentanyl and buprenorphine (transdermal or IV) are the safest opioids and the opioids of choice in patients with chronic kidney disease stages 4 or 5 (estimated glomerular filtration rate <30 mL/min) ––Buprenorphine is not recommended by the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Adult Cancer Pain because it is a partial agonist Methadone is a valid alternative but should be initiated by physicians with experience and expertise in its use •Opioid switching is a practice used to improve pain relief and/or drug tolerability 40 There is no high-quality evidence to support this approach, but it is frequently used in clinical practice The most frequent switch is from morphine, oxycodone, hydromorphone or fentanyl to oral methadone This approach requires familiarity with equianalgesic doses of the different opioids •Strong opioids may be combined with ongoing non-opioid analgesics Scheduling and titration •Dose titration using normal-release or immediate-release (IR) morphine administered every 4 hours plus rescue doses (up to hourly) for BTP are recommended in clinical practice Normal-release morphine has a short half-life and is indicated during the titration phase to reach the effective daily dose as well as preventive administration to treat predictable episodes of BTP pain of 20–30 minutes duration in patients receiving regular background analgesia •All patients should receive around-the-clock dosing with provision of a ‘rescue dose’ to manage transient exacerbations of pain The ‘breakthrough dose’ is usually 10–15% of the total daily dose •After titration, slow-release opioids are indicated If >4 ‘rescue doses’ are required per day, the baseline opioid treatment with a slow-release formulation should be adapted ––Opioids with a rapid onset and short duration are preferred as rescue medications Immediate release opioids should always be prescribed when necessary •Titration of IV morphine is indicated for patients with severe pain 41 TITRATION OF IV MORPHINE FOR SEVERE CANCER PAIN RCT 62 patients with pain intensity NRS ≥5 and naïve to strong opioids Patients were randomised to receive IV morphine (n=31) or oral IR morphine (n=31) IV Group: 1.5 mg bolus every 10 minutes until pain relief (or adverse effects) Oral group: Opioid-naïve patients: IR morphine 5 mg every 4 hours Patients on weak opioids: 10 mg Rescue dose: The same dose every 1 hour max IV Group: Oral IR morphine every 4 hours, on the basis of the previous IV requirements IV: PO conversion 1:1 Rescue dose: The same dose every 1 hour max Oral group: Follow the same scheme % OF PATIENTS ACHIEVING SATISFACTORY PAIN RELIEF • After 1 hour: IV group, 84%; oral group, 25% (p<0.001) • After 12 hours: IV group 97%; oral group 76% (p<0.001) • After 24 hours: IV group and oral group similar IV Group: Median morphine dosage (IV) to achieve pain relief: 4.5 mg (range 1.5–34.5). In the same group, mean oral morphine dosage after stabilisation: 8.3 mg (range 2.5–30) Oral group: Median morphine dosage to achieve pain relief: 7.2 mg (2.5–15) No significant adverse events IR, immediate release; RCT, randomised controlled trial: PO, oral (per os) Harris JT, et al. Palliat Med 2003;17:248–56 Reproduced by permission of Sage Publications Ltd. MANAGEMENT OF OPIOID ADVERSE EFFECTS •Many patients develop adverse effects such as constipation, nausea/vomiting, urinary retention, pruritus and central nervous system (CNS) toxicity (drowsiness, cognitive impairment, confusion, hallucinations, myoclonic jerks and – rarely – opioid-induced hyperalgesia/allodynia) •Sometimes, a reduction in the opioid dose may reduce the incidence and/or severity of adverse effects This may be achieved by using a co-analgesic or an alternative approach such as a nerve block or radiotherapy •Other strategies to reduce adverse events include: Switching to another opioid agonist and/or administration route may allow titration to adequate analgesia without disabling effects, as some adverse effects may be caused by accumulation of toxic metabolites ––This is especially true for symptoms of CNS toxicity (e.g. opioid-induced hyperalgesia/allodynia and myoclonic jerks) 42 ––Dose reduction or opioid switching is a potential effective way to manage delirium, hallucination, myoclonus and hyperalgesia There is limited evidence for the use of methylphenidate in the management of opioid-induced sedation and cognitive disturbance ––It’s not possible to recommend other drugs for the treatment of any other CNS adverse effect Continued use of antiemetics for nausea: Metoclopramide and antidopaminergic drugs are recommended Routine prescription of laxatives for both the prophylaxis and the management of opioid-induced constipation ––Methylnaltrexone (SC) should be used to treat opioid-related constipation resistant to traditional laxatives ––The potential clinical effects on constipation of new pharmacological developments (e.g. oxycodone and naloxone) have been demonstrated in patients with moderate-to-severe chronic cancer pain •Naloxone is a short-acting IV opioid antagonist able to revert symptoms of accidental severe opioid overdose BREAKTHROUGH PAIN (BTP) •There is no widely accepted definition, classification system or well-validated assessment tool for cancer-related BTP •IR formulation of opioids must be used to treat exacerbations of uncontrolled background pain •IR oral morphine is appropriate to treat predictable episodes of BTP (e.g. pain on moving or swallowing) when administered at least 20 minutes before potential painful triggers IV opioids and buccal, sublingual and intranasal fentanyl drug delivery have a shorter onset of analgesic activity than oral morphine ––Fentanyl pectin nasal spray significantly improved pain symptoms with superior acceptability compared with IR oral morphine BONE PAIN •The use of analgesics drugs in Algorithm 1 should always be considered in the treatment of bone pain •Radiotherapy, radioisotopes and targeted therapy given in association with analgesics have an important role in bone pain management 43 ALGORITHM 2: TREATMENT OF PAIN DUE TO BONE METASTASES Zoledronic acid, denosumab or pamidronate should be given also in the absence of pain. These drugs have demonstrated a delay in SREs and the appearance of pain The same strategies suggested for uncomplicated bone metastases with or without bone pain Zoledronic acid, denosumab or pamidronate should be given because they have been shown to delay first and subsequent SREs UNCOMPLICATED BONE METASTASES NO Bone Pain YES Zoledronic acid, denosumab or pamidronate (only in breast cancer) (plus calcium and vitamin D supplementation) should be given in addition to antalgic radiotheraphy. These drugs have been shown to delay SREs and to reduce pain. Patients should undergo a preventative dental screening by dentistry prior to initiating therapy with one of these drugs. The optimal duration of these drugs is not completely defined USE ANALGESIC THERAPY Complicated bone metastases (spinal cord compression or YES NO impending fracture) NO Previous SRE: Radiotherapy, bone surgery YES Radiotherapy and/or surgery should be promptly considered, when appropriate. Zoledronic acid, denosumab or pamidronate should be given because they have been shown to delay first and subsequent SREs USE ANALGESIC THERAPY Zoledronic acid, denosumab or pamidronate should be given because they have been shown to delay subsequent SREs USE ANALGESIC THERAPY SRE, skeletal-related event Radiotherapy •All patients with painful bone metastases should be evaluated for external beam radiotherapy (EBRT) at a single 8 Gy dose •Higher EBRT doses and protracted fractionations should be reserved for selected patients on the basis of better expected outcomes •Stereotactic body radiosurgery should be used for fit patients included in clinical trials 44 It permits the administration of very high radioablative doses to the tumour (typically in single fractions of 10–16 Gy or hypofractionated: 3 x 9 Gy or 5 x 6–8 Gy), avoiding excessive dose to surrounding normal tissues, such as the vertebrae or spinal cord Metastatic spinal cord compression (MSCC) •Early diagnosis (clinical and MRI) and prompt therapy are powerful predictors of outcome in MSCC •Dexamethasone (medium doses) should be prescribed immediately in patients diagnosed with MSCC Doses of 16 mg/day are most commonly prescribed •The majority of patients with MSCC should receive radiotherapy alone Hypofractionated radiotherapy regimens is the approach of choice ––More protracted RT regimens (e.g. 5 x 4 Gy, 10 x 3 Gy) can be used in selected patients with MSCC and a long life expectancy •Surgery should be reserved for particular cases, i.e. those with single-level MSCC and neurological defects Other indications for surgery may include: Stabilisation, vertebral body collapse causing bone impingement on the spinal cord or nerve root, compression recurring after radiotherapy and an unknown primary tumour requiring histological confirmation for diagnosis •Radioisotope treatment can be evaluated in selected patients with multiple osteoblastic bone metastases Targeted therapy Bisphosphonates •Bisphosphonates should be considered as part of the therapeutic regimen for the treatment of patients with/without pain due to metastatic bone disease They form part of the standard therapy for hypocalcaemia and the prevention of SREs in some cancers •While there is sufficient evidence to support the analgesic efficacy of bisphosphonates in patients with bone pain due to bone metastases from solid tumours or multiple myeloma, bisphosphonates should not be considered as an alternative to analgesic treatment After the first IV infusion, pain can appear or its intensity can increase, and the use of analgesics such as paracetamol or an increase in basal analgesic dose is necessary •Bisphosphonates should be started after preventive dental measures 45 Denosumab •Denosumab should be considered as a valid alternative to bisphosphonates for the treatment of patients with solid tumours with/without pain due to metastatic bone disease Denosumab is a targeted receptor activator of nuclear factor kappa-B (RANK) ligand inhibitor for the prevention of SREs •Evidence suggests that denosumab delays bone pain more than zolendronic acid; further evidence is required •Denosumab should be started after preventative dental measures NEUROPATHIC PAIN •Patients with neuropathic pain, either caused by tumour infiltration or due to paraneoplastic or treatment-induced polyneuropathy, should be treated with nonopioid and opioid drugs ± either a tricyclic antidepressant or an anticonvulsant Adverse effects should be monitored •In patients with neuropathic pain due to bone metastases, EBRT (20 Gy in 5 fractions) should be considered •Steroids should be considered in cases of nerve compression •IV lidocaine and oral mexiletine can decrease neuropathic pain in selected patients 46 ALGORITHM 3: ASSESSMENT AND TREATMENT OF NEUROPATHIC PAIN SEMANTIC DESCRIPTOR OF NEUROPATHIC PAIN Allodinia: Pain caused by a stimulus which normally does not provoke pain Causalgia: Continuous burning pain, allodinia and hyperpathia in succession or a traumatic nervous lesion; disturbed vasomotor functions are often intercurrent, as well as, later on, disturbances to trophism Central pain: Pain associated with a lesion of the central nervous system Dysesthesia: unpleasant sensation of tingling, stabbing or burning, whether spontaneous or provoked Hyperaesthesia: Increase in sensitivity to specific stimuli Hyperalgesia: Increased response to a stimulus which is normally painful Hyperpathia: Painful syndrome characterised by increased reaction to a stimulus, especially a repetitive stimulus Paraesthesia: Abnormal sensation, either spontaneous or evoked ASSESSMENT TOOLS FOR NEUROPATHIC PAIN CLINICAL ASSESSMENT OF NEUROPATHIC PAIN Reassess neuropathic component in mixed pain or search neuropathic mimicking pain Assessment tools: Neuropathic Pain scale Neuropathic Pain Sympton Inventory Assessment and screening tools: Scale of pain LANSS Neuropathic Pain Questionnaire Questionnaire DN4 Compression, dislocation, stretching of: Peripheral nerves, nervous roots plexies, neuraxis, cerebral centres Neoplastic infiltration (sensitive nervous structures) Iatrogenic causes (neuropathy caused by anticancer treatments: Drugs, RT, surgery) NO NEUROPATHIC PAIN? YES Non opioids ± strong opioids ± amitriptyline 25–75 mg/day or gabapentin 300-3600 mg/day RT for neuropathic pain due to bone metastases LANSS, leeds assessment of neuropathic symptoms and signs; DN4, douleur neuropathique 47 INVASIVE MANAGEMENT OF REFRACTORY PAIN •Interventions such as nerve blocks and spinal drug delivery (intrathecal or epidural), may allow patients refractory to all conventional strategies and/or with dose limiting analgesic-related adverse effects to achieve pain control when used as alone or, more frequently, in combination with systemic therapy An improvement in pain control and adverse effects has been shown by switching from oral morphine to epidural or continuous SC infusion of morphine No significant benefit (efficacy or adverse effects) have been shown with epidural vs SC administration of morphine Coadministration of local anaesthetics, α-2-adrenergic agonists or N-methyl-Daspartate (NMDA) antagonists may significantly improve the quality of epidural analgesia compared with SC analgesia Spinal drug delivery •Intraspinal techniques monitored by a specialised team should be included as part of a cancer pain management strategy; widespread use should be avoided Spinal opioids can be administered epidurally or intrathecally via percutaneous catheters, tunneled catheters or implantable programmable pumps •Spinal administration leads to decreased opioid consumption Only 20–40% and 10% of the systemic dose is required to produce equianalgesia via epidural and intrathecal administration, respectively •Intraspinal delivery should be considered in patients with: Inadequate pain relief despite escalating systemic opioid doses Inadequate pain control after switching the opioid or the route of administration due to increased adverse effects due to opioid dose escalation •Intrathecal drug delivery (ITDD) should be considered in patients experiencing pain in various anatomic locations: Head and neck, upper and lower extremities, trunk Life-expectancy >6 months justifies an implantable intrathecal pump, but only after a trial using a temporary epidural or spinal catheter to determine efficacy and appropriate dose range ––Fully implanted systems offer less risk of infection and require less maintenance than percutaneous administration, but the positioning is more complex ––Not appropriate in patients with infections or coagulopathy Compared with epidural drug delivery, ITDD presents fewer catheter problems, smaller drug dose requirement and less addictive adverse effects. It also 48 provides better pain control, a decreased risk of infection and is less affected by the presence of extensive epidural metastases Morphine, ziconotide and baclofen are administered intrathecally, sometimes with local anaesthetics (bupivacaine 0.125–0.25%) •Limited evidence supports the use of sub-anesthetic doses of ketamine, an NMDA antagonist, in intractable pain ALGORITHM 4: INTRATHECAL INFUSION FOR REFRACTORY CANCER PAIN LIFE EXPECTANCY <3 MONTHS EPIDURAL CATHETER Tunneled or with implantable system Somatic or neuropathic pain or SPINAL CATHETER Tunneled or with implantable system Somatic or neuropathic pain LIFE EXPECTANCY >3 MONTHS INTRATHECAL (IT) SINGLE SHORT TRIAL Somatic or neuropathic pain Pain intensity decreases >50% Pain intensity decreases <50% Trial with IT CATHETER NO IT CATHETER Pain intensity decreases >50% Pain intensity decreases <50% IT implantable pump Reassessment and treatment of total pain by an interdisciplinary team 49 Peripheral nerve block •Peripheral nerve blocks are rarely used as the principal pain treatment; they are always used with systemic analgesia, according to a multipharmacologic approach •Peripheral nerve blocks or plexus blocks can be used when pain occurs in the field of one or more peripheral nerves, or if pain is caused by complications such as pathological fracture or vascular occlusion •The use of neurolytic agents on peripheral nerves may cause neuritis Neurolytic blockade •Neurolytic blocks should be limited to those patients with a short life expectancy because they usually last 3–6 months •Sympathetic system neurolytic blocks should be considered as adjuvant therapy to decrease the use of oral and/or parenteral analgesics •Superior hypogastric plexus block is used to treat pelvic pain of visceral origin •Ganglion impar block is used to treat perineal pain of visceral origin •Celiac plexus block (CPB) is used to treat pain of visceral aetiology only and pain due to cancer of the upper abdomen or pancreas CPB appears to be safe and effective for the reduction of pain in patients with pancreatic cancer, with a significant advantage over standard analgesic therapy for up to 6 months END-OF-LIFE PAIN •53–70% of patients with cancer-related pain require an alternative route for opioid administration months and hours before death •A careful assessment of the total suffering is mandatory to plan the appropriate intervention •Pain is often accompanied by other symptoms such as dyspnoea, agitation, delirium and anxiety •On some occasions, as patients are nearing death, pain is perceived as ‘refractory’ To consider pain refractory, the clinician must, after a meticulous assessment of physical pain and total suffering, perceive that the further application of standard interventions as previously described is: ––Incapable of providing adequate relief ––Associated with excessive and intolerable acute or chronic morbidity ––Unlikely to provide relief, so that other interventional approaches may be necessary to control pain caused by obstruction of hollow organs 50 •In this situation, sedation may be the only therapeutic option The justification of sedation in this setting is that it is an appropriate and proportionate goal Commonly used agents include opioids, neuroleptics, benzodiazepines, barbiturates and propofol Administration initially requires dose titration to achieve adequate relief, followed by provision of ongoing therapy to ensure maintenance of the effect Continuous assessment of suffering should be performed during the sedation process 51 DEFINITION •Mucositis: Inflammatory and/or ulcerative lesions of the oral and/or gastrointestinal (GI) tract •Alimentary tract mucositis: The expression of mucosal injury across the continuum or oral and gastrointestinal mucosa, from the mouth to the anus RISK FACTORS •Risk of mucositis is associated with modality, intensity and route of delivery of the cancer therapy Combination therapy (e.g. head and neck radiotherapy + concurrent chemotherapy) may increase the severity of oral mucositis •Additional risk factors include those related to patient characteristics, such as genetic polymorphisms and comorbidities GRADING •Two of the most commonly utilised scales for assessment of oral mucositis are the World Health Organisation (WHO) and National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) scales COMMONLY USED ASSESSMENT SCALES FOR ORAL MUCOSITIS GRADE WHO SCALE CTCAE SCALE (V 4.0) 0 No oral mucositis n/a 1 Erythema and soreness Asymptomatic or mild symptoms; intervention not indicated 2 Ulcers, able to eat solids Moderate pain; not interfering with oral intake; modified diet indicated 3 Ulcers, requires liquid diet* Severe pain; interfering with oral intake 4 Ulcers, alimentation not possible* Life-threatening consequences; urgent intervention indicated *Due to mucositis; n/a, not applicable •There are a limited number of instruments available to assess GI mucositis 52 They typically measure indirect outcomes of mucosal injury, including diarrhoea, but interpretation of these data can be confounded by other clinical conditions and interventions MANAGEMENT OF MUCOSITIS •The oral and GI mucositis management guidelines summarised below are based on the guidelines developed by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO) Oral mucositis Basic oral care and good clinical practice •Patient and staff education on the use of systematic oral care protocols is recommended to reduce the severity of oral mucositis from chemotherapy and/ or radiation therapy. Multidisciplinary protocols should be consistent with good clinical practice, and include: Non-medicated oral rinses should be used frequently (e.g. saline mouth rinses 4–6 times/day) Use of a soft toothbrush replaced on a regular basis is suggested Alcohol-based mouth rinses should be avoided •In patients undergoing haematopoietic stem-cell transplantation (HSCT), patientcontrolled analgesia with morphine is recommended for oral mucositis pain Validated instruments should be used for regular, self-reported oral pain assessments •All patients should be screened for nutritional risk (high risk of malnutrition following high-dose chemoradiotherapy), with enteral nutrition started early in the case of swallowing problems •Topical anaesthetics can provide short-term pain relief on an empirical basis Prevention of oral mucositis: Radiotherapy •Midline radiation blocks and three-dimensional radiation treatment are recommended to reduce mucosal injury •In patients with head and neck cancer receiving moderate-dose radiation therapy, benzydamine oral rinse for preventing radiation-induced mucositis is recommended; chlorhexidine is not recommended Benzydamine is not available in the United States of America •Antimicrobial lozenges are not recommended for prevention of radiation-induced oral mucositis Prevention of oral mucositis: Standard-dose chemotherapy •In patients receiving bolus fluorouracil (5-FU) chemotherapy or bolus doses of edatrexate, oral cryotherapy is recommended •In patients with breast cancer, inclusion of granulocyte colony-stimulating 53 factor (G-CSF) in docetaxel/doxorubicin/cyclophosphamide (TAC) regimens may significantly reduce toxicities, including mucositis (stomatitis) •In patients receiving standard-dose chemotherapy, intravenous (IV) acyclovir and its analogues are not recommended to prevent mucositis Antivirals may be indicated to treat a newly-emergent or recurrent oral viral infection that may co-exist with mucositis •The use of palifermin (keratinocyte growth factor-1) IV in patients with solid tumours requires further evaluation Prevention of oral mucositis: High-dose chemotherapy ± total body irradiation + hematopoietic stem-cell transplantation (HSCT) •In patients with haematological malignancies receiving high-dose chemotherapy and total body irradiation with autologous stem cell transplantation, palifermin 60 μg/kg/day for 3 days before conditioning treatment and for 3 days posttransplant is recommended Oral cryotherapy is suggested in patients receiving high-dose melphalan •In patients undergoing HSCT, topical pentoxifylline as well as granulocyte– macrophage colony-stimulating factor (GM-CSF) mouthwashes are not recommended •In patients receiving high-dose chemotherapy or chemoradiotherapy before HSCT, low-level laser therapy (LLLT) is suggested, if available Treatment of oral mucositis: Radiotherapy •Oral sucralfate is not recommended Treatment of oral mucositis: Standard-dose chemotherapy •Chlorhexidine oral rinses are not recommended to treat established oral mucositis Chlorhexidine oral rinses may be an option as a topical antimicrobial to enhance the treatment of oral infection, based on professional judgment Treatment of oral mucositis: Supportive care •Some clinicians utilise approved topically administered agents for mucositis management (including Gelclair®, Caphosol® and Biotene®); evidence to support this intervention is limited, although these products appear to have an adequate safety profile and benefit some patients Gastrointestinal mucositis Basic bowel care and good clinical practice •Basic bowel care should include maintenance of adequate hydration 54 •Consideration should be given to the potential for transient lactose intolerance and the presence of bacterial pathogens Prevention of gastrointestinal mucositis: Radiotherapy •In patients receiving external beam radiotherapy to the pelvis, 500 mg sulfasalazine orally twice daily (bid) is suggested to reduce the incidence and severity of radiation-induced enteropathy Oral sucralfate is not recommended to reduce related side effects of radiotherapy •In patients with rectal cancer receiving standard-dose radiotherapy, amifostine (intrarectal; ≥340 mg/m2) is suggested to prevent radiation proctitis •Oral mesalazine (5-aminosalicylic acid) and its derivative, olsalazine, are not recommended to prevent gastrointestinal mucositis Prevention of gastrointestinal mucositis: Standard- and high-dose chemotherapy •In patients who have received standard-dose cyclophosphamide/methotrexate/ fluorouracil (CMF) or 5-FU ± folinic acid, either ranitidine or omeprazole orally are recommended for the prevention of epigastric pain •Systemic glutamine is not recommended for the prevention of GI mucositis Prevention of gastrointestinal mucositis: Chemoradiotherapy •In patients with non-small-cell lung cancer (NSCLC) receiving chemoradiotherapy, amifostine IV is suggested to reduce oesophagitis Treatment of gastrointestinal mucositis: Radiotherapy •In patients who have rectal bleeding, sucralfate enemas are suggested to help manage chronic radiation-induced proctitis Treatment of gastrointestinal mucositis: Standard- and high-dose chemotherapy •In patients undergoing HSCT receiving standard- or high-dose chemotherapy associated with HSCT, octreotide ≥100 μg subcutaneously (SC) bid is recommended when loperamide fails to control diarrhoea 55 DIAGNOSIS •Obstetricians and general practitioners should be aware that a breast lump, an atypical vaginal discharge, a changing mole or an enlarging lymph node may be associated with a diagnosis of cancer in a pregnant woman •When indicated, pathological examination (including immunohistochemical or molecular analysis) of suspected lesions should follow standard procedures as in the non-pregnant setting Pathological features and prognosis of patients diagnosed during pregnancy are usually comparable with age- and stage-matched non-pregnant patients It is unclear whether prognosis is poorer for patients diagnosed with breast cancer during pregnancy compared with non-pregnancy •It is recommended that once cancer diagnosis is confirmed during pregnancy, the patient should be referred to an institution with expertise in dealing with such cases This could involve the patient’s partner and family in the decision-making process Patients should be managed in a multidisciplinary team (MDT), including an obstetrician and a neonatologist, as well as the oncology team in order to adequately evaluate potential maternal benefits and possible foetal risks STAGING AND RISK ASSESSMENT •Whenever possible, imaging procedures should aim to limit exposure to ionising radiation Ultrasound is the preferred imaging modality for the breast, abdomen and pelvis Chest X-ray and mammography with abdominal shielding can be performed safely during pregnancy Magnetic resonance imaging (MRI) without gadolinium may be used if the above modalities are inconclusive or where there are suspicious bone or brain metastases Computed tomography, bone and positron emission tomography scans should be avoided throughout pregnancy •Evaluation of serum tumour markers, particularly CA125 and CA15.3, is not recommended in pregnancy because of considerable variation in results 56 OBSTETRIC CARE AND FOETAL FOLLOW-UP •During the first trimester, when organogenesis occurs, systemic treatment with chemotherapy is associated with a high risk of miscarriage and, in some cases, congenital malformations •Initiation of systemic chemotherapy is less problematic in the second trimester; however, chemotherapy is still associated with foetal complications when administered in the second and third trimesters, which include: Intrauterine growth restriction Premature rupture of membranes Premature labour •Current recommendations advocate standard chemotherapy regimens after the first trimester; however, this may not be feasible in all patients and a tailored approach may be required •Despite the lack of significant long-term complications in foetuses exposed to chemotherapy initiated in the second trimester, these pregnancies should be regarded as high risk and regular foetal monitoring should be considered during gestation •It is recommended that full-term delivery (i.e. ≥37 weeks) should be targeted whenever possible, since subtle but significant cognitive impairment may occur in preterm babies exposed to chemotherapy in utero Early (34–37 weeks) or very early (<34 weeks) delivery should be discouraged unless maternal and/or foetal health are endangered by the postponement of delivery until term •Whenever possible, it is recommended that the placenta is examined histologically, particularly in patients diagnosed with melanoma (the most common tumour associated with placental metastasis) LOCAL TREATMENTS General concepts: Surgery •A slightly higher risk of miscarriage is reported during the first trimester; however, surgery is safe at any time during the course of the pregnancy •Indications for major abdominal and pelvic surgery should follow a thorough discussion with the patient and the MDT, since there is an associated increased risk for morbidity and pregnancy complications •Surgery should not be postponed if deemed to be crucial in the management plan •Maternal and foetal conditions should be monitored, particularly after the 25th week of gestation 57 General concepts: Radiotherapy •Gestational radiotherapy carries several risks: childhood cancer; intrauterine growth restriction; mental retardation; and foetal death •It is preferable to postpone radiotherapy to the postpartum period, irrespective of the treated site, unless there is an urgent clinical need and provided that the site is located sufficiently far from the uterus Breast cancer •The decision to proceed to mastectomy or breast conservative surgery should follow the standard practice as in the non-pregnant setting •Although more data are needed on sentinel lymph node biopsy (SLNB) in pregnant patients, SLNB should not be discouraged in centres in which this technique is routine in the non-pregnant setting •Use of vital blue dye is discouraged in pregnant patients owing to potentially life-threatening allergic reactions •It is advised that adjuvant radiotherapy is postponed until after the baby is delivered, since treatment is not urgent •The local management strategy should be planned carefully in breast cancer patients diagnosed during the first trimester •A thorough discussion should occur between the patient and the MDT about the risks and benefits of different surgical modalities (e.g. breast conserving surgery) and the timing of radiotherapy (e.g. postponing radiotherapy until after delivery could delay its administration for >6 months, which may increase the risk for local recurrence) Cervical cancer •The main modalities for managing cervical cancer are radical hysterectomy and/ or pelvic radiotherapy with or without cisplatin; however, radical surgery and pelvic radiation result in pregnancy termination and foetal death •Patients who wish to preserve their pregnancy should be informed that management would require modification of standard local treatment; it is unknown whether this is detrimental to outcomes •In early-stage cervical cancer, definitive treatment may be postponed until after delivery, with close monitoring during pregnancy •In more advanced-stage cervical cancer, thorough radiological and surgical staging is used to discriminate between the need for immediate treatment and watchful waiting in patients who wish to preserve their pregnancy •The gold standard for predicting nodal metastases during pregnancy is lymphadenectomy, while pelvic MRI also has good positive predictive value 58 Lymphadenectomy can be performed safely laparoscopically during pregnancy •For patients with locally advanced or high-risk tumours, platinum-based chemotherapy with or without paclitaxel is an option •Radical surgery may be offered concomitantly to Caesarean section in qualified centres •The ESMO CPG for managing cervical cancer during pregnancy are summarised in the table below ESMO CLINICAL PRACTICE GUIDELINES IN PATIENTS DIAGNOSED WITH CERVICAL CANCER DURING PREGNANCY TIME OF DIAGNOSIS RECOMMENDATIONS First trimester Discuss pregnancy termination and standard treatment as outside pregnancy. If the patient wishes to preserve the pregnancy, discuss close monitoring up to second trimester (see below). Second trimester Stage IB1 Stage IB2-IVA Distant metastasis Third trimester Lymphadenectomy (i) Node-negative: watchful waiting or chemotherapy* during pregnancy, followed by hysterectomy or large cone after delivery. (ii) Node-positive: chemotherapy* during pregnancy followed by radical hysterectomy at delivery or chemoradiotherapy following delivery. Discuss pregnancy termination and standard treatment as outside pregnancy. Chemotherapy* during pregnancy. Manage the case by surgery and/or chemoradiotherapy according to the stage and level of nodal involvement after delivery. Discuss pregnancy termination and standard treatment as outside pregnancy. Chemotherapy during pregnancy. Discuss pregnancy termination and standard treatment as outside pregnancy. Delay treatment until delivery and consider early induction of labour. *Cisplatin (75 mg/m2 q 3 weeks) or carboplatin-based regimens ± paclitaxel regimens q 3 weeks or weekly 59 SYSTEMIC TREATMENTS General concepts on the use of chemotherapy during pregnancy •Chemotherapy is contraindicated during the first trimester of gestation owing to its associated high risk for foetal congenital malformations Termination of pregnancy should be considered in patients requiring chemotherapy to be initiated during the first trimester •In patients requiring chemotherapy during the second and third trimester, not all chemotherapeutic agents are regarded as ‘equally safe’ •Calculation of chemotherapy doses should follow standard procedures outside the pregnancy setting, while acknowledging that the pharmacokinetics of some cytotoxic drugs may be altered during pregnancy •Delivery should be avoided during the nadir period, therefore a period of 3 weeks should be allowed between the last chemotherapy dose and the expected delivery date Chemotherapy should not be administered beyond week 33 of gestation since spontaneous delivery could occur any time after 34 weeks of gestation Weekly administration of chemotherapy, particularly doxorubicin, epirubicin and paclitaxel, should be considered during pregnancy because of the lower risk for haematological toxic effects and shorter nadir periods compared with other agents and schedules Breast cancer •Indications for systemic therapy should follow those for the non-pregnant setting, taking into consideration the gestational age at diagnosis and the expected delivery date •The ESMO CPG for managing breast cancer during pregnancy are summarised in the table on the next page •Anthracycline-based regimens remain the first choice during pregnancy and one regimen is not preferred over another; the choice of regimen should be based on local practice in the non-pregnant setting •Taxanes are endorsed during pregnancy in cases where they are clinically indicated or the use of anthracyclines is contraindicated Weekly paclitaxel is the preferred option over docetaxel (3-weekly regimen) owing to its weekly schedule (enabling close pregnancy monitoring), superior toxicity profile and the lack of requirement for high-dose steroid premedication or prophylactic granulocyte colony-stimulating factor Docetaxel should be restricted to situations in which it is clinically urgent 60 •Tamoxifen is contraindicated at any time during pregnancy since it is associated with foetal malformation •Use of HER2-targeted agents (e.g. trastuzumab) in pregnant patients with HER2- positive disease should be postponed until after delivery because of the high risk of oligo-anhydramnios ESMO CLINICAL PRACTICE GUIDELINES IN PATIENTS DIAGNOSED WITH BREAST CANCER DURING PREGNANCY BREAST CANCER SUBTYPE RECOMMENDATIONS Hormonal agents (LHRH, tamoxifen) are contraindicated during pregnancy. Endocrine-sensitive Early (i.e. adjuvant, neoadjuvant) (i) If node-positive, and/or signs of aggressive disease (i.e. luminal-B), wait until second trimester and start anthracycline-based chemotherapy. Patients diagnosed in the third trimester could be counselled on a case-by-case basis and in some of them treatment could be deferred until delivery. (ii) If node-negative, low proliferative disease (i.e. luminal-A), observe until delivery, then start hormonal therapy Metastatic (i) Wait until the second trimester and start an anthracycline-based regimen HER2-targeted agents are contraindicated during pregnancy HER2-positive Early (i.e. adjuvant, neoadjuvant) (i) Wait until second trimester and start anthracycline-based chemotherapy until delivery. Taxanes could be added in sequence during pregnancy if needed, (ii) Trastuzumab to be added following delivery. (iii) Patients diagnosed in the third trimester could start chemotherapy until week 34 and aim to deliver at term Metastatic (i) If chemotherapy and/or trastuzumab need to be urgently started during the first trimester, discuss pregnancy termination. Otherwise, follow the procedure as in the early setting 61 BREAST CANCER SUBTYPE RECOMMENDATIONS Triple negative Early (i.e. adjuvant, neoadjuvant) (i) Wait until the second trimester and start an anthracycline-based chemotherapy until delivery. Taxanes could be added in sequence during pregnancy if needed. (ii) Patients diagnosed in the third trimester could start chemotherapy until week 34 and aim to deliver at term Metastatic (i) If chemotherapy needs to be urgently started during the first trimester, discuss pregnancy termination. Otherwise, follow the procedure as in the early setting LHRH, luteinising hormone-releasing hormone Lymphoma •Pregnant patients diagnosed with low-grade non-Hodgkin’s lymphoma (NHL) should be kept under close observation until delivery •Therapy should be initiated immediately in patients with aggressive NHL Termination of the pregnancy should be considered when the diagnosis is made early during the first trimester because of the high risk for foetal malformations •Cyclophosphamide-doxorubicin-vincristine-prednisolone (CHOP) is the standard chemotherapy for managing NHL and the first choice for those diagnosed during pregnancy •Administration of rituximab is not discouraged during pregnancy in patients with B-cell lymphoma in whom postponement of therapy would significantly compromise maternal prognosis Patients starting rituximab during pregnancy should be informed that it may increase the risk for B-cell depletion in the new-born baby and therefore affect foetal immunity for some time, even when there is spontaneous recovery of the neonatal B-cell count •Patients with Hodgkin’s lymphoma who need prompt chemotherapy may receive doxorubicin-bleomycin-vinblastine-dacarbazine (ABVD) starting from the second trimester Leukaemia •The use of cytarabine in combination with doxorubicin is proposed for managing acute myeloid leukaemia (AML) during pregnancy, instead of the standard chemotherapy regimen of daunorubicin or idarubicin in combination with cytarabine, as in the non-pregnant setting 62 •Interferon-alpha can be used safely, even during the first trimester, in pregnant patients with chronic myeloid leukaemia (CML) •Among targeted therapies, imatinib is the only agent for which there are data confirming its safe use only when administered during the second and third trimesters •The ESMO CPG for managing leukaemia during pregnancy are summarised in the table below ESMO CLINICAL PRACTICE GUIDELINES IN PATIENTS DIAGNOSED WITH LEUKAEMIA DURING PREGNANCY FIRST TRIMESTER SECOND TRIMESTER THIRD TRIMESTER Acute leukaemia (myeloid or lymphocytic leukaemia) Discuss pregnancy termination Induction therapy with doxorubicin and cytarabine Induction of labour and initiation of therapy after delivery Acute promyelocytic leukaemia Discuss pregnancy termination Induction of labour Doxorubicin and All and initiation of Trans-Retinoic Acid therapy after delivery Chronic myeloid leukaemia Interferon-alpha Interferon-alpha or imatinib Interferon-alpha or imatinib Other tumours •Surgical management of melanoma should follow standard procedures in the non-pregnant setting The SLNB procedure should be restricted to using Technetium-99 until more data with vital blue dye are available •Ipilimumab and vemurafenib should not be used in pregnant patients with metastatic melanoma because of insufficient safety data Interferon-alpha could be an alternative, if clinically appropriate •The ESMO CPG for managing other solid tumours commonly presenting with advanced and/or metastatic disease requiring systemic treatment (soft tissue sarcoma, ovarian and lung cancers) are summarised in the table on the next page 63 ESMO CLINICAL PRACTICE GUIDELINES FOR SYSTEMIC MANAGEMENT OF PATIENTS DIAGNOSED WITH SOFT TISSUE SARCOMA, OVARIAN AND LUNG CANCER DURING PREGNANCY Soft tissue sarcoma FIRST TRIMESTER SECOND TRIMESTER Observe until second trimester. If urgent treatment is required, discuss pregnancy termination Single agent doxorubicin (60–75 mg/m2) THIRD TRIMESTER Observe until second trimester. Epithelial ovarian If urgent treatment is required, cancer discuss pregnancy termination Carboplatin (AUC5 or 6) + weekly paclitaxel (80 mg/m2) Observe until second trimester. Germ cell ovarian If urgent treatment is required, tumours discuss pregnancy termination Cisplatin (75 mg/m2) and weekly paclitaxel (80 mg/m2) Non-small-cell lung cancer Observe until second trimester. If urgent treatment is required, discuss pregnancy termination Carboplatin (AUC5 or 6) + weekly paclitaxel (60–80 mg/m2) Carboplatin + weekly paclitaxel. If diagnosed later in the third trimester, consider pre-term delivery and initiation of therapy afterwards AUC5 or 6, target area under the curve dose of 5 or 6 •In pregnant patients with metastatic soft tissue sarcoma, single-agent doxorubicin is recommended in preference over combination doxorubicin ifosfamide; a switch to combination therapy is possible after delivery, if necessary •An alternative to etoposide platinum based combination therapies (because of the foetal toxicity of these regimens, particularly etoposide) is cisplatin-paclitaxel Paclitaxel is also effective as a single agent in relapsed germ cell tumours •The preferred combination for the treatment of lung and ovarian cancer in pregnant patients is carboplatin and weekly paclitaxel •Antimetabolites (e.g. gemcitabine and pemetrexed) should be avoided during pregnancy, while epidermal growth factor receptor inhibitors are discouraged because of limited data on their use in pregnancy MANAGING PREGNANCIES DIAGNOSED WHILE UNDERGOING ANTICANCER THERAPY •Use of active contraception is advised in all pre-menopausal patients undergoing any form of systemic anticancer therapy (chemotherapy, hormonal therapy, immunotherapy or targeted therapy) The same applies to male cancer patients, since some agents could influence sperm DNA integrity 64 Use of active contraception is advised up to 3–6 months following the last administered dose of systemic therapy •If pregnancy occurs while on tamoxifen or chemotherapy, the patient should be informed of the possible increased risk of foetal malformation secondary to exposure in the first trimester; termination of the pregnancy should therefore be considered •Termination of pregnancy is not encouraged in patients who become pregnant while on monoclonal antibody therapy, particularly trastuzumab and rituximab, provided trastuzumab or rituximab is stopped and the patient is informed that this recommendation is based on data from a limited number of patients •Exposure of the foetus to high concentrations of tyrosine kinase inhibitors, e.g. imatinib, is of concern because of the high risk of foetal malformation and miscarriage following exposure in the first trimester PREGNANCY IN CANCER SURVIVORS •Women diagnosed with breast cancer have almost 70% reduced chance of subsequent pregnancy compared with the general population, owing to prior frequent treatment with gonadotoxic chemotherapy, prolonged treatment periods with tamoxifen in patients with endocrine-sensitive disease and also a general misconception that pregnancy could stimulate cancer recurrence as it is a hormonally driven disease •Apart from breast cancer, there are no safety issues with respect to pregnancy following cancer •In women with a history of breast cancer (irrespective of oestrogen receptor status), pregnancy is not discouraged, while induction of abortion has no impact on maternal prognosis and is therefore strongly discouraged •The optimal timing of pregnancy following cancer diagnosis should consider when therapy is completed, the risk of relapse and the age and ovarian function of the patient In breast cancer patients, it is reasonable to postpone pregnancy for 2 years following diagnosis to allow resumption of adequate ovarian function and to overcome the time frame associated with a relatively high risk of recurrence •In patients receiving adjuvant tamoxifen for 5 years and for whom the completion of the full course of tamoxifen would hinder their likelihood of future pregnancy, it should be made clear that early interruption could have potential detrimental effects on their breast cancer outcome Interruption after 2–3 years of tamoxifen could be considered to allow pregnancy in women willing to consider the above risk to outcome and resumption of tamoxifen following delivery is strongly encouraged 65 FERTILITY PRESERVATION METHODS IN CANCER PATIENTS •For males who are scheduled for treatment that may be detrimental to their future fertility, sperm banking should be planned before treatment is initiated Semen cryopreservation with one to three sample collections is recommended Collection of one sample may suffice if intracytoplasmic sperm injection is used and further samples cannot be obtained Gonadal protection using any hormonal or pharmacological means is not advised •Women who wish to preserve their future fertility should be counselled by fertility 66 specialists soon after diagnosis on available fertility-preserving options before starting anticancer treatments The age of the patient, use of alkylating agents, total dose of chemotherapy and the field and dosage of pelvic radiotherapy (if used) all influence ovarian function The optimal available markers of ovarian reserve are anti-Müllerian hormone and antral follicle count performed in the first part of the menstrual cycle The use of gonadotropin-releasing hormone analogues concomitantly with chemotherapy, although it was very recently shown to reduce rates of premature ovarian failure in premenopausal women with hormone-receptor negative breast cancer, should not be regarded as a reliable means of preserving fertility and data on long-term ovarian function and pregnancy rates are warranted Embryo or oocyte cryopreservation is the main method to preserve female fertility and ovarian stimulation should be performed before commencing chemotherapy; any concerns regarding the associated increase in serum oestradiol levels and potential delay in starting treatment should be considered in hormone-driven tumours, e.g. breast cancer Gonadotropins and letrozole or tamoxifen are generally recommended for cancer patients because of an association with adequate yields of oocytes with a lower increase in serum oestradiol levels compared with standard stimulation regimens ––Use of such an approach should be considered in patients with endocrine receptor-positive breast cancer following discussion between the patient, oncologists, radiotherapists and reproductive medicine specialists An option to prevent chemotherapy- and radiotherapy-induced sterility in young girls with cancer is by freezing ovarian tissue before treatment, although the technique is considered experimental RISK FACTORS FOR VENOUS THROMBOEMBOLISM (VTE) •VTE is a multifactorial event; absolute risk depends on several factors including tumour type, stage of disease, administration of chemotherapy and/or hormonal therapy, surgical interventions, length of anaesthesia, the presence of an indwelling central venous catheter (CVC), age, immobilisation and history of VTE One of the most important factors is the use of cytotoxic drugs •A validated model is available to predict the risk of chemotherapy-associated VTE in ambulatory cancer patients (patients with poor performance status were under-represented) PREDICTIVE MODEL FOR CHEMOTHERAPY-ASSOCIATED VTE IN AMBULATORY CANCER PATIENTS CANCER-RELATED RISK FACTORS* Site of cancer and tumour histology RISK SCORE Very high risk (stomach or pancreatic adenocarcinoma) 2 High risk (lung, lymphoma, gynaecological, bladder, testicular) Low risk (breast, colorectal, head and neck) 1 Pre-chemotherapy platelet count ≥350 x 10 /L 1 1 HAEMATOLOGICAL RISK FACTORS 9 Haemoglobin <10 g/dL or use of erythropoiesis-stimulating agents (ESAs) 1 Pre-chemotherapy leukocyte count >11 x 10 /L 1 9 PATIENT-RELATED RISK FACTORS Body mass index ≥35 kg/m2 1 Low risk of VTE (VTE rate: 0.5%) 0 Intermediate risk of VTE (VTE rate: 2%) 1–2 High risk of VTE (VTE rate: 7%) ≥3 *Certain cancers known to be strongly associated with VTE (e.g. brain tumours) not included 67 DIAGNOSIS OF OCCULT CANCER IN PATIENTS WITH IDIOPATHIC VENOUS THROMBOEMBOLISM (VTE) •It is generally accepted that patients with idiopathic VTE have a higher risk of occult cancer •Patients with idiopathic VTE should undergo physical examination, occult faecal blood test, chest X-ray, urological examination (men) and gynaecological examination (women) More expensive examinations, such as a computed tomography (CT) scan, digestive endoscopy and tumour markers, should only be undertaken when there is a strong suspicion of occult cancer ––There are no definitive data demonstrating that early detection of occult cancer in patients with idiopathic VTE improves overall survival PREVENTION OF VENOUS THROMBOEMBOLISM (VTE) IN PATIENTS WITH CANCER Surgical patients •The role of thromboprophylaxis in patients with cancer undergoing surgery is unquestionable •In patients undergoing major cancer surgery, subcutaneous (SC) low-molecular weight heparins (LMWHs) or SC unfractionated heparin (UFH) are recommended e.g. LMWHs enoxaparin 4000 U anti-Xa activity or dalteparin 5000 U anti-Xa activity once daily; UFH 5000 U three times daily Mechanical methods, such as compression stockings and intermittent pneumatic compression, may be added to pharmacological thromboprophylaxis •In patients undergoing a laparotomy, laparoscopy, thoracotomy or thoracoscopy lasting >30 minutes, SC LMWH for ≥10 days postoperatively should be considered •Patients undergoing elective major abdominal or pelvic surgery should receive in-hospital and post-discharge prophylaxis with SC LMWH for up to 1 month after surgery Medical patients •In hospitalised patients with cancer confined to bed with an acute medical complication, thromboprophylaxis with UFH, LMWH or fondaparinux is recommended •In ambulatory patients receiving palliative chemotherapy for locally advanced or metastatic disease, extensive, routine prophylaxis is not recommended, but may be considered in high-risk patients 68 •In patients with myeloma receiving thalidomide + dexamethasone or thalidomide + chemotherapy, consider LMWH, aspirin or adjusted-dose warfarin (international normalised ratio [INR] ~1.5) •In patients receiving adjuvant chemotherapy and/or hormone therapy, thromboprophylaxis is not recommended •In patients with an indwelling CVC, extensive, routine thromboprophylaxis is not recommended to prevent CVC-related VTE TREATMENT OF VENOUS THROMBOEMBOLISM (VTE) IN PATIENTS WITH SOLID TUMOURS •The aim of VTE treatment is to prevent fatal pulmonary embolism (PE), recurrent VTE and long-term complications, such as post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension Acute treatment: Low molecular-weight heparins (LMWH) and unfractionated heparin (UFH) •Standard treatment (in patients with/without cancer) is administration of SC LMWH adjusted to body weight or UFH by continuous intravenous (IV) infusion LMWH: 200 U anti-Xa activity/kg of body weight administered once daily (e.g. dalteparin) or 100 U/kg administered twice daily (bid; e.g. enoxaparin) UFH bolus 5000 IU, followed by continuous infusion, nearly 30,000 IU over 24 hours, adjusted to achieve and maintain an activated partial thromboplastin time (aPTT) prolongation of 1.5–2.5 x the basal value •In patients with severe renal failure (creatinine clearance <25–30 mL), IV UFH or SC LMWH with anti-Xa activity monitoring is recommended Acute treatment: Thrombolytic therapy •Thrombolysis should be considered for specific patient subgroups, such as those with PE presenting with severe right ventricular dysfunction, and patients with massive iliofemoral thrombosis at risk of limb gangrene, where rapid venous decompression and flow restoration may be desirable •Treatment with urokinase, streptokinase and tissue-type plasminogen activator can achieve rapid lysis of fresh pulmonary emboli Long-term treatment •Although standard protocols recommend oral anticoagulation with vitamin K antagonists (VKAs), such as warfarin administered for 3–6 months at a therapeutic INR range of 2–3, oral anticoagulation with VKAs may be problematic in patients with cancer Drug interactions, malnutrition and liver dysfunction can lead to INR fluctuations 69 Patients with cancer receiving VKAs have a higher rate of VTE recurrence and anticoagulation-associated hemorrhagic risk compared with patients without cancer •In patients with cancer, long-term treatment for 6 months with 75–80% (i.e. 150 U/kg once daily) of the initial LMWH dose is recommended Duration of therapy to prevent recurrence of venous thromboembolism (VTE) •The optimal duration of anticoagulant therapy for the prevention of VTE recurrence in patients with cancer is unknown. There are at least four clinical scenarios: Patients with breast cancer treated with tamoxifen in the adjuvant setting: ––Substitute tamoxifen with an aromatase inhibitor ––Consider long-term treatment for 6 months with 75–80% (i.e. 150 U/kg once daily) of the initial LMWH dose Patients treated with chemotherapy in the adjuvant setting: ––Treat for 6 months with 75–80% (i.e. 150 U/kg once daily) of the initial LMWH dose Patients treated with a potentially curative strategy for metastatic disease (i.e. patients with metastatic germinal cancer): ––For patients achieving a complete remission of a potentially curative disease (i.e. germinal cancer), consider long-term treatment for 6 months with 75–80% (i.e. 150 U/kg once daily) of the initial LMWH dose ––For patients receiving chemotherapy in a metastatic setting with a neoadjuvant approach (e.g. colorectal cancer patients with potentially resectable liver metastases), the risk of recurrent cancer and/or VTE should be individually assessed Patients treated with palliative chemotherapy in the metastatic setting: ––For those achieving a complete remission but with a very high risk of recurrence, the duration of treatment (potentially indefinite) should be discussed with the patient Treatment of recurrent venous thromboembolism (VTE) •Patients adequately anticoagulated who develop VTE recurrence should be checked for progression of their malignancy •Patients on long-term anticoagulation with VKAs who develop VTE and have a sub-therapeutic INR can be retreated with UFH or LMWH until a stable INR (2–3) is achieved •If VTE recurs while the INR is in the therapeutic range, use another method of anticoagulation, e.g. SC UFH maintaining a therapeutic aPTT (aPTT ratio 1.5–2.5) or weight-adjusted dose LMWH 70 •In patients receiving a reduced dose of LMWH or VKA anticoagulation as a long- term therapy who experience recurrence, full-dose LMWH (200 U/kg once daily) can be resumed Escalating the dose of LMWH results in a second recurrent VTE (i.e. third VTE) rate of 9% Full-dose LMWH is well tolerated with few bleeding complications Use of a vena cava filter •Consider using an inferior vena cava filter in patients with recurrent PE despite adequate anticoagulant treatment or with a contraindication to anticoagulant therapy (i.e. active bleeding or profound, prolonged thrombocytopenia) Once the risk of bleeding is reduced, patients with a vena cava filter should receive or resume anticoagulant therapy in order to reduce the risk of recurrent deep vein thrombosis of the lower extremities CONTRAINDICATIONS TO ANTICOAGULATION •Relative contraindications: Active, uncontrollable bleeding; active cerebrovascular haemorrhage; intracranial or spinal lesions at high risk for bleeding; pericarditis; active peptic or other gastrointestinal ulceration; severe, uncontrolled or malignant hypertension; active bleeding (>2 units transfused in 24 hours); chronic, clinically significant measurable bleeding; thrombocytopenia (<50,000/mL); severe platelet dysfunction; recent operation at high risk for bleeding ANTICOAGULATION AND PROGNOSIS •There is no evidence to recommend the use of anticoagulation to influence cancer prognosis 71 CARDIOVASCULAR EVALUATION BEFORE ANTICANCER TREATMENT WITH POTENTIAL IRREVERSIBLE (TYPE I) OR REVERSIBLE (TYPE II) CARDIOTOXICITY •Patients receiving chemotherapy may be considered a Stage A heart failure group, i.e. at increased risk of developing cardiac dysfunction •Patients in whom chemotherapy is planned should undergo careful clinical evaluation and assessment of cardiovascular (CV) risk factors and comorbidities In patients receiving multitargeted agents, strict attention should be paid to comorbidities, particularly coronary artery disease and hypertension, which should be robustly managed prior to and during therapy •Patients should be considered at risk of cardiac toxicity if they have a history of exposure to any of the following cumulative doses of anthracyclines: Doxorubicin >500 mg/m2 Liposomal doxorubicin >900 mg/m2 Epirubicin >720 mg/m2 Mitoxantrone >120 mg/m2 Idarubicin >90 mg/m2 •Left ventricular ejection fraction (LVEF) assessment is mandatory for basal evaluation of cardiac function prior to initiating potentially cardiotoxic therapy •A standard 12-lead electrocardiogram (ECG) should be recorded QT time should be corrected for heart rate (QTc) with Bazett’s formula (QTc=QT/√RR) •Echocardiography (ECHO) is the standard procedure for basal assessment of cardiac structure, performance and haemodynamics •Multiple gated acquisition (MUGA) scan can reduce inter-observer variability, but exposes the patient to radioactivity and provides only limited information on cardiac structure and diastolic function •Magnetic resonance imaging (MRI) is another method used to evaluate myocardial function Spatial resolution is higher than for ECHO, but temporal resolution is lower •Ultrasound (US) assessment should be used to obtain two- or three-dimensional images in the left ventricular parasternal long-axis and short-axis views and in the apical four-chamber and two-chamber long-axis views 72 For analysis of diastolic function, the following should be measured: ––Ratio of early peak flow velocity to atrial peak flow velocity (E/A ratio; normal value >1) ––Deceleration time of the early peak flow (DT; normal value <220 msec) ––Isovolumic relaxation time (IVRT; normal value <100 msec) Left ventricular end diastolic diameter (normal value 47 ± 4 mm) should be measured to test for ventricular dilatation •The usefulness of routine monitoring of cardiac biomarkers to predict cardiotoxicity is unknown, but there is a strong case to incorporate their use in the clinical trial setting Cardiac biomarkers (troponins, brain natriuretic peptides [BNP], neutrophil glucosaminidase-associated lipocalin as a marker of renal injury) may be elevated in the presence of significant cardiotoxicity •Treatment of pre-existing CV conditions should be optimised Cardiomyopathy: β-blockers and angiotensin converting enzyme (ACE) inhibitors should be used where appropriate •For patients at high-risk of cardiotoxicity, the use of liposome-encapsulated doxorubicin and an appropriate cardioprotectant regimen should be considered Cardioprotectant regimens may include: ––Dexazoxane: Not routinely used in clinical practice, but recommended by the American Society of Clinical Oncology (ASCO) as a cardioprotectant in patients with metastatic breast cancer who have already received >300 mg/m2 doxorubicin ––β-blockers, e.g. carvedilol ––ACE inhibitors ––Angiotensin receptor blockers (ARB; e.g. valsartan) LEFT VENTRICULAR DYSFUNCTION (LVD) •Left ventricular dysfunction (LVD) and the development of overt heart failure are the most common manifestations of cardiotoxicity associated with anticancer agents (anthracyclines, alkylating agents, taxanes, monoclonal antibodies, targeted agents) •According to the Cardiac Review and Evaluation Committee supervising trastuzumab trials, LVD is characterised by: A decrease in cardiac LVEF that was global or more severe in the septum Symptoms of congestive heart failure (CHF) Associated signs of CHF including, but not limited to, S3 gallop, tachycardia or both 73 A >5% decline in LVEF to <55% with accompanying signs and symptoms of CHF, or a >10% decline in LVEF to <55% without accompanying signs or symptoms ––Recent definitions include a decline in LVEF below the lower limit of normal (LLN) or to <50% Anthracyclines and cytotoxics with cumulative dose-related cardiotoxicity (Type I agents) •Risk factors for anthracycline toxicity include: Cumulative dose; intravenous bolus administration; higher single doses; history of prior irradiation; the use of other concomitant agents known to have cardiotoxic effects including cyclophosphamide, trastuzumab and paclitaxel; female gender; underlying cardiovascular disease; age (young and elderly); increased length of time since completion of chemotherapy and an increase in cardiac biomarkers (troponins and natriuretic peptides) during and after administration •The risk of clinical cardiotoxicity increases with cumulative dose The recommended maximum lifetime cumulative dose for doxorubicin is 400–550 mg/m2 •The recommended management of cardiotoxicity in patients receiving anthracyclines is shown in the figure opposite 74 MANAGEMENT OF CARDIOTOXICITY IN PATIENTS RECEIVING ANTHRACYCLINES BASELINE CARDIOLOGIC EVALUATION, ECHO ANTHRACYCLINE -CTh Tnl evaluation at each cycle Tnl POS Tnl not evaluated during CTh ECHO at end of CTh Tnl NEG No LVD Enalapril for 1 year LVD ECHO at end of CTh + 3, 6, 9 months ECHO 3 months No LVD ECHO 12 months ECHO 12 months ECHO every 6 months for 5 years ECHO every year ECHO 6 months No LVD ECHO 9 months No LVD ECHO 12 months ACE inhibitor + BB No LVD Clinical Follow-up ECHO every year ACE inhibitor, angiotensin converting enzyme inhibitor; BB, beta-blocking agents; CTh, chemotherapy; TnI, troponin I 75 Monoclonal antibodies and targeted agents not associated with cumulative doserelated cardiotoxicity (Type II agents) •Rates of cardiac toxicity reported in adjuvant trials of the human epidermal growth factor receptor 2 (HER2)-targeted agent, trastuzumab, vary (see table below), reflecting differences in trial design, chemotherapy administration and definitions of cardiac events •Lapatinib, a receptor tyrosine kinase inhibitor (TKI) of HER2 and epidermal growth factor receptor (EGFR), appears to be associated with a relatively low rate of symptomatic cardiac failure (experience in a relatively small population) •Clinical trial data do not suggest a significant increase in cardiac toxicity during treatment with bevacizumab, a humanised monoclonal antibody directed against vascular endothelial growth factor (VEGF). However, VEGF receptor TKIs appear to have a more profound effect on cardiac function TRASTUZUMAB CARDIOTOXICITY REPORTED IN ADJUVANT TRIALS TRIAL DESIGN ASYMPTOMATIC DROP IN LVEF (≥10 PERCENTAGE POINTS TO <55%) SEVERE CHF/ DISCONTINUED CARDIAC EVENTS FOR CARDIAC (NYHA CLASS III/IV REASONS CHF OR DEATH) NSABP B31 N=2043 AC + TH + H vs AC +T 34% vs 17% 4.1% vs 0.8% NCCTG N9831 N=2766 AC + TH + H vs AC + T + H vs AC + T 5.8–10.4% vs 4.0–7.8% 3.3% vs 2.8% vs 0.3% vs 4.0–5.1% n/aa 11% vs 19% vs 9% 0.7% vs 2.0% vs 0.4% n/a AC + T vs BCIRG 006 AC + TH + N=3222 H vs TCaHb 19%a HERA N=5102 Adjuvant CThc g H vs Adjuvant CTh alone 7.1% vs 2.2% 0.6% vs 0.06% 4.3% FinHer N=232 V or T + H vs V or Td g FEC x 3 3.5% vs 8.6% 0% vs 3.4% n/a 6.7% did not receive H after A due to unacceptable drops in LVEF; bIncluded a non anthracycline arm; 96% of chemotherapy was A-containing; dNo prior anthracycline before H exposure; H exposure limited to 9 weeks A, anthracycline; C, cyclophosphamide; Ca, carboplatin; CTh, chemotherapy; E, epirubicin; F, 5-flourouracil; H, trastuzumab; NYHA, New York Heart Association; T, taxane; V, vinorelbine; n/a, not available a c 76 Management of trastuzumab cardiotoxicity •Management of trastuzumab-related cardiotoxicity has two distinct aspects: Withdrawal of trastuzumab therapy Treatment of cardiac dysfunction •The ‘stopping/restarting’ rules used in adjuvant trials were effective and are recommended, with some modifications regarding recommendations for a cardiology consult or treatment of cardiac dysfunction (or both), when appropriate •The recommended algorithm for continuation/discontinuation of trastuzumab is shown in the figure below ALGORITHM FOR CONTINUATION/DISCONTINUATION OF TRASTUZUMAB, BASED ON LVEF LVEF ASSESSMENT LVEF <50% LVEF ≥50% Start treatment LVEF <40% LVEF 40–50% Hold treatment Repeat LVEF in 3 weeks LVEF 10% below baseline LVEF >10% below baseline Hold treatment Repeat LVEF in 3 weeks Continue treatment LVEF <40% LVEF >45% OR LVEF 40–50% Stop treatment Resume treatment 77 •Symptomatic LVD must be treated with heart failure therapy: Patients with CHF and an LVEF of <40% should be treated with an ACE inhibitor + β-blocker, unless contraindicated ––An ACE inhibitor should be considered in patients with an LVEF of 40–50% to prevent further degradation of LVEF or the development of clinical CHF •Asymptomatic LVD should also be treated Patients with an LVEF of <40% should be treated with ACE inhibitors; β-blockers should be considered ACE inhibitors should be considered in those with an LVEF of <50% CARDIAC ISCHAEMIA •Cardiac ischaemia related to chemotherapy is unusual; an increased risk of acute coronary syndrome has been associated with cytotoxic and targeted anticancer agents •Frequent monitoring of vital signs is recommended during infusion of chemotherapeutic agents, particularly fluorouracil (5-FU) or paclitaxel •Monitoring BNP and troponin I is recommended in patients with anamnesis of cardiac ischaemia. A collaborative decision should then be made regarding whether more advanced cardiac tests (e.g. stress testing and coronary angiography) are required and whether the benefits of resuming therapy with aggressive supportive care outweigh the risks •Baseline ECG evaluation is recommended in patients with ischaemic events following or during infusion of antimetabolites or paclitaxel HYPERTENSION •Hypertension is a common class effect with VEGF inhibitors •Individuals should be considered at risk if they have: Systolic blood pressure (BP) ≥160 mmHg or diastolic BP ≥100 mmHg Diabetes mellitus Established cardiovascular disease, including any history of ischaemic stroke, cerebral haemorrhage, transient ischaemic attack, myocardial infarction, angina, coronary revascularisation or CHF Peripheral artery disease Subclinical organ damage previously documented by ECG or LV hypertrophy on ECHO Cigarette smoking Dyslipidaemia •Repeated BP measurements are recommended 78 •Aggressive management of BP elevations is recommended to prevent clinicallylimiting complications •There are no evidence-based guidelines for the use of follow-up ECHOs in asymptomatic patients receiving antiangiogenic agents •There are no data on which to base general recommendations for dose adjustments of antiangiogenic agents QT PROLONGATION •QT prolongation can lead to life-threatening cardiac arrhythmias, including torsade de pointes The clinical benefits of oncological therapy, including the possibility of cure, may outweigh the potential risks of QT prolongation, even when prolongation is significant (e.g. arsenic trioxide in relapsed acute promyelocytic leukaemia) •Patients should be screened and monitored if they: Have a history of QT prolongation Are taking antiarrhythmics Have relevant cardiovascular disease, bradycardia, thyroid dysfunction or electrolyte disturbances •Periodic monitoring (on-treatment ECGs, electrolyte levels) should be considered CARDIOVASCULAR MONITORING DURING AND AFTER ANTICANCER TREATMENT WITH POTENTIAL IRREVERSIBLE (TYPE I) OR REVERSIBLE (TYPE II) CARDIOTOXICITY •Cardiac function should be monitored in patients receiving anthracyclines and/ or trastuzumab in the adjuvant setting: At baseline, 3, 6 and 9 months during treatment, then at 12 and 18 months after treatment initiation Monitoring should be repeated during or following treatment as clinically indicated ––Increased vigilance is recommended for patients ≥60 years old •Patients treated for metastatic disease: LVEF should be monitored at baseline and then infrequently in the absence of symptoms •Cardiac biomarkers: Assessment of biomarker concentrations (troponin I or BNP) at baseline and during therapy (e.g. after each cycle) may identify patients at risk of cardiotoxicity who require further cardiac assessment •Assessment of cardiac function is recommended 4 and 10 years after anthracycline therapy in patients aged <15 years when treated and those aged >15 years with cumulative doses of doxorubicin >240 mg/m2 or epirubicin >360 mg/m2 79 •An LVEF reduction of ≥15% from baseline with normal function (LVEF ≥50%) is an indication to continue anthracyclines and/or trastuzumab •An LVEF decline to <50% during anthracycline therapy necessitates reassessment after 3 weeks If confirmed, hold chemotherapy and consider therapy for LVD and further frequent clinical and ECHO checks In the event of an LVEF decline to <40%, stop chemotherapy, discuss alternatives and treat LVD •An LVEF decline to <50% during trastuzumab therapy (post-anthracyclines) necessitates reassessment after 3 weeks If confirmed, continue trastuzumab and consider therapy for LVD and further frequent clinical and ECHO checks In the event of an LVEF decline to <40%, stop trastuzumab and treat LVD •Aggressive medical treatment for patients (symptomatic/asymptomatic) with LVD after anthracycline therapy is mandatory, particularly if the cancer could be associated with long-term survival Treatment comprises ACE inhibitors and β-blockers – earlier CHF treatment (i.e. within 2 months from the end of anthracycline therapy) is associated with a better therapeutic response TREATMENT OF LEFT VENTRICULAR DYSFUNCTION (LVD) INDUCED BY ANTICANCER TREATMENT WITH IRREVERSIBLE (TYPE I) OR REVERSIBLE (TYPE II) CARDIOTOXICITY •In patients with subclinical cardiotoxicity induced by Type I agents, identified by raised cardiac tropinin levels, treatment with ACE inhibitors (enalapril) may prevent LVEF reduction and associated CV events •Patients who develop cardiac dysfunction during or after treatment with Type II agents (trastuzumab) in the absence of anthracyclines can be observed if they remain asymptomatic with an LVEF ≥40% •Persistently low or further declines in LVEF or the development of symptoms should trigger discussion of risk and benefit with the treating oncologist, as well as consideration of pharmacological cardiac treatment •Patients who develop LVD should be treated with standard guideline-based CHF therapy CARDIAC TOXICITY INDUCED BY RADIOTHERAPY •There is considerable literature supporting evidence of radiation-induced cardiac toxicity after radiotherapy to the chest 80 •Injury of the various structures and tissues in the heart can cause a spectrum of radiation-induced CV diseases, including premature coronary artery disease, atherosclerosis, acute pericarditis, chronic pericardial effusion, myocarditis, CHF, valvular stenosis and regurgitation (mainly of mitral and aortic valves), fibrosis of the conduction system and disturbed heart rate, and complete or incomplete heart block •Radiation-induced cardiac toxicity is of particular clinical importance among patients with curable malignancies who have been treated with radiotherapy at a relatively young age (i.e. mainly those with Hodgkin’s lymphoma and early-stage breast cancer) Dose >30–35 Gy Dose per fraction >2 Gy Large volume of irradiated heart Younger age at exposure Longer time since exposure Use of cytotoxic chemotherapy Endocrine therapy or trastuzumab Presence of other risk factors such as diabetes, hypertension, dyslipidaemia, obesity, smoking •Risk factors for radiation-associated heart damage include: Recommendations to reduce cardiac toxicity in patients treated by radiotherapy •Newer irradiation techniques may decrease the risk of radiation-induced cardiac disease •Modern radiotherapy techniques include three-dimensional treatment planning with dose volume histogram (DVH) for accurate heart volume and dose calculation •Linear accelerator photons and multiple-field conformal or intensity-modulated radiotherapy (IMRT) are desirable for chest irradiation •Normal tissue complication probability (NTCP) is a method of reporting radiation dosing in radiotherapy, by taking into account the dose and volume of normal tissues that receives the corresponding dose NTCP model estimates predict that a V25Gy <10% (i.e. a dose of 25 Gy [in 2 Gy fractions] in <10% of the whole heart volume) will be associated with a 1–2% probability of cardiac mortality within 15 years after radiotherapy •Cardiac-sparing lead block during standard simulator planning will at least partially prevent cardiac irradiation for many patients 81 •The use of a four-field IMRT technique can offer better sparing than partial shielding as the maximum heart depth is increased IMRT plans also improve dose homogeneity within the planning target volume (PTV) but may be associated with increased irradiation of the contralateral breast •It has been proposed that maximum heart distance (MHD) is a reliable predictor of the mean heart dose in left tangential breast or chest wall irradiation A strong linear correlation has been shown between the MHD and the mean heart dose: For every 1 cm increase in MHD, the mean heart dose increased by an average of 2.9% •Electron beams can be used to treat superficial structures such as in the internal mammary lymph nodes or the boost dose on the breast after tumour resection in patients with breast cancer •For mediastinal radiotherapy, high energy photons from a linear accelerator should be used to treat patients with equal weighting of anterior and posterior portals All fields should be treated on each radiotherapy fraction Use of a subcarinal block after a dose of 30 Gy and shrinking-field technique are the most important parameters to minimise heart exposure •Although permanent complications may occur less frequently with a total dose of <40 Gy, systematically limiting treatment is not recommended since a lower dose may be inadequate to control the disease in some patients Treatment of radiotherapy-related cardiac complications •Radiation-induced cardiac disorders should be treated as non-radiation-induced ones, but with special attention to known changes to the heart and other structures of the chest caused by radiation Monitoring of cardiac function after chest radiotherapy •Patients at high risk of radiotherapy-induced complications should be informed and followed-up closely •Patients with breast cancer treated with postoperative breast radiotherapy (with or without adjuvant endocrine treatment) are not regularly monitored for cardiac problems, although radiotherapy should be considered as a risk factor when heart disease is diagnosed in these patients •There are no data to support definitive recommendations on the use and frequency of various cardiac tests, although long-term follow-up is required Screening and monitoring procedures are the same as those used by cardiologists for other patients; consequently, follow-up protocols are based on 82 departmental or personal experience and on each patient’s needs and clinical situation •Apart from clinical examination and medical history, tests to be performed depend on the abnormality: Coronary artery disease: Lipid profile, exercise stress test, radionuclide, angiography, ECHO, ECG Pericarditis: ECG, chest X-ray, ECHO Cardiomyopathy: ECG, ECHO, radioisotopic angiography Arrhythmias: ECG and 24 hour ECG Valvular disease: ECHO, cardiac catheterisation 83 DEFINITION OF EXTRAVASATION •The process by which any liquid (fluid or drug) accidentally leaks into the surrounding tissue •In terms of cancer therapy, extravasation refers to the inadvertent infiltration of chemotherapy into the subcutaneous or subdermal tissues surrounding the intravenous (IV) or intra-arterial administration site POTENTIAL FOR ANTICANCER AGENTS TO CAUSE LOCAL DAMAGE AFTER EXTRAVASATION •Extravasated drugs are classified according to their potential to cause damage as: Vesicant ––Some vesicant drugs are further divided into DNA binding and non-DNA binding Irritant Non-vesicant CLASSIFICATION OF ANTICANCER AGENTS ACCORDING TO THEIR ABILITY TO CAUSE LOCAL DAMAGE AFTER EXTRAVASATION 84 VESICANTS IRRITANTS NON-VESICANTS DNA-binding compounds Alkylating agents • Mechloretamine • Bendamustine* Anthracyclines • Doxorubicin • Daunorubicin • Epirubicin • Idarubicin Others (antibiotics) • Dactinomycin • Mitomycin C • Mitoxantrone* Alkylating agents • Carmustine • Ifosphamide • Streptozocin • Dacarbazine • Melphalan Anthracyclines (other): • Liposomal doxorubicin • Liposomal daunorubicin • Mitoxantrone Topoisomerase II inhibitors • Etoposide • Teniposide • Arsenic trioxide • Asparaginase • Bleomycin • Bortezomib • Cladribine • Cyclophosphamide • Cytarabine • Etoposide phosphate • Gemcitabine • Fludarabine • Interferons • Interleukin-2 • Methotrexate VESICANTS IRRITANTS NON-VESICANTS Non-DNA-binding compounds Vinca alkaloids • Vincristine • Vinblastine • Vindesine • Vinorelbine Taxanes • Docetaxel* • Paclitaxel Others • Trabectedin Antimetabolites • Fluorouracil Platin salts • Carboplatin • Cisplatin • Oxaliplatin* Topoisomerase I inhibitors • Irinotecan • Topotecan Others • Ixabepilone • Monoclonal antibodies • Pemetrexed • Raltitrexed • Temsirolimus • Thiotepa *Single case reports describe both vesicant and irritant properties RISK FACTORS FOR EXTRAVASATION •Patient-related risk factors that could lead to increased preventative measures or to recommendations for insertion of a central venous access device (CVAD) include: Small and fragile veins Hard and/or sclerosed veins as a consequence of multiple previous chemotherapy courses or drug abuse Prominent but mobile veins (e.g. elderly) Diseases or situations associated with altered/impaired circulation, e.g. Raynaud syndrome, advanced diabetes, severe peripheral vascular disease, lymphoedema or superior cava syndrome Predisposition to bleeding, increased vascular permeability or patients with coagulation abnormalities Obesity in which peripheral venous access is more difficult Sensory deficits that impair the patient’s ability to detect a change in sensation at the site of chemotherapy administration Patients with communication difficulties or young children; hinders ability to report the early signs and symptoms of extravasation •Procedure-related risk factors include: Untrained or inexperienced staff Multiple cannulation attempts Unfavourable cannulation site Bolus injections High flow pressure 85 Choice of equipment (peripheral catheter choice, size, steel ‘butterfly’ needle) Inadequate dressings or poor cannula fixation Poorly implanted CVAD (too deep for cannula, difficult to secure cannula) Prolonged infusion PREVENTION OF EXTRAVASATION •Extravasation can generally be prevented with the systematic implementation of careful, standardised, evidence-based administration techniques •Staff involved in the infusion and management of anticancer drugs must be trained in the implementation of several preventive protocols Site of insertion: Identification of the most appropriate cannulation site before insertion. If venous access continually proves difficult, placement of a CVAD should be considered ––Large veins in the forearm are recommended for peripheral administration ––Avoid cannulation over joints, the inner wrist and lower extremities ––Veins in the anticubital fossa or on the dorsum of the hand should not be used, particularly for vesicant drugs ––Avoid cannulation where lymphoedema is present ––Cannulation on the side of a mastectomy is still a matter of discussion Procedures ––After cannulation, blood flow should be checked; rinse with 10 mL of normal saline and check for signs of extravasation ––Flushing with 10–20 mL of saline solution between different drug infusions is recommended ––A blood return (flashback) should always be obtained before vesicants are administered and checked regularly throughout a bolus infusion ––Continue monitoring of the cannula insertion site and check regularly for symptoms such as swelling, pain, redness or a sluggish infusion rate (highly recommended during infusion of all drugs) ––Bolus dosages of vesicant drugs may be administered concurrently with fastrunning infusions of compatible IV fluid DIAGNOSIS OF EXTRAVASATION •Patients must be advised to report any changes in sensation, signs or symptoms during IV administration of any chemotherapy drug to the healthcare professional Additional information should be provided when vesicant drugs are administered •Extravasation must be suspected if any of the specific signs or symptoms are present 86 Most common initial symptoms: Tingling, burning, discomfort/pain or swelling, redness at the injection site Later symptoms: Blistering, necrosis, ulceration •Signs that frequently raise suspicion of eventual extravasation: The absence of blood return, resistance on the syringe plunger when administering a bolus drug, interruption to the free-flow of an infusion Differential diagnosis •A differential diagnosis assessment should be carried out if extravasation is suspected •Some chemotherapy drugs can cause a local reaction that resembles extravasation, even if administered correctly Signs and symptoms of local non-extravasation reactions include: Erythema around the cannula site and along the accessed vein (‘flare’), urticaria, local itching •Several drugs can cause chemical phlebitis – vein inflammation is frequently followed by a thrombosis or sclerosis of the veins that may cause a burning sensation at the cannula site and cramping along the vein proximal to the cannula site CHEMOTHERAPY DRUGS POSSIBLY CAUSING LOCAL REACTIONS LOCAL SKIN REACTIONS CHEMICAL PHLEBITIS Asparaginase Amsacrine Cisplatin Carmustine Daunorubicin Cisplatin Doxorubicin Dacarbazine Epirubicin Epirubicin Fludarabin 5-Fluorouracil (as continuous infusion with cisplatin) Mechlorethamin Gemcitabine Melphalan Mechlorethamine Vinorelbine 87 MANAGEMENT OF EXTRAVASATION •No randomised trials have been carried out for ethical reasons and difficulties in patient accrual •Extravasation may cause very little damage if left untreated •Many of the reported management policies are based on data that were not confirmed by biopsy and, in many cases, simultaneous treatment with antibiotics was used General measures •Early treatment initiation is mandatory, regardless of the chemotherapy drug involved •General measures are recommended as soon as an extravasation is diagnosed (see Figure on the opposite page) •Patient education is crucial for prompt identification of the extravasation 88 STEPS TO BE TAKEN IN CASE OF PERIPHERAL LINE EXTRAVASATION Step 1 Stop and disconnect infusion. Leave the needle in place Step 2 Identify extravasated agent Step 3 Leaving the cannula in place, try to gently aspirate as much extravasated solution as possible. Record volume removed in patient records. Avoid manual pressure over the extravasated area. Remove cannula Step 4 Mark with a pen an outline of the extravasated area Step 5 Notify physician. Start specific measures as soon as possible Vesicant or irritant Localise and neutralise Agents: • Anthracyclines • Antibiotics (mitomycin/ dactinomycin) • Alkylating agents Disperse and dilute Agents: • Vinca alkaloids • Taxanes • Platin salts Step 5A: Localise Apply dry cold compresses for 20 minutes 4 times daily for 1–2 days Avoid alcohol compresses Step 5A: Disperse Apply dry warm compresses for 20 minutes 4 times daily for 1–2 days Step 5B: Neutralise Use specific antidotes Anthracyclines Topical DMSO Dexrazosane Mitomycin C Topical DMSO Step 5B: Dilute Administer agents increasing resorption Vinca alkaloids and Taxanes Hyaluronidase Non-vesicant Local dry cold compresses Step 6 Elevate the limb. Administer analgesia if necessary DMSO, dimethylsulfoxide 89 Specific measures •Many ‘antidotes’ are considered ineffective or may further damage the extravasated area Many are not available or have limited access for use in many European countries •Corticosteroids (SC) are not recommended RECOMMENDED ANTIDOTES FOR USE AFTER EXTRAVASATION EXTRAVASATED DRUG SUGGESTED ANTIDOTE Anthracyclines Dexrazoxane IV Start as soon as possible (≤6 hours): 1000 mg/m2 on days 1 and 2, 500 mg/m2 on day 3 Anthracyclines Topical DMSO (99%) Start as soon as possible (preferably ≤10 minutes) Apply every 8 hours for 7 days Mitomycin C Topical DMSO (99%) Start as soon as possible (preferably ≤10 minutes) Apply every 8 hours for 7 days Mechlorethamine Sodium thiosulfate 0.17 M SC Start immediately: 2 mL of solution made from 4 mL sodium thiosulfate + 6 mL sterile water Vinca alkaloids Hyaluronidase SC Administer 150–900 IU around the area of extravasation Taxanes Hyaluronidase SC Administer 150–900 IU around the area of extravasation SC, subcutaneous SURGICAL MANAGEMENT OF SEVERE TISSUE DAMAGE •Surgical debridement is indicated for the treatment of unresolved tissue necrosis or pain lasting >10 days and for patients in whom conservative therapy has not been appropriately initiated ~Only one-third of extravasations evolve to ulceration •Surgical debridement should comprise: 90 Wide, three-dimensional excision of all involved tissue Temporary coverage with a biological dressing Simultaneous harvesting and storage of a split-thickness skin graft Once the wound is clean, delayed application of the graft is performed (usually after 2–3 days) CENTRAL VENOUS ACCESS DEVICE EXTRAVASATION •Extravasation of chemotherapy agents administered through a CVAD is rare •In this situation, solution may accumulate in the mediastinum, pleura, or in a subcutaneous area of the chest or neck The most frequent symptom is acute thoracic pain •Diagnosis must be based on clinical presentation and confirmed with imaging techniques, usually a thoracic computed tomography (CT) scan 91 STEPS TO BE TAKEN IN CASE OF CENTRAL VENOUS ACCESS DEVICE EXTRAVASATION Step 1 Stop and disconnect infusion. Do not remove the cannula Step 2 Identify extravasated agent Step 3 Leaving the CVAD in place, try to gently aspirate through the cannula as much extravasated solution as possible. Avoid pressure in the surrounding area Start non-specific measures if applicable Step 4 Specific measures: If the drug extravasated is an anthracycline, consider early administration of intravenous dexrazoxane Step 5 Identify extravasated area: Urgent chest X-ray or thoracic CT Immediate consultation with surgeon Pleura Step 6: Consider urgent thoracocentesis and thoracic tube Mediastinum Step 6: Consider urgent thoracoscopy or thoracotomy Subcutaneous Step 6: Consider surgical drainage of cumulated solution Fluid therapy Analgesia Consider antibiotic and oxygen therapy Progressive resolution Outpatient management No resolution Perform CT Progressive withdrawal of analgesia Consider other surgical procedures Remove central venous access device Consider new insertion of a contralateral central venous access device or peripheral cannula for next infusions 92 DOCUMENTATION •Documentation requirements may vary; however, certain information is mandatory for patient safety and legal purposes: Patient name and number Date and time of extravasation Name of drug extravasated as well as dilutant used Signs and symptoms (including patient-reported signs and symptoms) Description of IV access Extravasation area and the approximate amount of drug extravasated Management steps, including time and date •Photographic documentation can be helpful for follow-up procedures and decision making FOLLOW-UP •Data regarding appropriate follow-up are scarce •Follow-up daily or every 2 days during the first week and then weekly until complete resolution of symptoms is recommended Initially, local signs or symptoms are not always evident Initial inflammation may increase with more redness, oedema and pain over the following days After several days or weeks (depending on the vesicant drug), skin blisters may appear and inflammation may evolve to a necrosis Patients must be informed about the follow-up policy before leaving the treatment area 93 5-FU, fluorouracil 5-HT3, 5-hydroxytryptamine 3 ABVD, doxorubicin/bleomycin/vinblastine/dacarbazine AC, doxorubicin/cyclophosphamide AC/T, doxorubicin/cyclophosphamide/paclitaxel ACE, angiotensin converting enzyme ALL, acute lymphoblastic leukaemia AML, acute myeloid leukemia ANC, absolute neutrophil count aPTT, activated partial thromboplastin time ARB, angiotensin receptor blocker ASCO, American Society of Clinical Oncology bid, twice daily BNP, brain natriuretic peptides BP, blood pressure BTP, breakthrough pain CAE, cyclophosphamide/doxorubicin/etoposide CHF, congestive heart failure CHOP, cyclophosphamide/doxorubicin/vincristine/prednisolone CHOP-14, cyclophosphamide/doxorubicin/vincristine/prednisolone given every 14 days CLL, chronic lymphocytic leukaemia CMF, cyclophosphamide/methotrexate/fluorouracil CML, chronic myeloid leukaemia CNS, central nervous system COX-2, cyclo-oxygenase-2 CPB, celiac plexus block CPG, Clinical Practice Guidelines CRI, catheter-related infection CRP, C-reactive protein CT, computed tomography CTCAE, Common Terminology Criteria of Adverse Events CV, cardiovascular CVAD, central venous access device CVC, central venous catheter DCF, docetaxel/cisplatin/fluorouracil DHAP, dexamethasone/cisplatin/cytarabine DMSO, dimethyl sulfoxide DN4, douleur neuropathique DP, docetaxel/carboplatin DT, deceleration time of the early peak flow DTTP, differential time to positivity 94 DVH, dose volume histogram EBRT, external beam radiotherapy E/A ratio, ratio of early peak flow velocity to atrial peak flow velocity ECG, electrocardiogram ECHO, echocardiograph EGFR, epidermal growth factor receptor EMA, European Medicines Agency EPO, erythropoietin ESA, erythropoiesis-stimulating agent ESMO, European Society for Medical Oncology FN, febrile neutropenia G-CSF, granulocyte colony-stimulating factor GI, gastrointestinal GM-CSF, granulocyte–macrophage colony-stimulating factor Hb, haemoglobin HER2, human epidermal growth factor 2 hGF, haematopoietic growth factor HIV, human immunodeficiency virus HSCT, hematopoietic stem-cell transplantation ICE, ifosfamide/carboplatin/etoposide ID, infectious diseases IMRT, intensity-modulated radiotherapy INR, international normalised ratio IR, immediate release ISOO, International Society of Oral Oncology IT, intrathecal ITDD, intrathecal drug delivery IV, intravenous IVRT, isovolumic relaxation time LANSS, leeds assessment of neuropathic symptoms and signs LHRH, luteinising hormone-releasing hormone LLLT, low-level laser therapy LLN, lower limit of normal LMWH, low molecular weight heparin LVEF, left ventricular ejection fraction LVD, left ventricular dysfunction MAID, mesna/doxorubicin/ifosfamide/etoposide MASCC, Multinational Association of Supportive Care in Cancer MDS, myelodysplastic syndrome MDT, multidisciplinary team MHD, maximum heart distance MRI, magnetic resonance imaging MSCC, metastatic spinal cord compression MUGA, multiple gated acquisition MVAC, methotrexate/vinblastine/doxorubicin/cisplatin NCCN, National Comprehensive Cancer Network 95 NCI, National Cancer Institute NHL, non-Hodgkin’s lymphoma NK, neurokinin NMDA, N-methyl-D-aspartate NRS, numerical rating scale NSAIDs, non-steroidal anti-inflammatory drugs NSCLC, non-small-cell lung cancer NTCP, normal tissue complication probability PBSC, peripheral blood stem cell PE, pulmonary embolism PO, oral (per os) PTV, planning target volume q3w, once every three weeks QoL, quality of life QTc, QT interval corrected for heart rate qw, once weekly RANK, receptor activator of nuclear factor kappa-B R-ICE, rituximab/ifosfamide/carboplatin/etoposide RCT, randomised controlled trial SC, subcutaneous SLNB, sentinel lymph node biopsy SRE, skeletal-related event TAC, docetaxel/doxorubicin/cyclophosphamide TC, paclitaxel/cisplatin TFS, transferrin saturation tiw, thrice weekly TKI, tyrosine kinase inhibitor UFH, unfractionated heparin US, ultrasound VAS, visual analogue scale VEGF, vascular endothelial growth factor VIP, 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Access the full ESMO Clinical Practice Guidelines © 2014 European Society for Medical Oncology All rights reserved. No part of this booklet may be reprinted, reproduced, transmitted or utilised in any form by any electronic, mechanical or other means, now known or hereafter invented, including photocopying and microfilming, or in any information storage or retrieval system, without written permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any license permitting limited copying issued in the UK by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London WiP 9HE, or in the USA by the Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923. Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. This booklet contains information obtained from authentic and highly regarded sources (http://www.esmo.org). Although every effort has been made to ensure that treatment and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publisher or the Guidelines Working Groups can be held responsible for errors or for any consequences arising from the use of information contained herein. For detailed prescribing information on the use of any product or procedure discussed herein, please consult the prescribing information or instructional material issued by the manufacturer. 99
