ROYAL ADELAIDE HOSPITAL CANCER CENTRE CALVARY CANCER CENTRE REMOTE CLINICS (BROKEN HILL/NORTHERN TERRITORY) MEDICAL ONCOLOGY

Y TREATMENT POLICY GUIDELINES 2002

(8th edition)

CONTENTS

PAGES:

SECTION 1
General Information, Drug Information and Prevention & Management of Symptoms/Toxicities: General Information: Introduction Medical Oncology Personnel Blood Products ordering Performance Status Scales - ECOG & Karnofsky Special Access Scheme Vascular Access Drug Information: Anthracyclines Bleomycin Carboplatin AUC Dosing - how to calculate Cisplatin Etoposide 5Flurorouracil Granulocyte colony stimulating factor GCSF Mercaptopurine Methotrexate Oxaliplatin Paclitaxel Streptozocin Vincristine Warfarin Prevention & Management of Symptoms/Toxicities including RAH and Medical Oncology Protocols: W.H.O (Miller) Toxicity Grading Dose Modification For Toxicity - Haematological And Non Haematological Anticoagulation Prophylaxis of DVT in immobilised patients Treatment Of Venous Thromboembolism (DVT, PE) Constipation Depression Antidepressant Guidelines Diarrhoea Emesis (Chemotherapy Induced Emesis; Emesis In Advanced Malignancy) Extravasation Prevention and Treatment Hiccups Treatment Hypercalcaemia Treatment Hypomagnesaemia - Magnesium Replacement Infections Prophylaxis And Treatment RAH Restricted Antibiotics Program Febrile Neutropenia Gentamicin dosing and monitoring Vancomycin dosing and monitoring Helicobacter Pylori Treatment TB Prophylaxis Viral Infections in the immunosuppressed patient Mouth Care Dry Mouth (Xerostomia) Mucositis (Stomatitis) 5

5 5 6 7 8 9 10 11 11 11 11 12 13 13 13 14 14 15 15 16 16 16 17 17 18 19 19 20 24 25 26 26 32 34 36 37 38 38 38 39 40 40 40 41 42 42 42

Pain In Cancer Chronic Cancer Pain Pleural Effusion Talc Pleurodesis Protocol Post-Menopausal Symptom Management Pruritus drug treatment Sperm Collection and Storage Symptom Control Terminal Care

43 43 48 49 50 51 53

SECTION 2 STANDARD TREATMENT POLICY GUIDELINES

ANAL CANCER BILIARY CANCER BLADDER (TRANSITIONAL CELL) CANCER. BRAIN BREAST CANCER CERVIX CANCER COLORECTAL CANCER ENDOCRINE CANCERS ENDOMETRIAL CANCER GASTRIC CANCER HEAD AND NECK CANCER (SQUAMOUS CELL) HODGKIN'S DISEASE KAPOSI'S SARCOMA LIVER CANCER (PRIMARY) LUNG CANCER (SMALL CELL) LYMPHOMA (NON-HODGKIN'S (LOW AND HIGH GRADE) MELANOMA MERKEL CELL TUMOUR MESOTHELIOMA OESOPHAGEAL CANCER OVARIAN CANCER PANCREAS PNET TUMOURS RENAL CANCER SARCOMA Soft tissue Ewing's Osteogenic Rhabdomyosarcoma SKIN CANCER (NON MELANOMA) TESTICULAR CANCER UNKNOWN PRIMARY

56

57 58 59 60 61 65 66 69 71 72 73 74 75 76 77 78 81 82 83 84 85 86 87 88 89 89 90 90 90 91 92 94

SECTION 3 CLINICAL TRIALS

95-110

SECTION ONE

General Information Drug Information Prevention and Management of Symptoms/Toxicities

GENERAL INFORMATION INTRODUCTION The Medical Oncology Treatment Policy Guidelines Booklet is divided into 3 sections. The first contains general information such as management of toxicities and information about drugs which require special precautions. This can be applied to many treatment situations. The second section contains the chemotherapy regimens currently considered as standard treatments for a variety of disease types and will be used when patients are not being entered into clinical trials. Tumour types not listed are those where it is considered that no chemotherapy regimen has been reported as showing sufficient benefit to be routinely offered to patients. The final section is a listing of the chemotherapy and supportive care regimens currently being investigated in clinical trials. Before commencing a patient on these regimens the full protocol, kept in the wards or with the data managers or investigators, must be consulted to ensure compliance with eligibility criteria and to obtain the full treatment details and schedules for evaluation of efficacy and toxicity. Patients must be informed that the regimen is part of a clinical trial and informed of the alternative management options. They must give written informed consent prior to treatment. These guidelines will be updated regularly to ensure that the latest treatments of proven efficacy are incorporated into standard treatments and to ensure that the listing of active clinical trials remains current.

PERSONNEL CLINICAL DIRECTOR: Ian Olver Office: Level 7 East Wing Phone: 8222 5577 Mobile: 0401123794 Fax: 8232 2148 Email: ian.olver@adelaide.edu.au iolver@mail.rah.sa.gov.au

STAFF SPECIALISTS:
Dorothy Keefe Office: Level 7 East Wing Phone: Ext. 24363 Mobile: 0417861157 Email: dkeefe@mail.rah.sa.gov.au Michael Brown Office: Level 7East Wing Phone: Ext. 22024 Mobile: 0401713968 Email: mbrown@mail.rah.sa.gov.au Tony Michele Calvary Cancer Centre phone 82399242 VISITING STAFF SPECIALIST: Jack Russell Rooms: 89 Payneham Road, St. Peters 5069 Telephone 83625344 (rooms) Mobile: 0417227295 CLINICAL PSYCHOLOGIST: Kate Morton Phone: 8222922 (pager 22772) Michele Hurn Phone 82225626 (pager 22772) Anne Taylor Office: Level 7 East Wing Phone: Ext. 22023 Mobile: 0401123826 Email: ataylor@mail.rah.sa.gov.au Tabitha Healey Office: Level 7East Wing Phone: Ext. 24398 Mobile: 0402356082 Email: thealey@mail.rah.sa.gov.au

Ward C6 Clinical Nurse Consultant

Helen Kradolfer Ext 24577 Ward Clerk - Pamela Bullard Ext 24574

Data Managers Medical Oncology

Nancy Olszewski -Page 1884, Ext. 24765 Toni Marafioti - Page 22075, Ext. 24358 Melinda Myers - Page 1883, Ext. 25637

Oncology Day Centre

CNC Judy Eden Ext 24396

Dietitian
David Cleghorn 8222 4000 (Page)

Day Centre Receptionist

Corinne Spearman Ext 24396

Outpatient Clinics
Registered Nurse - Nicole Baker Ext. 24406 Receptionist Maria Applekamp Ext. 24406

Pharmacy Oncology Clinical Pharmacist -Jude Lees Page1507 Cytotoxic Production Level 2 EW Ext 25456 Social Worker:
Marie McNamee 82224000 (page)

Secretaries
Angela Casarin Ext. 24384/25577 Margaret Collins Ext 24398

BLOOD PRODUCTS - ORDERING To order blood products ring Transfusion Ext 25430. Need to know: blood group, reason for platelet transfusion platelet count. Order irradiated products for patients where high dose therapy and a transplant is a possibility ie. lymphoma (intermediate grade and above), testicular. CMV status should be checked prior to transplant

PERFORMANCE STATUS - ECOG & KARNOFSKY ECOG: STATUS 0 1 2 3 4 DESCRIPTION Fully active, able to carry on all pre-disease performance without restriction. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light sedentary nature Ambulatory and capable of all self-care but unable to carry out any work. Up and about > 50% of waking hours. Capable of only limited self-care, confined to bed or chair > 50% of waking hours. Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair

KARNOFSKY: DESCRIPTION: Normal; no complaints Able to carry on normal activities; minor signs or symptoms of disease Normal activity with effort Cares for self; unable to carry on normal activity or to do active work Requires occasional assistance but able to care for most of his/her needs Requires considerable assistance and frequent medical care Disabled; requires special care and assistance Severely disabled; hospitalisation indicated though death is not imminent Very sick; hospitalisation necessary; active supportive treatment necessary Moribund Dead STATUS (%) 100 90 80 70 60 50 40 30 20 10 0

Reference: Karnofsky DA, et al. Cancer 1948; 1:634-656

SPECIAL ACCESS SCHEME It is sometimes possible to import drugs that are not licensed in Australia for use in a specific patient. This requires:1. Notification of the Clinical Pharmacist (pager 1507) or the Investigational Drugs Pharmacist (Ext. 25793 or mobile 0401 123 822) who will advise whether the drug is readily available, or will take some time to arrange. 2. Completion of a Category A Form (most chemotherapy patients fulfill the criteria for Category A Seriously ill patients with a condition from which death is reasonably likely to occur within a matter of months, or from which premature death is reasonably likely to occur in the absence of early treatment. The responsibility for prescribing an unapproved therapeutic good appropriately rests with the medical practitioer and the patient. It is required to obtain the patient's written consent. Category A forms are obtainable from outpatient clinics or the Pharmacy Dept. Ext 25793, or the Clinical Pharmacist Pager 1507. 3. Send the completed Category A Form and a drug order including the patients UR number to the Pharmacy Department (marked Attention Peter Slobodian). 4. If the Investigational Drugs Pharmacist advises that the patient fits Category B, which is life threatening but not critical, the required procedure will be advised.

VASCULAR ACCESS
Guidelines For IV Access for & administration of Chemotherapy; Devices & Their Management

GUIDELINES FOR IV ACCESS & ADMINISTRATION OFCHEMOTHERAPY: Only medical staff or senior nursing staff deemed competent are permitted to insert intravenous cannulae. Aseptic technique must be used for insertion of all cannulae and must be secured using steri strips and protected by nikogard for added security and easy visualisation. Three way taps with extension tubing are placed on all IV cannulae and are changed when cannulae are replaced as are existing IV lines. Cannulae are to be resited every 48 hours, particularly during fluorouracil infusion to prevent/reduce thrombophlebitis. Various infusaports are an option for planned long term chemotherapy and/or poor venous access. Insertion is done under general anaesthetic by a surgical team. Contact Mr. Gill's registrar to arrange insertion. Where possible ward staff should site the infusaport prior to insertion to include the patients' preferences and anatomical structures. Infusaports can be used on the day after insertion if a needle can be inserted safely. Sutures must be removed only after consultation with the surgical team and OPD appointments may be necessary for suture removal. Only senior nursing staff having completed an accepted postgraduate oncology course or those deemed competent are permitted to administer bolus chemotherapy. Extravasation kits are available from cytotoxic pharmacy and are kept routinely in the cytotoxic drug cupboard in C6 Office. For more detailed information on drug preparation, management of spillage and extravasation see Pharmacy Manual blue pages.

DEVICES & THEIR MANAGEMENT: Temporary Central Lines Flush with 300 u Heparin in 3mls N.Saline in each lumen. Infusaports Flush with 500 units Heparin in 5mls N.Saline every 3 months using Huber (non-coring) needle To unblock an Infusaport: Use a Huber (non-coring) needle and 3 way stop cock Inject Streptokinase 10,000 per ml. Turn stop cock while applying pressure so that at least 0.1-0.2 mls remains in the reservoir. Leave 30-45 mins and attempt to aspirate. If unsuccessful repeat streptokinase. Arterial Lines Flush with 2000 units Heparin every 1-2 weeks. PICC lines: 1. Groshong lines flush with Normal Saline 10mls weekly 1. Open ended lines flush with 50u Heparin in 5 mls daily

10

DRUG INFORMATION
ANTHRACYCLINES 1. Cardiotoxicity

Doxorubicin, epirubicin and a related drug mitozantrone have a cumulative cardiac toxicity. It is suggested that at total doses of doxorubicin 450mg/m2, epirubicin 900mg/m2 and mitozantrone 120mg/m2 cardiac ejection fractions be performed before further doses are given, then with every alternate dose. Cardiotoxicity should be considered cumulative when interchanging from one anthracycline to another. 2. Dose in Liver impairment

Modify doxorubicin dose for liver impairment (Bilirubin >30). If bilirubin 30-50 give 50% dose reduction, if > 50 give 75% dose reduction. BLEOMYCIN 1. Premedication Hydrocortisone 100mg IV (or dexamethasone with antiemetics) 2. Pulmonary fibrosis Cumulative toxicity. DCO should be measured pretreatment. Patients with pulmonary dysfunction e.g. a dry cough or fine crepitations, should not be treated with bleomycin. With clinical deterioration in pulmonary function (e.g. a dry cough or fine crepitations) or a decrease in DCO, bleomycin should be stopped. A total cumulative dose of 300 units should not be exceeded. CARBOPLATIN DOSE CALCULATION- using Area under Concentration/Time Curve (AUC) Initial dose of carboplatin is based on renal function:- the dose predicted to produce a defined AUC. If used as a single agent the AUC required = 7mg/ml/min If used in combination chemotherapy the AUC required = 5mg/ml/min To calculate total dose of carboplatin independent of body surface area use the Calvert formula: TOTAL CARBOPLATIN DOSE (mg) = target AUC x (GFR + 25) Single agent total carboplatin dose = 7 x (GFR + 25) In combinations total carboplatin dose = 5 x (GFR + 25) If GFR is replaced by calculated creatinine clearance, decrease resulting dose by 10% e.g. Renal Clearance Carboplatin Dose Carboplatin Dose IF renal function measured by EDTA If renal function measured by < 60ml/min calculate creatinine clearance(decrease by 10%) yourself Mg ml/min ml/sec mg 383 425 60 1.00 428 475 70 1.17 473 525 80 1.33 518 575 90 1.50 563 625 100 1.67 608 675 110 1.83 653 725 120 2.00 COCKCROFT-GAULT FORMULA FOR CALCULATING CREATININE CLEARANCE Females: Creatinine = (140-age) x weight (in Kg) Clearance 961 x serum creatinine (in mmol/L) Males: Creatinine = (140-age) x weight (in Kg) Clearance 814 x serum creatinine (in mmol/L)

Dosage Attenuation: Carboplatin dose will be determined by renal function for the first cycle only. In subsequent cycles the carboplatin dose will be determined by the platelet nadir in the previous cycle. 11

PLATELET NADIR > 100x109/L 50x109/L for 7 days or less not associated with thrombocytopenic bleeding (ie Grade I and II thrombocytopenia) 50x109/L more than 7 days or 50, associated with bleeding (ie Grade III or IV thrombocytopenia)

NEUTROPHIL NADIR > 1.0x109/L

CARBOPLATIN DOSE Increase dose of by 10%. Reduce dose by 10%.

Reduce dose by 20%.

Reference: Calvert AH, Newell DR, Gumbrell, LA et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function J. Clin Oncol 1989; 7: 1748-1756 Ando Y. Minami H,Saka S, Shimokata K. Adjustment of creatinine clearance improves accuracy of Calvert`s formula for carboplatin dosing. British Journal of Cancer 76(8):1067-71,1997

CISPLATIN 1. Renal Effects Cisplatin is nephrotoxic and prior to the initial therapy the creatinine clearance should be calculated and renal function monitored prior to each course. Magnesium (see Hypomagnesaemia page 37, Magnesium Replacement Protocol) and potassium levels should be monitored frequently as renal loss of both of these may occur. These should be checked with restaging. Avoid giving other nephrotoxic drugs concomitantly with cisplatin, particularly aminoglycosides. If gentamicin must be given, use RAH dosage guidelines (see page 39) according to renal function, and monitor serum levels. To avoid nephrotoxicity, pre and post cisplatin hydration is given. RAH Infusion Therapy Charts have been prepared for several cisplatin regimens: (1) Standard: Normal saline 2000mls over 2 hours, with MANNITOL 20%, 200mls over hour. Cisplatin is given in 1 litre over 2 hours then 1 litre N.Saline over 4,6, and 8 hours (with potassium and magnesium added as necessary). CNS regimen (using smaller volumes of 5% glucose). For Cisplatin/5-FU For Cisplatin/Etoposide 100mg/m2 For Cisplatin 5 day outpatient schedule Prehydrate with N saline 1000mls over 2 hours. Cisplatin is given in 1 litre over 2 hours. No posthydration is necessary if the patient is drinking adequately. For Vinblastine/Cisplatin/Ifosfamide For Etoposide/Cisplatin/Ifosfamide For Ifosfamide + Mesna For Vincristine/doxorubicin/cyclophosphamide (ANZ Ewings) For Etoposide/ifosfamide/mesna (Ewings)

(2) (3) (4) (5)

(6) (7) (8) (9) (10) 2. Ototoxicity

High frequency hearing loss can occur with cisplatin and audiograms can be used to monitor this. 3. Cisplatin Drug Interactions Cisplatin/phenytoin: Effect significant decrease in phenytoin level resulting in seizures occurs with oral and IV Mechanism ? decreased absorption 12

 ? enhanced metabolism ? concomitant medications Management baseline phenytoin level repeat level 2-3 days after cisplatin (and ? weekly) may need to adjust dose during cisplatin to avoid failure may need to readjust dose after cisplatin to avoid phenytoin toxicity Cisplatin/aminoglycosides Clinical Studies Early study in 4 patients on gentamicin and cephalothin severe progressive acute renal failure Subsequent studies found renal impairment usually mild EXCEPT where pre-existing cisplatin-induced renal dysfunction was present when aminoglycosides were started. Management For patients with febrile neutropenia after cisplatin in whom aminoglycosides are indicated: check serum creatinine and weight adjust dose accordingly monitor levels (see page 38) repeat monitoring if serum creatinine changes or in 3 to 5 days. Cisplatin/lithium Effect Possible decreased lithium level, but no reports of clinical effect Mechanism ? due to the cisplatin or the fluid load Management Recommend monitoring lithium level ETOPOSIDE Etoposide/phenytoin interactions: Reduced systemic exposure (? clinical significance) possible with etoposide FLUOROURACIL Fluorouracil (5FU) can cause chest pain, often accompanied by ECG changes and elevated cardiac enzymes indicative of cardiac ischaemia. If this symptom occurs, discontinue the drug. Hand/foot syndrome with ambulatory infusion 5FU may respond to pyridoxine 100 to 150mg per day. GRANULOCYTE COLONY STIMULATING FACTOR (G-CSF) RAH INDICATIONS Section 100 of the Pharmaceutical Benefits Scheme (P.B.S.) allows RAH to be reimbursed for certain High Cost drugs used OUTSIDE hospital (ie d/c or OPD scripts). Granulocyte colony stimulating factor (GCSF) is one such drug. Use is restricted to the following indications. Oncology Tumour types for which G-CSF is reimbursable to allow full dose chemotherapy: intermediate + high grade NHL relapsed Hodgkins first line Hodgkins (only for patients who have had a prior episode of severe febrile neutropenia or prolonged severe neutropenia {<1000} where clinical justification for using same drugs/dose/schedule and where good response is anticipated if planned CT is delivered*) Ewings sarcoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma germ cell tumours breast cancer (std. adjuvant CT and conditions above *) mobilisation of PBSC (filgrastim only) DOSE: 1 vial lenograstim (Amrad - 263mcg) s/c daily starting 24 hours after CT is completed and continued for 10 days or until WCC >10,000 (if country patient self-administering, AMGEN filgrastim (in solution in pre-loaded syringe) is preferred) or 13

1 syringe filgrastim (Amgen - 300 mcg) s/c daily starting 24 hrs after CT is completed and continued for 10 days or until WCC > 10,000. NB 480mcg syringe may be needed in pts > 96 kg. Precaution omit on day bleomycin administered. N.B. Blue Section 100 declaration form must be filled in by the doctor and sent with the first prescription for either brand. The declaration states that the patient fits the criteria for Section 100 reimbursement. IT IS ONLY REQUIRED ONCE MERCAPTOPURINE Mercaptopurine & allopurinol interaction This is the best known and most studied interaction, but the 2 drugs are often co-administered. Effect Significant increase in haematological toxicity Mechanism Allopurinol inhibits xanthine oxidase, the enzyme which metabolises mercaptopurine 5 fold increase in peak concentration and AUC. Management Reduce mercaptopurine dose to or 1/3 usual dose METHOTREXATE 1. Third space collections Patients with third space fluid collections, e.g. pleural effusions or ascites, should have them drained before methotrexate is administered since severe myelosuppression may result by accumulation of the drug in such collections. 2. High dose methotrexate Monitoring methotrexate levels High dose methotrexate should be monitored, usually with 24 and 48 hour blood levels. Contact Haematology Lab 25430. Leucovorin Rescue Calcium Leucovorin (calcium folinate, folinic acid) is used to rescue normal cells from methotrexate after High Dose infusions. The dose and timing varies with protocol, and must be strictly adhered to in order to avoid excessive toxicity (severe mucositis, myelosuppression). A common rescue protocol is oral (or IV for the first dose) calcium folinate 30mg every 6 hours for six doses (or until Serum MTX level is less than 0.1umol/l) commencing 24 hours after the START of methotrexate infusion. 3. Methotrexate Interactions Well known potential for interactions with drugs that delay MTX clearance. The severity of toxicity is related to duration of exposure and threshold concentrations (different for different organ systems). Methotrexate/NSAIDS or Aspirin Effect Reports of the following toxicity with low dose MTX cutaneous g/i pancytopaenia severe mucositis liver dysfunction death Mechanism competition by weak organic acids for renal tubular secretion - delayed MTX clearance inhibition of renal prostaglandin synthesis decreased renal perfusion decreased protein binding (7-OH MTX is 91-93% bound) Management caution when using concurrently - consider adding folinic acid, or increasing its dose or duration 14

 consider MTX level monitoring - consider withholding NSAID/aspirin during MTX Methotrexate with trimethoprim +/- sulfamethoxazole Effect reported serious toxicity with low dose MTX kinetic study in childhood ALL 66% increased systemic exposure and probable increased myelotoxicity Mechanism ? additive folate antagonism Management Observe for unexpected toxicity Other reported suspected methotrexate interactions Increased toxicity (levels) with amiodorone, etretinate, omeprazole, penicillins, probenecid, remain to be confirmed. OXALIPLATIN Peripheral Sensory Neuropathy 85-95% of patient experience neuropathy - two types acute and cumulative. NOT like cisplatin. Acute peripheral sensory neuropathy The majority of patients with neuropathy experience ACUTE neuropathy usually mild and painless, starts during the infusion (or within a few hours) and last from minutes to a few days. Characterised by dysaesthesia and/or paraesthesia of the extremeties with or without cramps. A SMALL percent (1-2%) experience acute pharyngolaryngeal dysaesthesia characterised by unpleasant (usually painless) sensation in throat, sometimes feeling like shortness of breath, but without objective evidence of respiratory distress (hypoxia, laryngospasm, bronchospasm) . ALL THESE SYMPTOMS CAN BE INDUCED OR EXACERBATED BY COLD. Precautions: keep warm. Wear thick gloves on cold days, and thin gloves for handling hot or cold items. Avoid barefeet, swallowing food or drink that is either very hot or cold, avoid direct contact with cold water (warm shower/bath). Treatment: acute laryngopharyngeal dysaesthesia increase infusion time from 2 to 6 hours; if have discomfort with breathing have warm drinks, wear scarf or high necked sweater. Use of drugs is under investigation. Jaw spasm, abnormal tongue sensation with possible subsequent dysarthria and feeling of chest pressure have been observed. Signs and symptoms rapidly reverse without treatment although antihistamines and bronchodilators have been used. Prolonging infusion time may reduce this on subsequent cycles. Cumulative neuropathy Pain and/or functional disorder may require adjustment of dose or cessation of oxaliplatin
Reference: P. Gent, K. Massey. An overview of chemotherapy-induced peripheral sensory neuropathy, focusing on oxaliplatin. International Journal Of Palliative Nursing, 2001, Vo.7, No 7 Product information

PACLITAXEL Hypersensitivity Reactions Premedication as shown in Section Two Quick premed is ranitidine 50mg IV, promethazine 25mg IV (or diphenhydramine 50mg oral) and dexamethasone 20mg IV approximately 30 minutes prior to paclitaxel. Reference: Bookman MA, Kloth DD, Kover PE, Smolinski S, Ozols RF. Short-course intravenous prophylaxis for paclitaxel-related hypersensitivity reactions. Ann Oncol. 1997 Jun;8(6):611-4. Myalgias/Arthralgias May respond to prophylactic paracetamol or NSAID 15

A number of other drugs including prednisolone may work in refractory cases. Consult Clinical Pharmacist. STREPTOZOCIN This drug should not be given in the presence of marked renal dysfunction Renal and hepatic function and glucose levels should be monitored during treatment (See ADEC guidelines). VINCRISTINE Vincristine Interactions Itraconazole increases neurotoxicity in children on vincristine Nifedipine may decrease the clearance of vincristine WARFARIN See also page 21 Treatment of Venous Thromboembolism. Warfarin & Cytotoxic Drug interactions Anticoagulants are often prescribed either for a pre-existing condition or for DVT or PE (thrombotic complications are often seen in cancer patients). Warfarin & Tamoxifen Effect several individual reports and retrospective reviews significant increase in prothrombin times significant bleeding problems in some cases Mechanism Unknown Management Monitor INR if stopping or starting tamoxifen Warfarin & Ifosfamide/Mesna Effect Raised INR within 48 hours of starting ifosfamide/mesna Mechanism ? inhibition of warfarin metabolism Management Monitor INR and adjust dose if needed Warfarin & Cyclophosphamide Conflicting reports: one report of raised prothrombin time on stopping oral cyclophoshamide 450 mg per day 4 other cases of raised prothrombin times or bleeding monitor INR Warfarin & Etoposide; Teniposide; 5Fluorouracil Raised prothrombin or INR reported.
References: Drug Interactions in the therapy of malignant disease. HJ Illiger et al, 3rd edition. Drug Interactions Facts, Editor David S Tatro Henriksson R and Grankvist K. Interactions between anticancer drugs and other clinically used pharmaceuticals. Acta Oncologica 1989, 28: 451-462 Balis F.M. Pharmacokinetic drug interactions of commonly used anticancer drugs. Clinical Pharmacokinetics 1986, 11: 223-235. Frenia ML and Long KS. Methotrexte and nonsteroidal anti-inflammatory drug interactions. The Annals of Pharmacotherapy, 1992, 26: 234-5. Grossman SA, Sheidler VR and Gilbert MR. Decreased phenytoin levels in patients receiving chemotherapy. The American Journal of Medicine, 1989, 87: 505-510. Curtin JP et al. Chemotherapy-induced neutropenia and fever in patients receiving cisplatin-based chemotherapy for ovarian malignancy. Gynecologic Oncology, 1991, 40: 17-20

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Prevention & Management of Symptoms/Toxicities

W.H.O. (MILLER) TOXICITY GRADES
GRADES Haemoglobin (g.dl) White cells (109/L) Neutrophils (10 9/L) Platelets (10 9/L) Nausea & Vomiting 0 11.0 4.0 2.0 100 none 1 9.5-10.9 3.0-3.9 1.5-1.9 79-99 Nausea 2 8.0-9.4 2.0-2.9 1.0-1.4 50-74 transient vomiting 3 6.5-7.9 1.0-1.9 0.5-0.9 25-49 vomiting requiring therapy intolerable requiring therapy ulcers, requires liquid diet only intolerable paraesthesia and/or marked motor loss multifocal PVC 4 < 6.5 < 1.0 <0.5 <25 intractable vomiting

Diarrhoea

none

transient < 2 days

tolerable but > 2 days

haemorrhagic dehydration

Stomatitis

none

soreness/ erythema

erythema, ulcers, can eat solids severe paraesthesia and/or mild weakness unifocal PVC, atrial arrhythmia

alimentation not possible

Peripheral neuropathy

none

paraesthesia and/or decreased tendon reflexes

paralysis

Cardiac (rhythm)

none

sinus tachycardia > 110 at rest

ventricular tachycardia

Alopecia

none

minimal hair loss

moderate, patchy

complete

Hand/foot syndrome

none

Mild

moderate

severe

life-threatening

Cutaneous

none

Erythema

dry desquamation vesiculation, pruritus mild blood loss

moist desquamation ulceration

exfoliative dermatitis, necrosis requiring surgery

Haemorrhage

none

Petechiae

gross blood loss

debilitating blood loss

Lethargy

none

mild fever < 38oC mild symptoms

moderate fever 38-40 pC exertional dyspnoea moderate

severe fever > 40oC dyspnoea at rest severe

fever with hypotension complete bed rest required life-threatening

Fever Pulmonary

none none

Bladder

none

Mild

Allergic

none

Oedema

bronchospasm, no parenteral therapy needed moderate

bronchospasm, parenteral therapy required severe

anaphylaxis

Other

none

mild

life-threatening

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DOSE MODIFICATION FOR TOXICITY Some general policies for dose reduction can be stated. Specific exceptions will be listed with specific treatment regimens using the WHO (Miller) toxicity criteria: HAEMATOLOGICAL: Grade 3 or 4 nadir neutrophil and platelet counts: reduce the subsequent dosage by 25%. If neutrophils and platelets have not recovered by Day 1 of next cycle delay therapy until neutrophil count is 1500 and platelet count 100,000. May require 25% reduction for subsequent courses. Where Section 100 indication for use of G-CSF is met, this should be considered for subsequent cycles (see G-CSF page 14) For reversible grade 3 toxicity (except alopecia) may require dose reduction of 25%. Grade 4 non-haematological toxicities may dictate withdrawal of treatment or subsequent dose reduction of 25%.

NON-HAEMATOLOGICAL:

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ANTICOAGULATION DVT PROPHYLAXIS IN IMMOBILISED PATIENTS Low dose low molecular weight heparin is now approved for the prophylaxis of deep venous thrombosis in bedridden patient with malignancy. Enoxaparin 40 mg subcutaneously daily until mobilising

19

ANTICOAGULATION - TREATMENT OF VENOUS THROMBOEMBOLISM RAH Drug Committee Guidelines 2002 Low molecular weight heparin combined with oral warfarin is the treatment of choice for the management of venous thromboembolism. Administration of twice daily low molecular weight heparin should be commenced as soon as a decision is made to anticoagulate the patient. Warfarin should be commenced on the day of admission and should be co-administered until a therapeutic INR is achieved. The heparin dosages may then be reduced or ceased. The following algorithm provides an overview of management of venous thromboembolism with low molecular weight heparin and warfarin:
Strong suspicion of DVT or PE

Consider initiating treatment before diagnosis confirmed

Perform appropriate diagnostic investigations

Obtain baseline CBE, INR and APTT

Diagnosis confirmed

Begin warfarin Begin administration of enoxaparin 1mg/kg bodyweight (to nearest 2.5kg) subcutaneously twice daily (= total daily dose of 2mg/kg) Syringes contain: 60mg/0.6ml or 80mg/0.8ml or 100mg/1.0ml Select appropriate syringe size and inject calculated volume subcutaneously

Monitor INR daily. Adjust warfarin dose according to laboratory result

Discontinue enoxaparin when INR therapeutic on 2 consecutive days, and continue warfarin for at least 3 months

Monitor INR twice weekly for 2 3 weeks until stable therapeutic range achieved. Monitor weekly or less frequently thereafter.

20

Low Molecular Weight Heparin for Treatment of Venous Thrombosis and Pulmonary Embolus Route and Method of Administration Subcutaneous: Severe bruising may result if an incorrect injection technique is used. The injection should be made into the anterior abdominal wall, using a different site for each injection. The whole length of the needle should be introduced vertically into the thickness of a skin fold pinched up between thumb and forefinger. This skin fold should be held throughout the duration of the injection. Pressure should then be applied to the site with the palm of the hand for 5 minutes. Dosage Note: 1mg enoxaparin is equivalent to 100 units anti-Xa activity Enoxaparin 1mg/kg bodyweight, to nearest 2.5kg bodyweight subcutaneously twice daily. Laboratory Control Before therapy is commenced, send 4ml of blood in a blue top container for determination of International Normalised Ratio (INR, previously called prothrombin ratio (PR)), and activated partial thromboplastin time (APTT) and to exclude a preexisting coagulation problem. Once therapy has been commenced, laboratory monitoring of low molecular weight heparin anticoagulant activity is unnecessary, however platelet counts should be monitored weekly to detect heparin induced thrombocytopaenia. Duration of Therapy Heparin is usually ceased when the INR is therapeutic for 2 consecutive days, and oral anticoagulants are then continued for at least 3 months. Heparin should be continued until warfarin is having a therapeutic effect (see Section 2.2 for therapy with oral anticoagulants). Overdosage or Bleeding Complications In emergency situations, the anti-coagulant activity of low molecular weight heparin may be largely neutralised by intravenous protamine sulfate, (1mg protamine sulfate neutralises 1mg of enoxaparin). However, some anti-Xa activity will remain. The Haematologist on call or the Pharmacy Drug Information Centre (Ext. 25546) should be consulted for further advice concerning dosage in these situations. Oral Anticoagulants Note: It is recommended that prior to discharge of a patient with warfarin therapy for long term anticoagulation, the patient is counselled and provided with written patient information. Contact clinical pharmacist Page 1507 Alternatively the advice of the Drug Information Centre may be sought on Ext 25546. Laboratory Control Baseline coagulation studies should be performed before starting therapy; send 4ml of blood in a blue top container for International Normalised Ratio (INR), and activated partial thromboplastin time (APTT) determination and to exclude a coagulation disorder. R.A.H. ranges for normal INR and normal APTT are 0.8-1.2 and 20-39 seconds respectively. Subsequent monitoring is by the International Normalised Ratio (INR). Dosage The recommended initial dosage for warfarin is 6 - 10mg/day (depending on age, according to loading protocol below), with daily adjustments made thereafter depending on laboratory results. The average maintenance dose varies from 2 to 10mg although some patients require doses outside this range. Due to the long half-life of warfarin, the maximum effect of a dose is seen 48-72 hours after administration. Two to-3 weeks are generally required for full stabilisation on warfarin therapy. Warfarin dose should be given at 6pm each day during the loading phase Blood samples for INR should be taken between 9am11am the next morning INR must be performed daily for the first 5 days Some patients may require further marginal dosing adjustment at the completion of the protocol

The goal of warfarin loading regimens is to rapidly attain a stable therapeutic INR without over-anticoagulation. If the baseline INR (before commencement of warfarin) is 1.4 or more then careful consideration must be given to initiating warfarin for any condition. The recommended therapeutic range for oral anticoagulant therapy is 2.0 - 3.0. For patients with prosthetic heart valves the recommended ranges are 2.0 - 3.0 (low risk valves) and 2.5 - 3.5 (high risk valves). 21

The following Age Adjusted Warfarin Loading Protocol* is a guide to warfarin dosing during the induction period. Dose according to age (mg) 50 years 5165 years 6680 years Day INR > 80 years 1 2 (16hrs after 1st dose) 3 (16hrs after 2nd dose) <1.4 1.5 1.6 1.7 1.82.3 2.42.7 2.83.1 3.23.3 3.4 3.5 3.64.0 >4 4 (16hrs after 3rd dose) 1.5 1.6 1.71.8 1.9 2.02.6 2.73.0 3.13.5 3.64.0 4.14.5 12 >4.5 10 10 0.5 10 5 4 3 2 1.5 1 0.5 0 1015 8 7 6 5 4 3.5 3 9 9 0.5 9 4.5 3.5 2.5 2 1.5 1 0.5 0 914 7 6 5 4.5 3.5 3 2.5 0.51.5 7.5 7.5 0.5 7.5 4 3 2 1.5 1 1 0.5 0 7.511 6 5 4.5 4 3 2.5 2 0.51.5 6 6 0.5 6 3 2 1 1 1 0.5 0.5 0 69 5 4 3.5 3 2.5 2 1.5 0.51

omit next dose, then Nil. Hold dose.

* Roberts GW, Gallus AS, Druskeit T et al. Comparison of an age adjusted warfarin loading protocol with empirical dosing and Fennertys protocol. Aust NZ J Med. 1999; 29: 731-6. Duration of Warfarin Therapy For treatment of thromboembolism, warfarin therapy is usually continued for 3 months Management of In-patient Maintenance Warfarin Therapy Following admission of any patient on maintenance warfarin therapy to the R.A.H., the maintenance warfarin dose should be written on the Medication Chart for Regularly And Intermittently (PRN) Administered Drugs (UR-71B). Testing for INR should be performed every two or three days. The medical officer responsible for the care of the patient is responsible for checking the INR result on the day of the test. However in the event that: (a) A new drug is ordered, or a drug is ceased, which is suspected of interacting with warfarin, or (b) The INR falls below, or rises above, the recommended therapeutic level, the order for regular doses of warfarin should be discontinued, and a new variable dose warfarin order commenced, with daily testing of INR, followed by subsequent selection of an appropriate dose for that day guided by the results of the INR test. The new variable dose warfarin order may be written on either the UR-71B, or Medication Chart For Variable Dose Drugs (UR-72), according to usual ward practice. Patients should not be changed from their usual brand of warfarin. The RAH Pharmacy Department stocks both brands of warfarin. Tablet strengths and colours are: 1mg (light tan), 2mg (lavender), 5mg (green) RAH brand of warfarin for initiation of warfarin therapy COUMADIN MAREVAN 1mg (brown), 3mg (blue), 5mg (pink) Specify this brand if patient usually takes it. 22

Drug Interactions
Regular monitoring of warfarin is mandatory. There is significant potential for drug interactions with warfarin therapy. Caution should be exercised when adding or deleting any newly approved drug until its safety in combination with warfarin is known. Changes in warfarin effect can occur with either the introduction or cessation of drug therapy. Bleeding is the most important adverse effect. The concomitant use of antiplatelet drugs (e.g aspirin, NSAIDs, clopidogrel, ticlopidine, dipyridamole) can also increase the risk of bleeding. Some complementary medicines (eg ginkgo, dong quai) may also have an antiplatelet effect. The elderly, the critically/acutely ill, those with impaired renal function, those with impaired hepatic function and those taking multiple drug therapies are particularly at risk. Those patients with fluctuating dietary intake may require more frequent INR monitoring, e.g. patients with anorexia, nausea, vomiting and diarrohea. This is not an exhaustive list of potential drug interactions Increased anticoagulant effect Decreased anticoagulant effect
Amiodarone, Anabolic steroids, Bicalutamide, Chloramphenicol, Cimetidine, Ciprofloxacin, Clarithromycin, Cotrimoxazole, Danazol, Disulfiram, Dong quai, Doxycycline, Erythromycin, Fluconazole, Flutamide, Gemfibrozil, Ginkgo biloba, Itraconazole, Ketoconazole, Metronidazole, Miconazole (including oral gel), Nilutamide, Norfloxacin, Protease inhibitors (indinavir, saquinavir, ritonavir, nelfinavir), Quinidine (also decreased), Simvastatin, SSRIs, Sulphinpyrazone, Tamoxifen, Tetracycline, Thyroxine, Paracetamol. *Small occasional doses of paracetamol do not normally affect INR. Larger amounts of paracetamol (2 to 4 grams daily) taken for several days may increase the INR. More frequent monitoring is indicated especially if paracetamol administration coincides with other risk factors, eg febrile illness. Barbiturates, Carbamazepine Cholestyramine Griseofulvin Non-nucleoside reverse transcriptase inhibitors (some nevirapine, efavirenz) Nutritional supplements rich in Vitamin K Phenytoin (or more rarely increased) Rifampicin St. John s Wort (Hypericum perforatum ) Sucralfate

Overdosage In any case of overdosage specialist haematologist advice may be sought if necessary The appropriate antidotes to warfarin overdosage are Vitamin K1 (phytomenadione), alone or with fresh frozen plasma (2-4 units) +/- Prothrombinex (Factor II, IX and X concentration) -1200-2400 units IV. Note: (a) The use of Prothrombinex has been associated with an increased incidence of thromboembolism. (b) The dangers of viral transmission associated with blood products must be considered.(Patient consent must be obtained. The effect of fresh frozen plasma is immediate whereas it takes 8-12 hours for the effects of Vitamin K1 to become apparent. Large doses of Vitamin K1 (eg 10-20mg) may produce some resistance to re-warfarinisation, but there is less resistance to smaller doses of 1-5mg, which are still effective in correcting an abnormally high INR within 24 hours in most cases. Vitamin K1 should be given by the oral route, except where there is malabsorption or obstructive jaundice. If using parenteral vitamin K1 (Konakion MM ), the IV route is recommended. The required dose should be given at a rate equivalent to administering 10mg (1ml) over a minimum of 30 seconds. A maximum total dose of 40mg in 24 hours. IV phytomenadione may in rare cases cause severe anaphylactoid reactions. It should not be administered intramuscularly as this route of administration exhibits depot characteristics which may cause difficulties in the reinstitution of anticoagulant therapy. The following table provides a guide to reversal of the anticoagulant effect of warfarin
Clinical Picture Significant bleeding No bleeding No bleeding No bleeding Elective surgery Semi elective surgery (24-48 hours available) Emergency surgery (< 24 hours available) INR Therapeutic or above >10 7-10 4.5-7 Therapeutic Therapeutic Therapeutic Warfarin Hold Hold Hold Hold for 1-2 days Hold for 3-4 days before surgery Hold Hold Vitamin K1 Dose 10mg (IV if bleeding severe) 1-3mg 1-3mg FFP +/- Prothrombinex 2 - 4 units 2 units

. .
5mg 5mg

. . . .
2 - 4 units

23

CONSTIPATION Prevention/Treatment of Opioid Induced Constipation Precautions: 1. Neutropenic patients should not have rectal suppositories 2. Prior to giving laxatives or enemas ensure that tumour related bowel obstruction is not the underlying cause. 1. Commence regular laxative protocol on initiation of opioid analgesia. (a) Coloxyl with Senna 1-2 tablets twice daily strictly (acts in 6 to 12 hours). (b) Encourage mobilisation, fluids and increased fibre intake. (Note: Increased fibre is contraindicated in bowel obstruction and in debilitated, dehydrated patients). 2. Chart and describe bowel actions daily. 3. Increase dose of Coloxyl with Senna if necessary up to 2 tablets three to four times daily. 4. Rectal examination should be performed if patient has:(a) rectal discomfort (b) no bowel action for 3 days 5. If rectum full the following should be tried sequentially. (a) glycerin suppository or disposable enema (eg microlax). (b) high enema by flexible catheter (eg. glycerin and oil or tap water). (c) magnesia pellegrino (15 ml in water stat) (acts in 2 to 4 hours). (d) manual evacuation. 6. For persistent constipation add alternate day glycerin suppository or disposable enema to daily Coloxyl with Senna. 7. Patients presenting with pre-existing opioid-induced constipation require treatment as in (4) and (5) and commencement of regular laxative protocol as in (1). 8. Alternative laxatives eg. sorbitol (osmotic laxative) 20 ml TDS should be reserved as third line. Onset of effect may take several days. Requires good hydration to work, and does not stimulate bowel motility. Use with caution in diabetics as it may elevate blood glucose levels (usually after extended use). Tolerance is also reported after prolonged use. Lactulose another osmotic laxative is significantly more expensive than sorbitol and at RAH lactulose is ONLY available for treatment of hepatic encephalopathy, NOT constipation. Many patients find sorbitol/lactulose unpalatable. 9. Remember diarrhoea may be due to faecal impaction with overflow.

24

DEPRESSION ANTIDEPRESSANT GUIDELINES

It is recommended to use a selective serotonin re-uptake inhibitor (SSRI) first line. Two are currently available at RAH FLUVOXAMINE recommended in younger patients as it has less effects on sexual function, and SERTRALINE. There are significant drug interactions associated with both drugs less with sertaline. See below for detailed information. SERTRALINE Dose Starting dose 50 mg once daily in the morning, or evening, with or without food. Patients not responding may benefit from dose increases up to a maximum of 200mg/day. Dose changes should not occur at intervals of less than one week. Treatment should cease if there is no response after 6 weeks of treatment with the maximum tolerated dose. Depressed patients responding during an initial 6 weeks treatment phase should continue antidepressant medication for 6 months after recovery from the depressive episode. Discontinuation should be achieved by a gradual reduction in dosage.In patients with liver disease, metabolism of sertraline is reduced, and plasma half life increased. Patients with active liver disease should start at lower doses, be monitored, and doses increases should take place more gradually. Adverse Effects Most common - nausea, headache, dry mouth, diarrhoea, insomnia, dizziness, tremor, fatigue, agitation, drowsiness and male sexual dysfunction. (in >10% of patients). Drug interactions Concomitant administration of MAOIs is contraindicated, and other serotonergic agents (other SSRIs, tryptophan, tricyclic antidepressants, pethidine and sumatriptan) should be used cautiously to avoid the serotonin syndrome. Concomitant administration of sertraline and warfarin has led to an increase in prothrombin time- monitor on initiation and ceasing of sertraline therapy. Sertraline has a modest inhibitory effect on CYP 2D6, and may inhibit the metabolism of drugs known to be substrates for CYP 2D6 such as tricyclic antidepressants, antipsychotics, metoprolol, propranolol, perhexiline, oxycodone, codeine, dextromethorphan, venlafaxine, flecainide, mexiletine. At lower doses, sertraline is a less potent inhibitor of CYP2D6 than paroxetine or fluoxetine.1 FLUVOXAMINE Dose Starting dose 50mg once daily for one week, given as a single dose in the evening. Doses should be gradually increased by 50mg per week, until an effective dose is reached (usually 100mg), to a maximum of 300mg daily. Doses greater than 150mg should be given in 2 or 3 divided doses. Treatment should cease if there is no response after 6 weeks of treatment with the maximum tolerated dose. Depressed patients responding during an initial 6 weeks treatment phase should continue antidepressant medication for 6 months after recovery from the depressive episode. Discontinuation should be achieved by a gradual reduction in dosage. Adverse Effects Most - nausea (16%), somnolence, asthenia, headache, dry mouth, insomnia, abdominal pain, dizziness, nervousness, tremor, vomiting, dyspepsia, constipation, diarrhoea, anorexia, and vertigo (all > 2%)3. Sexual dysfunction is reported to occur in less than 0.1% of treated patients. Drug interactions Concomitant administration of MAOIs is contraindicated, and other serotonergic agents (other SSRIs, tryptophan, tricyclic antidepressants, pethidine and sumatriptan) should be used cautiously to avoid the serotonin syndrome. Fluvoxamine is a potent inhibitor of CYP 1A2, inhibiting the metabolism of drugs known to be substrates for CYP 1A2 such as clozapine, theophylline, propranolol and warfarin. If coadministration is necessary, the dosage of these drugs must be reduced. Fluvoxamine has only a weak effect on CYP 2D6, and is not likely to increase plasma concentration of drugs metabolised by CYP 2D6. Fluvoxamine has a modest inhibitory effect on CYP 3A3/4, therefore combination of fluvoxamine with cisapride, terfenadine and astemizole is not recommended. Caution is recommended with coadministration of caffeine, paracetamol, lithium, alprazolam, bromazepam, midazolam, carbamazepine, tricyclic antidepressants, amiodarone, quinidine, calcium channel blockers, erythromycin, steroids, omeprazole.

25

DIARRHOEA
Diarrhoea in the cancer patient can be: an extension of chemotherapy-induced stomatitis (oral mucositis) caused by drugs (e.g. capecitabine, fluorouracil, irinotecan) a symptom of constipation (overflow) caused by radiotherapy especially to pelvic area (e.g. for colorectal; prostate or cervix cancer) PREVENTION/TREATMENT 1. IRINOTECAN Irinotecan can induce two distinct types of diarrhoea: EARLY DIARRHOEA early diarrhoea occurs during or soon after administration, is cholinergic in nature and may be accompanied by rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing and hyperperistalsis that can cause abdominal cramping atropine 250 micrograms to 1 mg IV or SC can be used to prevent or treat early diarrhoea LATE DIARRHOEA late diarrhoea occurs >24 hours after the dose, can be prolonged, and may lead to dehydration, electrolyte imbalance and is potentially life-threatening. PROMPT TREATMENT IS ESSENTIAL. patients must have loperamide available and start taking it at the first episode of poorly formed or loose stools, or the earliest onset of more frequent than usual bowel movements for that patient. high dose loperamide is used 4mg (2 capsules) STAT then 2mg every 2 hours (or 4mg every 4 hours during the night) until diarrhoea free for 12 hours. Patients should notify the doctor and need careful monitoring and fluid/electrolyte replacement if dehydrated. Make sure the patient understands that the dose will be higher than recommended on the pack, and that this is intentional. 2. CAPECITABINE, FLUOROURACIL Determine the NCIC grade of diarrhoea, and follow the guidelines below. Grade 2 Increase of 4 - 6 stools/day or nocturnal stools Grade 3 Increase of 7-10 stools/day or incontinence and malabsorption Grade 4 Increase in 10 stools/day or grossly bloody diarrhoea or need for parenteral support *NCIC National Cancer Institute of Canada If grade 2, 3 or 4 diarrhoea occurs, treatment should be immediately interrupted until the diarrhoea resolves or reduces to Grade 1. Start standard antidiarrhoeal treatment with loperamide 4mg to start and 2mg after each loose stool until diarrhoea is controlled (maximum 16mg per 24 hours). Subsequent dosing:NCIC Grade 2 3 Dose 100% 1st occurrence - 25% reduction 2nd occurrence - 50% reduction 3rd occurrence - discontinue permanently 4 Discontinue permanently or reduce by 50%

26

EMESIS 1. Chemotherapy-Induced Emesis INTRODUCTION

Nausea and vomiting associated with cancer chemotherapy can be severely distressing and debilitating to patients and may even lead to refusal of further chemotherapy unless controlled. It is possible to categorise cyotoxics into five groups according to their emetogenic potential, and recommend appropriate antiemetics for each group. It should be noted that combinations of cyototoxics are usually more emetogenic than single agents. Likewise combined antiemetic regimens are significantly more effective than single agents particularly with severely emetogenic cytotoxic drugs. In addition to the variation in emetogenicity of individual cytotoxics, other factors may influence the severity of emesis. These include the dose and schedule of the cytotoxic, the patients age, sex, alcohol intake history, prior emetic history and concurrent medical problems All patients regardless of cytotoxic protocol should have PRN antiemetics available TYPES OF EMESIS Chemotherapy-induced nausea and vomiting are classified as acute, delayed, anticipatory, breakthrough or refractory. Acute nausea and vomiting usually occurs within the first few hours after chemotherapy (see Table I) and lasts up to24 hours Delayed vomiting starts about 24 hours after chemotherapy, and may last a week or longer. It is most common with cisplatin Anticipatory nausea and vomiting is learned from previous experience with poorly controlled vomiting. Breakthrough vomiting occurs despite optimum preventitive therapy, and requires additional therapy. Refractory vomiting occurs after one or several cycles of chemotherapy when the patient no longer responds to treatment. DRUG CLASSES AND RECOMMENDED ACUTE ANTIEMETIC PROTOCOL Class V (very high emetic incidence - > 90% patients vomit) DRUG & DOSE if relevant carmustine 250mg/m2 cisplatin# cyclophosphamide > 1.5g/m2# Dacarbazine lomustine > 60mg/m Streptozocin
2

ONSET (hours) 2- 4 Acute 1- 6 Delayed 16-24 6-18 1- 3 2- 6 1- 4

LASTS (hours) 4-24 >24 7days+ 18-36 6-24 6-12 12-24

ANTIEMETIC PROPHYLAXIS PROTOCOL Acute Emesis Tropisetron 5mg oral (or IV if vomiting) or ondansetron 8mg oral wafer (Zydis) if cannot swallow capsule (more expensive) + Dexamethasone 20 mg IV over 30 minutes pre chemotherapy + for severe acute or anticipatory emesis Lorazepam 1 3mg oral or sublingual pre chemotherapy

#requires delayed emesis antimemetic protocol *Information unavailable.

27

Class IV (moderate to high emetic incidence - 60-90% patients vomit) DRUG & DOSE if relevant Carboplatin# carmustine < 250mg/m
2

ONSET (hours) 2-10 2- 4 4-12 6-12 2- 6 2- 6 2- 6 3- 6 2-6

LASTS (hours) 48 4-24 4-10 3-5 12-24 <24 6-24+ 6-24+ 6-12 6-12 * 3-12

ANTIEMETIC PROPHYLAXIS PROTOCOL Acute Emesis Tropisetron 5mg oral (or IV if vomiting) or Ondansetron 8mg Zydis if cannot swallow capsule (more expensive) + Dexamethasone 20 mg IV over 30 minutes pre chemotherapy

cyclophosphamide 7501500mg/m2 cytarabine 1g/m2 dactinomycin > 1.5mg/m2 Daunorubicin >50mg/m doxorubicin > 60mg/m ifosfamide > 3.5g/m Irinotecan lomustine < 60mg/m
2 2 2 2

2-6 6-12 4-12

melphalan (high dose IV) methotrexate _ 1g/m

2

#may require delayed emesis antiemetic protocol *Information unavailable.

Class III (moderate emetic incidence - 30 - 60% patients vomit) DRUG & DOSE if relevant altretamine Cyclophosphamide < 750mg/m2 IV and oral cytarabine 250mg/m2 to 1g/m2 dactinomycin < 1.5mg/m2 daunorubicin < 50mg/m2 doxorubicin 20 60mg/m2 epirubicin fluorouracil (bolus) 1g/m2 idarubicin ifosfamide < 3.5g/m mitomycin mitozantrone teniposide *Information unavailable.
2

ONSET (hours) 3-6 4-12 6-12 2-6 2-6 2- 6 3- 6 3- 6 2- 3 3- 6 1- 4 * 3- 8

LASTS (hours) * 4-10 3-5 12-24 <24 6-24 6 3-6 * 6-12 18-24 * 6-12

ANTIEMETIC PROPHYLAXIS PROTOCOL Acute Emesis Tropisetron 5mg oral (or IV if vomiting) or Ondansetron 8mg Zydis if cannot swallow capsule (more expensive) + Dexamethasone 20 mg IV over 30 minutes pre chemotherapy

28

Class II (low to moderate emetic incidence - 10-30% patients vomit) DRUG & DOSE if relevant asparaginase cytarabine (standard dose) doxorubicin 20mgmg/m2 etoposide fluorouracil (bolus) < 1g/m2 fluorouracil (infusions)
*Information unavailable.

ONSET(hrs) 1- 3 6-12 4- 6 3- 8 3- 6 *

LASTS(hs) * 3- 5 6 * * *

ANTIEMETIC PROPHYLAXIS PROTOCOL Acute Emesis Single agent metoclopramide 10 30mg or prochlorperazine12.5 25mg or domperidone 1020mg or dexamethasone 4-8mg. NOTE: individual patients may require treatment similar to Class III. Combinations of agents in this class may cause more emesis and require treatment similar to Class III.

CLASS 1 (very low emetic incidence - < 10% patients vomit) bleomycin busulfan (standard dose) capecitabine chlorambucil cladribine daunorubicin, liposomal *Information unavailable. doxorubicin, liposomal floxuridine fludarabine hydroxyurea melphalan (oral) mercaptopurine methotrexate 50mg/m thioguanine vinblastine vincristine vinorelbine
2

ANTIEMETICS No prophylaxis is normally required.

Delayed Emesis - cisplatin Dexamethasone 8mg once or twice a day for 2 to 4 days (dose may be reduced on days 3 to 4) In cases of prolonged delayed emesis, the course may be lengthened to 7 days. + metoclopramide 10 to 30 mg (up to 0.5mg per kg if required)oral QID for 4 days (may be continued if required) OR prochlorperazine 10-15 mg oral QID or 25mg rectal QID OR *domperidone 10 to 20 mg oral QID
*for patients who have experienced or are at high risk of extrapyramidal side effects with metoclopramide or prochlorperazine

Delayed Emesis non-cisplatin Dexamethasone 4 - 8mg once or twice a day for 2 to 4 days as a single agent, or in combination with metoclopramide 10 to 30 mg (up to 0.5mg per kg if required)oral QID for 2 - 4 days OR prochlorperazine 10-15 mg oral QID or 25mg rectal QID for 2 4 days OR domperidone 10 to 20 mg oral QID for 2 4 days

Anticipatory emesis Breakthrough emesis Refractory emesis

Lorazepam 1 to 3 mg oral or sublingual pre-chemotherapy (can start the night before and the morning of chemotherapy) Metoclopramide 20 to 60 mg 2 hourly PRN OR Prochlorperazine 25 mg IV or rectal 6 hourly PRN Lorazepam 1 to 3 mg oral/sublingual pre-chemotherapy and consider adding a dopamine antagonist (metoclopramide or prochlorperazine as above) to standard antiemetics

Adapted from: Gralla RJ, Osoba D, Kris MG, Kirkbride P, Hesketh PJ, Chinnery LW, Clark-Snow R, Gill DP, Groshen S, Grunberg S, Koeller JM, Morrow GR, Perez EA, Silber JH, Pfister DG. Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. American Society of Clinical Oncology. J Clin Oncol. 1999 Sep;17(9):2971-94. Mullin S, Beckwith MC. Prevention and management of chemotherapy-induced nausea and vomiting. Part One. Hosp Pharm 2001, 36:67-80 and Part Two. Hosp Pharm 2001, 36: 280-305.

29

ASHP Commission on Therapeutics. ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health-Syst Pharm. 1999 56:729-64

30

ANTIEMETIC FLOWCHART
Determine risk factors and assess patient and regimen before each cycle Risk factors or history of anticipatory emesis? Give lorazepam 1 to 3 mg oral/SL pre-chemotherapy and PRN

YES

NO Select antiemetic regimen with best efficacy and lowest cost

Class III to V tropisetron 5mg oral (IV if vomiting) OR ondansetron 8mg oral wafer + dexamethasone 20 mg IV/oral + delayed emesis protocol where noted

Class II Single agent either metoclopramide 10 30mg or prochlorperazine10 25mg or domperidone 10-20mg or dexamethasone 4-8mg.

Class I no prophylactic antiemetic required

Ensure patient has PRN antiemetics for breakthrough nausea/vomiting

Failure

Determine cause/timeframe & modify regimen e.g. 1. increase dose of same antiemetics 2. change to alternative antiemetic 3. add another antiemetic 4. add delayed antiemetic regimen 5. correct any other causes 6. add anticipatory regimen

Assess patients response no. of vomits severity of nausea need for rescue antiemetics compliance with prophylactic antiemetics any side effects satisfaction with treatment

Success

Continue initial antiemetic regimen

31

Emesis In Advanced Malignancy 1. After reversible causes have been excluded one or several anti-emetics may be required to control nausea and vomiting. 2. Drugs commonly used: Metoclopramide oral, subcutaneous Prochlorperazine oral, rectal Haloperidol oral, subcutaneous Domperidone oral Chlorpromazine oral, rectal Dexamethasone oral, subcutaneous (see suggested doses below)

3. In certain situations consider: octreotide 50mg subcutaneous 8 hourly Useful to prevent gut reversal in patients in terminal phase of abdominal malignancy

RAH Drug Committee approved for intractable vomiting due to malignant bowel obstruction ONLY 4. For subcutaneous infusions suggested doses are: metoclopramide 10-60 mg per 24 hours haloperidol 1-10 mg per 24 hours

5. Breakthrough anti-emetics doses should also be given where an infusion is ordered. 6. Avoid metoclopramide and domperidone in high small bowel obstruction as they may aggravate.

32

EXTRAVASATION PREVENTION AND TREATMENT 1. INTRODUCTION Extravasation during administration of cytotoxic drugs may cause pain, inflammation or severe tissue damage if the drug is irritant or vesicant. 2. MINIMISING THE RISK OF VESICANT DRUG EXTRAVASATION
use skilled personnel to administer chemotherapy avoid sites on dorsum of hand and near joints avoid limbs with impaired circulation place a suitable line and cannula taped to allow visualisation do not use cytotoxic solution to test the line observe site for swelling and check patency ask patient to report ANY sensation of pain or burning if in doubt STOP infusion and consider changing site check frequently for venous blood return, signs of redness or swelling DURING administration - flush line between boluses and generously at end administer vesicant agents first

3. GENERAL MANAGEMENT OF SUSPECTED EXTRAVASATION Stop the injection immediately but DO NOT REMOVE THE IV LINE. Attempt to aspirate extravasated drug from the cannula Check the following tables to ascertain the irritant or vesicant potential of the extravasated agent If an injectable antidote is recommended inject up to 5ml of the antidote through the existing IV line, then remove it. This infiltrates the area of extravasation. If no injectable antidote is recommended remove the IV line. Apply cooling packs intermittently for up to 24 hours, as tolerated N.B. cooling must NOT be used for extravasation of vincristine or vinblastine. If topical dimethyl sulfoxide (DMSO) is recommended apply as directed, DO NOT apply pressure Elevation of the affected limb for up to 24 hours may be helpful. Document and follow up the patient Consider plastic surgery consult if injury appears worsening rather than improving

4. TABLES OF LOCAL EFFECTS OF INDIVIDUAL CYTOTOXICS 1. Cytotoxic drugs which do not usually cause local problems on extravasation asparaginase (colaspase & erwinase) gemcitabine bleomycin ifosfamide* cisplatin* irinotecan cladribine methotrexate cyclophosphamide mitozantrone* cytarabine topotecan etoposide* *rare reports of local effects on extravasation
33

2. Cytotoxic drugs which may cause local IRRITATION after extravasation amsacrine melphalan carboplatin mitozantrone (IF concentrated) carmustine paclitaxel (see also Table 3) cisplatin (IF concentrated) streptozocin dacarbazine (DTIC)(IF concentrated)# teniposide docetaxel thiotepa etoposide (IF concentrated) fluorouracil #protect exposed tissues from light floxuridine* *one report 3. VESICANTS See Table 5 for specific antidotes if known dactinomycin mitomycin daunorubicin paclitaxel* doxorubicin vinblastine epirubicin vincristine idarubicin * mild vesicant in some cases ifosfamide (IF concentrated) 5. SPECIFIC ANTIDOTES FOR SPECIFIC CYTOTOXIC DRUGS (listed alphabetically) in addition to general measures item 3. Drug Dactinomycin Daunorubcin Doxorubicin Epirubicin Idarubicin Mitomycin Vinblastine Vincristine Vindesine Vinorelbine Management Sodium thiosulfate injection (isotonic) 1.6ml of 25% injection diluted with 3ml of WFI, injected through cannula and SC. Topical DMSO painted on to twice the estimated area of extravasation 4 times daily for 7 to 14 days. Allow to air dry do not occlude. Advise patient that garlic-like breath odour may occur. Possible side effects include scaling skin, and a hot feeling on application (not to be interpreted as worsening of injury) Rare cases of hypersensivity have occurred. Do not cool or heat. Inject hyaluronidase 250 units in 6ml of NS through cannula or if removed as 6 x SC injections around the site.

REFERENCES: Cox, K et al. The management of cytotoxic-drug extravasation: guide-lines drawn up by a working party for the Clinical Oncological Society of Australia. Med J Aust 1988; 148: 185-189 Olver, IN. The optimal management of cytotoxic-drug extravasation: solving the burning question. Med J Aust 1988; 149: 506-7 Olver, IN et al. A prospective study of topical dimethyl sulfoxide for treating anthracycline extravasation. J Clin Oncol 1988; 6: 1732-5 Dorr, RT. Antidotes to vesicant chemotherapy extravasations. Blood Reviews 1990; 4: 41-60 Bertelli, G et al. Hyaluronidase as an antidote to extravasation of vinca alkaloids: clinical results. J Cancer Res Clin Oncol 1994; 120: 505-6 McCaffrey Boyle, D et al. Vesicant extravasation: myths and realities. Oncol Nurs Forum 1995; 22: 57-67 Bertelli, G et al. Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: a prospective clinical study. J Clin Oncol 1995; 11: 2851-5 Bicher, A et al. Infusion site soft-tissue injury after paclitaxel administration. Cancer 1995; 76: 116-20 Bertelli, G. Prevention and management of extravasation of cytotoxic drugs. Drug Safety 1995; 12:245-55 Comas, D et al. Treatment of extravasation of both doxorubicin and vincristine administration in a y-site infusion. Ann Pharmacother 1996; 30: 244-6 Dorr, RT et al. Skin ulceration potential of paclitaxel in a mouse skin model in vivo. Cancer 1996; 78: 152-6

34

HICCUPS - TREATMENT
Drugs Reported to Possibly Cause Hiccup Antibiotics (cefotetan, imipenem/cilastatin, sulphonamides) Barbiturates (particularly short acting eg phenobarbitone) Benzodiazepines (diazepam, midazolam, chlordiazepoxide) Cytotoxics (cyclophosphamide, etoposide) General Anaesthesia Heroin Addiction Methyldopa Methylprednisolone Nicotine (including the gum & patches) Steroids (dexamethasone, megesterol acetate, methylprednisolone)

Treatment Regimens Examples of Folk Remedies Respiratory Manoeuvres Breath holding associated with: neck extension, quickly drinking water, steady inspiratory effort against closed airway, application of 20-40cm H2O CPAP Coughing, Valsalva manoeuvres, hyperventilation Rebreathing in a bag or breathing a 5% CO2 mixture Compression of the diaphragm by drawing legs up or leaning forward, compression of thyroid cartilage. Application of ice or mustard plaster on epigastrum Nasal and Pharyngeal Stimulation Pressure on bridge of nose, sneezing, pressure on upper lip. Inhalation or installation of irritants (smelling salts, ether, ammonia) Gargling with water. Firm traction of the tongue. Drinking: -from far side of a glass, -from a glass covered with a piece of fabric -quickly 1 can of lemonade then lie down -carbonated beverages, ice water, alcohol, tea vinegar, sweet pickle juice. Swallowing: -granulated sugar, -crushed ice or stale bread or pepper, -sugar lump dipped in vinegar, -lemon wedge and angostura bitter. Touch: -soft palate with tip of the tongue then swallow, -Posterior pharyngeal wall stimulation -Massage of hard/soft palate junction Miscellaneous Vagal stimulation Occular compression, carotid massage, digital rectal massage Psychiatric treatment Behaviour therapy, hypnosis

35

Gastric Distension Relief Fasting for 24 hours,gastric aspiration or lavage, vomiting Other Remedies Bilateral compression of radial arteries while gazing into the subjects eyes, rest in bed, fright, acupuncture, prayers, wrap patient in wet cold sheets, hydrotherapy, relaxation, concentration, bilateral pressure on external auditory meatus, homeopathy, mesotherapy, pinching the external side of the wrist Treatment with medication may finally be necessary and is often the only effective treatment of chronic hiccup. In the past, a large number of medications have been used in an attempt to treat chronic hiccup without overwhelming effectiveness. However, a review of recent case reports indicated that baclofen is becoming more recognised as an effective agent in the treatment of hiccup, and is often used when other agents have failed. HICCUPS TREATMENT PROTOCOL 1. If possible identify a cause (disease or drug) for the hiccups and treat the cause or cease the causative drug. 2. If the above is not possible or the hiccups continue, try a non drug treatment (see Folk Remedies) 3. If Folk Remedies do not work or the hiccups recur then drug treatment may be considered. First Line Drug Treatment Metoclopramide 10 mg IV or IM If effective continue oral metoclopramide 10-20mg QID If ineffective even with cautious dose escalation or causes unacceptable adverse effects, then use a second line agent. Second Line Drug Treatment Baclofen 5mg to 10mg TDS (low starting dose) Increase cautiously if required by a maximum of 5mg TDS every 5-7 days to minimise adverse effects. If ineffective Baclofen should be withdrawn slowly. Abrupt discontinuation may precipitate withdrawal symptoms, such as anxiety, seizure, tachycardia and hallucinations. Only if baclofen has failed should any of the other listed agents be tried as their use has been associated with adverse effects and none have shown great efficacy. Adapted from a review of hiccups treatments by Janet McNeece, RAH Pharmacy Drug Information Centre, April 2000.
References Walker P et al Baclofen, A treatment for Chronic Hiccup J Pain & Symptom Management 1998: 125-132 Friedman NL Hiccups a treatment review. Pharmacotherapy 1996; 16(61): 986-995 Rousseau Paul Hiccups South Med J 1995; 88 (2): 175-181 Thompson DF et al Drug Induced Hiccups Ann Pharmacother 1997, 31(3): 367-9 Pertel P et al Intractable Hiccups induced by the use of megestrol acetate [letter] Arch Int Med 1998; 158(7): 809-10 Einarson TR et al Hiccups following nicotine Gum Ann Pharmacother 1997; 31 (10): 1263-4 Drug Dex Drug monographs. Micromedex Data Base Jan 2000

36

HYPERCALCAEMIA - TREATMENT Suspect hypercalcaemia as a cause of nausea, anorexia, thirst with polydipsia and polyuria, abdominal cramps and constipation, clouding of consciousness. TREATMENT: (1) Saline diuresis Commence with 1 litre N Saline over 4 hours x 6 for 24 hours and reassess Only use frusemide if there is a problem with fluid overload. (2) Pamidronate: Pamidronate (aminohydroxypropylidene disphosphonate) is a bisphosphonate class drug. It selectively inhibits osteoclast activation without inhibiting mineralisation of bone. DOSAGE, DILUTION AND INFUSION RATE: Dose is selected according to the patient's total calcium level. This dose will achieve normocalcaemia in 90 to 100% of patients. Calcium (corrected for albumin) < 3.0 3.1 to 3.5 >3.6 Dose (mg) 30 30 to 60 90 Dilution & Infusion Rate * 250ml over 2-4 hrs 250 500 ml over 2-4 hrs 500mls over 4 hrs

*In renal impairment (CrCl < 30mls/min) maximum infusion rate is 20mg/hour TOXICITY: Very few side effects are seen with pamidronate mild asymptomatic transient pyrexia of 1-3 degrees temperature rise often occurs 24 to 48 hours after infusion transient leucopenia without consequence has been reported. thrombophlebitis at the site may occur if short catheters are used. hypocalcaemia 2 to 14 days after the dose (av. 7 days) may occur, lasting a day or more. rarely transient bone pain and malaise occur (Paget's disease patients) EFFECT: Decrease in plasma calcium commences on day one and increases each day (the slope of the decrease curve is constant). Time to normocalcaemia is between 3 to 7 days depending on initial level. Rehydration with 3 to 6L of normal saline is an important adjunct to pamidronate treatment as the renal components of hypercalcaemia including impaired GFR due to dehydration etc. must be treated separately (pamidronate is only effective against the bone reabsortive components of hypercalcaemia) (3) (4) (5) Calcitonin can be given 200 bd s/c Prednisolone has been useful for outpatients usually after or with other measures. Zoledronic Acid (Non-Formulary) 4mg over 15 minutes initial dose. For repeat dosing 8mg is required. Caution in renal impairment. Adverse effects similar to other bisphosphonates.

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HYPOMAGNESAEMIA MAGNESIUM REPLACEMENT Hypomagnesaemia is reported to occur in over 75% of patients receiving cisplatin, and is due to renal magnesium wasting. Parenteral magnesium replacement for cisplatin-induced hypomagnesaemia Serum Mg mmol/L 0.5 to 0.7 0.3 to 0.5 < 0.3 Dose (magnesium sulfate) 5g (approx.20 mmol) over 4 hours 5g over 4 hours plus 5g over 6 hours (=10g) 10g as above then 10g over 24 hours (=20g)

In addition, patients receiving cisplatin should routinely be discharged with magnesium aspartate tablets 1g oral TDS sufficient supply to last until next review
Reference: Stanley A. Management of symptoms associated with cancer treatment (1). The Pharmaceutical Journal 1992. 249 (6694):50-53.

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INFECTIONS PROPHYLAXIS & TREATMENT 1. RAH RESTRICTED ANTIBIOTIC PROGRAM RAH Drug Committee September 2000 Restricted agents which may be prescribed without ID/Micro approval or declaration form:
Timentin vancomycin Meropenem ganciclovir ciprofloxacin sodium fusidate 2. FEBRILE NEUTROPAENIA Infection in a neutropaenic patient is a medical emergency and must be treated immediately with broad spectrum antibiotics to avoid septic shock. Sepsis may be diagnosed if Temp > 38.5oC or if a neutropaenic patient begins to feel unwell, or develops rigors or hypothermia. Cultures of blood, urine plus sputum, skin lesions, throat or vagina if indicated should be taken. Perineal area can be a common source of infection. Chest x-ray should be taken. EMPIRICAL ANTIBIOTIC THERAPY FOR FEBRILE NEUTROPAENIA NO PENICILLIN ALLERGY PENICILLIN ALLERGY SHOCK OR SEPSIS cefepime fluconazole valaciclovir or famciclovir aciclovir IV rifampicin teicoplanin

Restricted agents requiring ID/Micro approval PRIOR to prescribing:

cefepime 2 g 12 hourly for 72 hours, then 1 g 12 hourly if clinically stable and culture negative PLUS Gentamicin (see Gentamicin Dosing and Monitoring Guidelines)

ADD vancomycin to empiric regimen (see Vancomycin Dosing and Monitoring Guidelines)

Timentin 3.1g 6 hourly PLUS Gentamicin (see Gentamicin Dosing and Monitoring Guidelines)

In the presence of renal impairment CHANGE to meropenem 500 mg 8-12 hourly depending on creatinine clearance

(Do not use cefepime if previous severe reaction to a beta-lactam. Obtain Infectious Diseases advice regarding an alternative agent antibiotic.)

Review therapy if positive culture or no improvement after 48 hours (see Infectious Diseases protocols)

Meropenem used when renal dysfunction precludes gentamicin use. Dose 500 mg 8 hourly In renal impairment: Creatinine clearance Meropenem Dose 26-50 ml/min 500mg 12/24 10-25 ml/min 250mg 12/24 <10 ml/min 250mg 24 hrly 39

3. GENTAMICIN DOSING & MONITORING gentamicin is potentially nephrotoxic, ototoxic and vestibulotoxic toxicity is largely predictable and, in the case of nephrotoxicity, reversible toxicities are cumulative and even when appropriate doses are used, toxicity will inevitably occur after 10 to 15 days of continuous treatment gentamicin is cleared almost entirely unchanged by renal filtration failure to modify dose in renal dysfunction results in more rapid accumulation and a more rapid onset of clinical toxicity single daily dose is as effective and less nephrotoxic than in divided doses a) CALCULATE CREATININE CLEARANCE CL CR = (140 age) x wt (lean BW if obese) X 0.85 if female 815 x se creatinine Lean Body Weight Male: 50kg + 0.9kg for each cm > 150cm height; Female: 45kg + 0.9kg for each cm > 150cm height b) CALCULATE FIRST DOSE - THERE ARE 3 OPTIONS CrCl > 60ml/min 7 mg / kg (lean BW if obese) over 15 mins CrCl 20 to 60 ml/min 5 mg / kg (lean BW if obese) over 15 mins CrCl < 20 ml/min Do not use gentamicin (consult ID)

ROUND all doses to nearest 40 mg max. dose 640 mg. Write dose as variable and when dose determined write on administration chart

c) MONITOR LEVELS FOR FIRST DOSE THEN ONCE MORE (or more often if renal function unstable, or the patient will be on gentamicin for > 5days) FIRST LEVEL PEAK Take blood at 30 mins to 2 hours after infusion finished SECOND LEVEL Take blood at 6 to 10 hours after dose (This is NOT a trough level)

IF THE SAMPLING TIME IS NOT RECORDED IT AND CANNOT BE USED

d) DOSE CALCULATION VIA COMPUTER PROGRAMME Weekdays 9am to 5pm Weekends 9am to 4.30pm Page Clinical Pharmacist 1507 or Antibiotics Ring Level 2 dispensary Ext.25418 Pharmacist 1609 WHAT INFORMATION SHOULD YOU HAVE READY? SUBSEQUENT LEVELS
Ring before the next dose is due (if you have several do them all at once) Avoid doing levels on Fridays/Saturdays unless essential. If required on weekends, a dispensary pharmacist will put the results through if you provide all the information (Ext 25418). If you order levels Friday or Saturday don t forget to tell the w/end MO for the next day to check the results & have them put through the program for dose calculation

FIRST LEVEL

Patient name UR number Weight Height Creatinine Age Gender Date given Dose given Time started Time levels taken and results

WHAT ARE WE AIMING FOR? Cmax of 15 ( 8-10 x MIC) or >20 for pseudomonas; AUC 70 to 100; Cmin <0.5

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4. HELICOBACTER PYLORI First-Line Treatment: (commercially available as Losec HP7) Omeprazole 20 mg bd Amoxycillin 1 g bd Clarithromycin 500 mg bd All for 7 days For patients with penicillin allergy: Omeprazole 20 mg bd Clarithromycin 250 mg bd Metronidazole 400 mg bd

All for 7 days

References: Misiewicz JJ, Harris AW, Bardhan KD et al. One week triple therapy for Helicobacter pylori: a multicentre comparative study. Gut 1997;41:735-9. Lind T, Veldhuyzen Van Zanten S, Unge P et al. Eradication of Helicobacter pylori using one-week triple therapies combing omeprazole with two antimicrobials: The MACH 1 Study. Helicobacter 1996;1:138-44. 5. T.B. PROPHYLAXIS In patients with a history of TB Isoniazid 300 mg oral daily Pyridoxine 25mg oral daily (to prevent neuropathy) Consider the possibility of isoniazid resistance (e.g. younger patient, migrant) and in those cases seek the advice of the Infectious Diseases Unit. 6. VANCOMYCIN DOSING AND MONITORING GUIDELINES Dosage and Administration usual dose: 1g IV 12 hourly ideal daily dose (mg/day) = 15-20 x creatinine clearance (CrCl) mL/min adjust total daily dose to the closest increment of 500mg dosage based on renal function CrCl > 75 mL/min: 1g every 12 hours CrCl 50-75 mL/min: 500-750mg every 12 hours CrCl 10-50 mL/min: 500mg-1g every 24-48 hours CrCl < 10 mL/min: 500mg-1g every 4-10 days infuse dose over 1-2 hours (10mg/minute) higher doses may be necessary for endocarditis, meningitis, obesity and burns (consult Infectious Diseases or Clinical Microbiology) Therapeutic Drug Monitoring Vancomycin levels should be monitored if: concurrent treatment with nephrotoxic drugs (e.g. gentamicin, cyclosporin)
41

unstable renal function endocarditis or meningitis duration of therapy longer than 7 days

Vancomycin levels are not indicated if: short term therapy (e.g. < 7 days) in patients with normal renal function When levels are required: take the first level before the 5th dose (usually on day 3) take a trough level within 1 hour before the next dose repeat level once weekly thereafter (if renal function is stable) normal trough level = 5-15 mg/L In renal impairment: take daily levels initially to determine dosing interval give next dose when level falls within the normal range (5-15 mg/L) once dosing interval is established, daily monitoring is no longer required (if renal function is stable) for advice contact Pharmacy, Infectious Diseases or Clinical Microbiology Additional information vancomycin is a glycopeptide antibiotic, not an aminoglycoside (e.g. gentamicin) vancomycin exhibits time-dependent bactericidal action monitor serum creatinine during treatment nephrotoxicity is rare without concomitant aminoglycoside use routine monitoring of vancomycin levels for all infections is unnecessary 7. VIRAL INFECTIONS in Immunosuppressed Patients See RAH formulary for details: Primary Herpes Simplex Or Episodic Recurrent Herpes Simplex Famciclovir 500mg every 8 hours for 7 days or in severe cases Acyclovir 5 mg/kg IV every 8 hours for 7 days Chicken Pox Primary Or Initial Infection Acyclovir 10mg/kg IV every 8 hours for 10 days or in less severe cases as an alternative to IV treatment Famciclovir 500mg oral every 8 hours for 10 days Herpes Zoster - to prevent dissemination Famciclovir 500mg oral every 8 hours for 10 days or Acyclovir 10mg/kg IV every 8 hours for 10 days Renal impairment may necessitate dosage reduction (see RAH formulary).

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MOUTH CARE GUIDELINES 1. CHEMO-RADIOTHERAPY MUCOSITIS PROTOCOL All patients receiving potentially stomatotoxic drugs or head and neck radiotherapy, must be commenced on a prophylactic mouth care protocol. Should mucositis occur, the mouth care protocol for the appropriate signs/symptoms should be added. Drugs likely to cause stomatoxicity include: etoposide fluorouracil (infusion) doxorubicin methotrexate bleomycin epirubicin lomustine

PROPHYLAXIS
1.Good toothbrushing technique 2. Warm water/saline rinse after meals and at night
(Amosan sachet in a glass of warm water may be used as an alternative)

IF MUCOSITIS OCCURS
Continue cleansing as for prophylaxis, and add the following as required

FOR PAIN, ULCERS

Benzydamine mouthwash 10ml swished for 3 minutes BEFORE meals (may be diluted with warm water if stinging occurs) AND/OR systemic analgesia 60 minutes before meals if necessary.

FOR CANDIDA
Nystatin drops 1ml swished in mouth QID after meals (miconazole oral gel spoon QID is an alternative)

ORDER OF ADMINISTRATION
1. 2. 3. 4. PAIN:- analgesic mouthwash first (before meals and if severe pain before other mouth care). CLEANSING:- after meals and at night (wait 10 minutes before using other mouthcare) ANTIFUNGAL TREATMENT MOISTURISER to lips (e.g. lanolin)

2. DRY MOUTH
For dry mouth secondary to radiotherapy Pilocarpine Solution 1mg/ml, 5mg tds to start. Add 5mg at bedtime after 7 days Results may take 90 days or longer Adverse Effects - flushing and sweating which may be dose limiting. Contraindication - uncontrolled asthma or when miosis is undesirable.
43

CHRONIC PAIN IN CANCER MANAGEMENT GUIDELINES

Prepared by Pharmacy, Palliative Care and Chronic Pain Services, Royal Adelaide Hospital
1. GENERAL PRINCIPLES 1.1 General Principles of Pain Management Provide support and reassurance including an explanation of the cause of the pain - increasing pain does not always indicate disease progression - pain does not always escalate as the disease worsens. Set realistic goals. Neuropathic pain, incident pain and longstanding pain will be harder to abolish. Modify pathology where possible, eg with radiotherapy, surgery, chemotherapy, hormonal management. 1.2 General Principles of Pharmacological Management of Pain For persistent pain, prescribe regular analgesics to keep pain away. p.r.n. therapy should only be prescribed for intermittent or episodic pain, incident pain or breakthrough pain. Assessment of the type and severity of pain will guide the choice of analgesic. Regular simple analgesic eg paracetamol can be of value and in may decrease opioid requirements. There is no maximum dose when prescribing opioids for pain relief. The opioid dose should be titrated to achieve pain control and a breakthrough or rescue dose of analgesia prescribed as well. Consider each new medication as a trial of therapy: - monitor response carefully frequent reassessment will be essential - titrate to maximum dose - cease if no response. Co-analgesics should be considered particularly in neuropathic pain. Oral medication is preferred. The s/c route can be used if patients are unable to swallow regular medications. If a patient is in severe pain, rapid analgesia may be achieved using intravenous opioids by bolus titration. This should be conducted in a suitable area by staff with appropriate training. Consult Acute or Chronic Pain Services. When pain cannot be controlled with oral or s/c medications, epidural or intrathecal routes should be considered. Consult Palliative Care or Chronic Pain Services for advice. 2. ANALGESIC LADDER OF CANCER PAIN RELIEF

Step 4 Step 2 & 3 Step 1

Spinal opioids Neurolytic procedures

Opioid non-opioid or NSAID co-analgesic

Non-opioid e.g. paracetamol or aspirin or NSAID co-analgesic

3. PAIN MECHANISM AND CHOICE OF ANALGESIC SOMATIC NOCICEPTIVE Aching, gnawing Well localised Aggravated by movement VISCERAL NOCICEPTIVE Constant or colicky Aching, dull, deep NEUROPATHIC Burning Pins and needles Pain in a numb area Shooting pain Nerve or dermatome Distribution Allodynia

Bone metastases Liver capsule pain Chest wall Ovarian cancer Bowel cancer Pancreatic cancer Mixed nociceptive & neuropathic: Brachial and lumbosacral plexopathies

Anti-inflammatories Opioids Co-analgesic Opioids Anti-spasmodics Co-analgesic Mixed: Opioid Steroid/anti-inflammatory Tricyclic antidepressant Anticonvulsant Local anaesthetic Pure: Anticonvulsant Antidepressant Opioid

Pure neuropathic: Post-herpetic neuralgia

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4. DRUG THERAPY 4.1 Mild to Moderate Pain (Step 1 Analgesic Ladder) DRUG DOSE Paracetamol 500mg 2 tablets 4 hourly IF PAIN NOT CONTROLLED USE Paracetamol 500mg/Codeine Phosphate 8mg 2 tablets 4 hourly (Panadeine, Codalgin or Dymadon Co) OR Paracetamol 500mg/Codeine Phosphate 30mg 1 - 2 tablets 4 hourly (Panadeine Forte) OR Paracetamol 1000mg/Codeine Phosphate 60mg/10ml 5 - 10ml 4 hourly (Panadeine Forte Syrup) Prepared by RAH Pharmacy Although these drugs are mentioned here, for persistent ongoing pain codeine is not the opioid of choice, and fixed combinations of drugs are not recommended. 4.2 Moderate to Severe Pain (Steps 2 and 3 of Analgesic Ladder) Simple analgesic Paracetamol 500mg OR Anti-inflammatory (if appropriate) Particularly useful in bone pain, by inhibition of prostaglandin synthetase, Salicylates use aspirin with caution in potentially thrombocytopaenic patients. NSAIDS according to usual prescribing guidelines. COX II inhibitors - if compliant with RAH Drug Committee restrictions. PLUS 2 tablets 4 hourly

Opioid

Morphine is the usual first choice opioid. There is no maximum dose for pain relief. The correct dose is that which relieves pain without producing intolerable side effects. Morphine dose should be titrated carefully until pain is relieved using a short acting (immediate release) formulation. Slow release morphine formulations should not be commenced until dose requirements are known. 4.2.1 Oral Morphine DOSAGE FORM DOSE SCHEDULE Morphine oral solution Available in strengths of 1mg/ml, 2mg/ml, strictly 4 hourly 5mg/ml, 10mg/ml Tip: Patients should be taught to think of their dose in mg of morphine, not mls of solution Morphine sulfate tablets controlled release MS Contin 5mg, 10mg, 15mg, 30mg, 60mg, 100mg strictly 12 hourly (sometimes needed 8 hourly) Tip: tablets must not be crushed or chewed. Morphine sulfate capsules (two brands, different strengths available) sustained release Kapanol strictly 12 hourly or 10mg, 20mg, 50mg, 1000mg strictly once every 24 hours Tip: capsules may be opened and the pellets sprinkled on soft food pellets must not be crushed or chewed. sustained release MS MONO 10mg, 30mg, 60mg, 90mg strictly 12 hourly or strictly once every 24 hours

Morphine sulfate suspension sustained release sachets MS Contin strictly 12 hourly 30mg, 60mg, 100mg (sometimes needed 8 hourly) Tip: The granules in 1 sachet should be reconstituted with 10ml water, mixed thoroughly and taken immediately. Suitable for use through wider bore feeding tubes.

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Dose Starting dose of morphine depends on: previous opioid use eg Panadeine Forte, oxycodone age intensity of pain. eg. opioid naive patient with mild to moderate pain, usual starting range morphine is 2.5 to 10mg orally 4 hourly, with breakthrough dose of 2.5 to 5mg as needed. If pain is not controlled after 2 to 3 oral doses, increase dose for a further 2 to 3 doses and titrate until pain is controlled for 4 hour period. Starting Slow Release Formulations establish the total dose of oral morphine needed in a 24 hour period to control pain and divide into two for the 12 hourly dose give the last dose of mixture with the first dose of slow release morphine prescribe oral morphine solution for breakthrough pain usually 1/6 1/10 total daily dose every two hours if needed.

Tip: Remember as total daily dose increases breakthrough dose will need to be increased. eg For MS Contin 30mg bd, breakthrough dose 10-15mg morphine solution 2 hourly prn For MS Contin 200mg bd, breakthrough dose 50-70mg morphine solution 2 hourly prn 4.2.2 Subcutaneous morphine The subcutaneous route is used: for rapid pain relief in severe pain* if oral route unavailable eg vomiting if side effects are troublesome eg constipation, nausea, confusion S/C route enables dose reduction. * In severe acute pain the intravenous route and Acute Pain Protocol can be used to allow more rapid titration of opioid. Use of this protocol is restricted to approved units. Method A butterfly needle is inserted eg into infraclavicular region and morphine administered either: intermittently bolus doses 4 hourly with breakthrough doses as required, OR by continuous infusion eg Graseby syringe driver pump the improved bioavailability compared to the oral route means the equivalent S/C dose is 1/3 oral dose to commence S/C infusion, calculate previous total daily opioid use as morphine oral equivalents and divide by 3 remember to order S/C breakthrough dose, usually 1/6 - 1/10 of the total daily dose ther drugs - compatibility Other drugs compatible with morphine in syringe: (Usual maximum of three drugs combined) anti-emetics - metoclopramide 40mg/24 hours (or less) to start - haloperidol 2.5 mg/24 hours to start (larger doses may precipitate anxiolytic -midazolam 5-7.5/mg25hours to start (at 10-15mg/24 hours sedation seen) anticholinergic - hyoscine hydrobromide antispasmodic - hyoscine butylbromide60 to 80 mg/24 hours to start Intraspinal morphine 4.2.3 Other Routes Epidural or intrathecal routes allow further reduction in morphine dose and possible combination with local anaesthetic agents. Contact Chronic Pain Service for advice.

Morphine intolerance If side effects from morphine prevent dose escalation to achieve pain control, consider: dose reduction by using an alternative route of delivery eg. oral S/C, S/C intrathecal. adding suitable co-analgesics to reduce morphine requirements changing to alternative opioid

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4.2.4 Alternative Opioids 4.2.4.1 Fentanyl indicated for use in patients with morphine intolerance, renal failure, or intermittent or sub-acute bowel obstruction single doses are very short acting but fentanyl can be delivered by continuous S/C infusion or continuous transdermal patch transdermal fentanyl patches (Durogesic) are available as 25 mcg/hr, 50 mcg/hr, 75 mcg/hr and 100 mcg/hr (see RAH Drug Committee Guideline for conversion dose). The duration of the patch is 72 hours the lowest strength patch, 25mcg/hr, is equivalent to a daily dose of 60-90mg oral morphine when commencing transdermal fentanyl, remember slow onset (24 to 72 hours to peak analgesia, so additional analgesia may be required at first) and offset 12-24 hours transdermal fentanyl should not be commenced in the opioid nave patient.

4.2.4.2 Oxycodone Oxycodone immediate release oral tablets (Endone 5mg) or capsules (Oxynorm 5mg, 10mg, 20mg) every 4 to 6 hours Oxycodone 30 mg rectal suppositories (Proladone ) usually for night time use Oxycodone 10mg, 20mg, 40mg, or 80mg slow release tablets (Oxycontin) every 12 hours.

4.2.4.3 Methadone Methadone has variable equianalgesic dose compared with other opioids which is due to its complex pharmacokinetic and pharmacodynamic properties. There is potential for severe toxicity due to accumulation, and it is suggested to seek advice from Chronic Pain or Palliative Care units before use. Factors include: prior opioid use long and highly variable half life - need to titrate cautiously, preferably as an in-patient wide interpatient variability in bioavailability and duration of analgesia prolonged time to steady state after dose change (4 to 5 days) age (use particular caution in the elderly)

Methadone blocks NMDA receptors. 4.2.4.4 Hydromorphone recently re-marketed in Australia higher lipid solubility than morphine better oral bioavailability and 5 - 7 times more potent than morphine may replace pethidine refer to RAH Drug Committee Guidelines for use

5. EQUIANALGESIC DOSES TABLE Drug Morphine Methadone Equianalgesic Doses IM (S/C) 10 variations seen in equianalgesic dose 100 0.15 ORAL 30 variations seen in equianalgesic dose 300 400 30 2 130 46 200 Duration Of Effect (hours) 3-4 4 - 48 + Other Comments Extensive first pass effect Initial doses need careful titration. Accumulation occurs Not recommended for use in chronic cancer pain Less constipation than morphine Suppository has longer duration (8-10 hours)

Pethidine Fentanyl Oxycodone Hydromorphone Codeine

2-3 0.5 - 1 4-6 3-4 4-6

Very constipating

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6. CO-ANALGESICS (ALSO KNOWN AS ANALGESIC ADJUVANTS) Use of co-analgesics will generally allow pain control at lower opioid doses. They should be considered from the start of pain treatment. 6.1 Tricyclic antidepressants Useful for continuous or lancinating neuropathic pain. Response is usually seen in the first few days, at doses lower than antidepressant action. A trial of 2 weeks should be considered before discontinuing. amitriptyline or 25 75mg oral at night doxepin or dothiepin 6.2 Anticonvulsants Particularly useful in lancinating or episodic pain, but can be tried in any neuropathic pain clonazepam sodium valproate carbamazepine 6.3 Local anaesthetics 0.25 0.5mg TDS oral or S/C 200mg BD to TDS oral with meals 100 - 200mg BD oral

For burning dysaesthesia, or lancinating pain lignocaine S/C 500 - 1000mg/24 hours mexiletine 50 - 200mg TDS oral 6.4 Corticosteroids Used for pain related to nerve compression, capsular stretching and soft tissue infiltration. dexamethasone 4mg 15mg daily oral, S/C, I/V prednisolone 25mg daily oral 6.5 Ketamine (refer to Pain or Palliative Care Services) Probable role in neuropathic or chronic cancer pain NMDA receptor antagonist used in subanaesthetic doses eg 25 - 200mg per 24 hours appears to be compatible with morphine in a syringe driver for S/C use 6.6 Clonidine For anxiolytic and opioid sparing action. Clonidine may also prevent withdrawal effects during opioid changeover. adrenergic agonist dose range 150 - 300mcg daily continuous S/C infusion or 2 divided doses oral compatible with morphine in syringe driver 7. MANAGEMENT OF SIDE EFFECTS OF OPIOIDS Opioids induce constipation in 95% of patients due to decreased intestinal secretions and reduced peristalsis. Regular prophylactic stool softener/peristaltic stimulant should be used e.g. Coloxyl with Senna. If possible the patient should be well hydrated and active. Refer to RAH Guidelines For Prevention And Treatment Of Opioid-Induced Constipation. Opioids induce nausea and vomiting in about 30% of patients. Regular antiemetics may be needed at commencement of therapy. This side effect usually wears off in a few days. Drowsiness is predictable when commencing morphine. It usually passes within a few days and should not prevent regular administration or dose increment if necessary. Dependence and respiratory depression are not a problem when the dose of opioid is titrated against the patients pain. Tolerance is rarely a significant clinical problem. Dose escalation may be required if pain increases. Pruritus occurs occasionally with systemic opioids. The mechanism is poorly understood and currently recommended treatments are usually ineffective. Opioid rotation should be considered. 8. PATIENT EDUCATION Many patients are reluctant to take regular analgesia, particularly morphine. This often involves a number of fears, including fear that there will be nothing left for the end fear of addiction to morphine fear that if they use morphine it must mean the end is near. Education, counselling and reinforcement by the health care team is important to allay concerns of the patient and family. Revised 2001 48

PLEURODESIS DETAILS OF PROCEDURE: (a) Complete drainage of pleural space by a (24Fr Argyle catheter) inserted in the 6th-7th intercostal space in the posterior axillary line and connected to an underwater seal drain. When drainage is completed (shown by chest X-ray), the following substances in order are instilled into the pleural space using a 23 gauge needle injected tangentially through the drainage tubing:(i) (ii) 5 ml of 1% Lignocaine Steritalc-F, 100ml dispersion or Bleomycin 60 units 200 ml of air.

(b)

(iii)

(c)

The tube is clamped for 2 hours (in the absence of a bronchopleural fistula). During this time the patient is instructed to rotate through prone, supine, right and left lateral positions at 30 minute intervals. At the end of 2 hours the tube is unclamped for approximately 48 hours until drainage is less than 150mls/24 hours for 2 consecutive days. Careful nursing observation is implemented according to procedure in S2 using intercostal drain nursing chart. If, after 48 hours, there has been no evidence of an irritative response (temperature, tachycardia for 12-24 hours) or the drainage is still greater than 150 mls/24 hours, a repeat instillation of talc is given as above. The tube is removed and the procedure is complete provided the repeat chest x-ray examination indicates that the lung is appropriately expanded. Follow up chest x-ray at 2-3 weeks.

(d)

(e)

(f)

(g)

(h)

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POST-MENOPAUSAL SYMPTOM MANAGEMENT Oestrogen used alone (oestrogen replacement therapy) or with the addition of progesterone (Hormone replacement therapy HRT) is known to be effective in reducing menopausal symptoms including hot flushes, vaginal dryness and urinary symptoms. Oestrogen is also beneficial in preventing osteoporosis and less certainly cardiovascular disease. Concerning use in women with a prior diagnosis of breast cancer, there are basic scientific data but little methodologically strong observational data, and none from randomised studies. Alternatives for menopausal symptoms include: KY Jelly (or similar) for vaginal dryness and local menopausal symptoms venlafaxine for hot flushes - starting dose 37.5mg daily gradually increasing to 75mg daily if not effective (higher doses produce more side effects) (currently non-PBS and non-Formulary for this indication) Alternatives the prevention of osteoporosis include: calcium supplements, bisphosphonates, diet and exercise, Alternatives for cardiovascular disease include: diet, exercise and statins.
References: Pritchard KI. Hormone replacement in women with a history of breast cancer. Oncologist. 2001;6(4):353-62. Barton D, La VB, Loprinzi C, Novotny P, Wilwerding MB, Sloan J. Venlafaxine for the control of hot flashes: results of a longitudinal continuation study. Oncol Nurs Forum. 2002 Jan-Feb;29(1):33-40. Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL, Novotny PJ, Dakhil SR, Rodger K, Rummans TA, Christensen BJ. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet. 2000 Dec 16;356(9247):2059-63.

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PRURITUS For itch associated with skin irritation or allergy a trial of sedating antihistamines is recommended. e.g. Promethazine 10 to 25mg every 6 hours Or Hydroxyzine 25 to 50mg every 6 to 8 hours For itch associated with cholestasis (1) Cholestyramine 1 sachet (4g) qid. If this is unsuccessful (2) Rifampicin 150 to 300 mg bd.

Reference: Price TJ, Patterson WK, Olver IN. Rifampicin as treatment for pruritis in malignant cholestasis. Support Care Cancer, 1998, 6: 533-535. Connolly C S; Kantor G R; Menduke H Hepatobiliary Pruritus: What Are Effective Treatments?J Am Acad Dermatol, vol 33, iss 5I, p 801805, yr 1995

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SPERM COLLECTION & STORAGE

REPRODUCTIVE MEDICINE UNIT The University of Adelaide, The Queen Elizabeth Hospital INFORMATION STATEMENT ON THE CRYOPRESERVATION AND STORAGE OF SPERM Prepared in accordance with the Code of Ethical Clinical Practice (Reproductive Technology Act, 1988) Sperm can be cryopreserved (frozen) and stored in liquid nitrogen at - 196oC for may years. The effectiveness of sperm cryopreservation is quite variable, however, and there is no guarantee that the sperm will survive thawing. There is also no guarantee that the thawed sperm will be fertile or that they will give rise to a conception if they are used in conjunction with reproductive technologies such as artificial insemination, in vitro fertilization and sperm microinjection. Before we cryopreserve your sperm, we may ask you to undergo a blood test to check for infectious diseases such as HIV (the AIDS virus), syphilis and hepatitis. This is merely a precaution against cross-infection from one sample to another during storage. If these tests have recently been done, then we wont repeat them and we will obtain the results from your doctor. If you are infected with hepatitis, we will store your frozen sperm in a separate container which also contains sperm from other men who are infected with hepatitis. We do not routinely store sperm from men who carry infectious diseases such as HIV. Semen Collection: The procedure for semen collection will be explained to you by one of the laboratory staff. A separate information statement is also available. It is important that you do not ejaculate for at least 2 days (ideal period is 3-7 days) prior to the collection of each semen sample so that the best sample is stored each time. It is usually advisable to store more than one sample so that enough semen is available for future use. However, this also depends on your semen quality and the reason for storage - the laboratory staff will advise you on the number of samples. If you are concerned about the cost of storing more than one sample, bear in mind that the recommended number of samples will enable us to consider the most suitable treatment option(s) if you need to use the frozen semen. Please make an appointment for each sample. Phone the Andrology Laboratory on (08) 8222 6827. Sperm Cryopreservation and Storage: After collection, the semen will be analysed, mixed with a solution to reduce the freezing damage and then frozen in colourcoded, labelled plastic straws and stored at -196oC in a tank containing liquid nitrogen. The semen analysis and cyropreservation results will be sent to your doctor. While all reasonable care will be taken during the handling, cyropreservation and storage of sperm, there is a slight risk of damage to or loss of viability of the sperm. If the semen is frozen at a site other than The Queen Elizabeth Hospital, it may be necessary to transfer it to the Reproductive Medicine Unit at The Queen Elizabeth Hospital for long term storage. And in the future, it may be necessary to transfer it between the Reproductive Medicine sites and/or other sites. There is a slight risk of damage to or loss of the frozen sperm during such transfers. LEGAL REQUIREMENTS: The Reproductive Technology Act (1988) sets guidelines on sperm storage. A copy of the Act, the regulations under the Act, and the standards and codes of practice adopted by or referred to in the regulations are available for inspection during normal working hours at the Reproductive Medicine Units. There is no charge for inspection. The Act requires that a consent form is signed prior to sperm cyropreservation, and that anyone who give consent for sperm cyropreservation and storage under the Code of Ethical Clinical Practice is entitled to a copy of the signed consent form. Consent may be revoked at any time by notice in writing to the Head of the Reproductive Medicine Unit. If consent is revoked, the Reproductive Medicine Unit will dispose of the frozen sperm.

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The Head of the Reproductive Medicine Unit may require personal information to be provided in order to comply with the Act or the Code of Ethical Clinical Practice and must ensure that confidential information kept by the Reproductive Medicine Unit is disclosed only as authorised by the Act or the Code of Ethical Clinical Practice. If the Head of the Reproductive Medicine suspects that confidential information has been disclosed in breach of the Act or the Code of Ethical Clinical Practice, he/she must investigate and submit a written report to the South Australian Health Commission (and to the Commissioner of Police if there is suspicion that an offence has been committed). A person in relation to whom the Head of the Reproduction Medicine Unit keeps a record may consent to the disclosure of any information in that record relating to his or her personal affairs. Cost of Sperm Cryopreservation and Storage A standard semen analysis fee is charged for analysing EACH semen sample - this is covered by Medicare and will either be bulk-billed directly to Medicare or you will be sent an account. There is an additional $50.00 fee PER SAMPLE for cyropreservation and storage for up to 12 months. At the end of 12 months, and again every 12 months thereafter, a storage of $100.00 will be charged to cover continued storage of the sample(s) for up to 12 months. The cyropreservation and annual storage fees are not covered by Medicare or private health insurance. Accounts will be issued by the Reproductive Medicine Unit (Repromed Pty Ltd). Public patients who are about to undergo chemotherapy or radiotherapy, and patients with a health care card (HCC), are eligible for 50% concessional rates on the cyropreservation and storage fees. If you have difficulty paying the fees, please phone the Reproductive Medicine Unit Accounts Department on 08 8222 6782. We are happy to accept part payments until the full account is settled. The Future It is your responsibility to inform the Reproductive Medicine Unit of any changes of address. Otherwise we wont be able to contact you each year to obtain instructions regarding your frozen sperm. If the fees are not paid or you cannot be contacted, the Reproductive Medicine Unit is under continue storage and the frozen sperm may be discarded. no obligation to

You are welcome to discuss sperm cyropreservation or your future fertility with the medical staff and/or counsellor of the Reproductive Medicine Unit. Ask the laboratory staff for assistance. If you are having chemotherapy, radiotherapy or surgery which might impair your fertility, it is advisable to have a follow-up semen analysis to determine the long term effect of the treatment on your sperm production. This should be done about 2 years after the finish of chemotherapy or radiotherapy. Additional Information Telephone the Andrology Laboratory at the Queen Elizabeth Hospital on (08) 8222 6827 Account enquiries should be directed to the Repromed Accounts Department on (08) 8222 6782

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SYMPTOM CONTROL - TERMINAL CARE TERMINAL RESTLESSNESS Midazolam Diazepam 2.5-10 mg subcutaneous 2-4 hourly or 10-30 mg per 24 hours subcutaneous infusion 5-10 mg oral or rectal

TERMINAL RESPIRATORY CONGESTION (or Death Rattle) Hyoscine 0.4-0.8 mg subcutaneous 2-4 hourly prn Atropine 0.3-0.6 mg subcutaneous 2-4 hourly prn DEHYDRATION (symptomatic) Hypodermoclysis i.e. subcutaneous fluids Use normal saline 500 ml - 2L per 24 hours COUGH/BREATHLESSNESS Morphine mixture 2.5-5 mg 4-6 hourly Pholcodine Linctus If above fails try methadone 2.5 mg at night - up to 2.5mg b.d. nebulized morphine 5-20 mg in 5 mls normal saline nebulized lignocaine 1-2% 5 mls Recent data suggest nebulized normal saline 5 mls is as effective as nebulized morphine for many patients. ANOREXIA: Loss of appetite frequently causes anxiety and tension between patient and family. Acknowledgment of the problem and reassurance may help. Steroids may stimulate appetite in the short term e.g. Prednisolone 15-25mg orally Dexamethasone 1-4 mg orally daily Look for and treat correctable causes e.g. Oral Candidiasis Topical Nystatin suspension 1-4mls 4-6 hourly Miconazole oral gel spoonful 4-6 hourly Systemic Fluconazole 50 mg daily (available only on advice from Infectious Diseases Unit) If patient has dentures these should be soaked in 0.5% chlorhexidine overnight, then apply nystatin ointment 100,000 U/ml (ad lib) to mucosal surface before reinsertion. Anorexia may indicate underlying nausea and anti-emetic, eg. Metoclopramide, may be helpful. INTESTINAL OBSTRUCTION: Nasogastric tubes are avoided where possible. Try nil orally, ice chips. Avoid the oral route for analgesics and other medications Hypodermoclysis should be considered for thirst e.g. N Saline 1 Litre SC over 8-12 hours. Symptoms caused by the intestinal obstruction are identified and treated eg.
54

pain - S/C morphine colic - S/C Hyoscine butylbromide (Buscopan) 20-80 mg/24 hours nausea -S/C Haloperidol 5-10 mg/24 hours These three drugs can all be combined in a S/C infusion. Metoclopramide and other pro-kinetic drugs are not usually recommended once the bowel is obstructed. Other anti-emetics that can be useful:Hyoscine hydrobromide 400-800mcg/24 hours S/C Prochlorperazine suppositories 25mg/6-8 hourly PR Chlorpromazine suppositories 100mg mg/6-8 hourly PR A short course of Dexamethasone - dose range 8-6mg/24 hours S/C which acts possibly by reducing bowel wall or tumour oedema, is worth considering, For intractable vomiting percutaneous endoscopic gastrostomy (PEG) as a venting procedure is very useful

Reference: Ashby MA., Game PA, Devitt P, Britten-Jones R, Brooksbank MA, Davy MLJ, Keam E. Percutaneous gastrostomy as a venting procedure in palliative care. Palliative Medicine 1991, 5: 147-150).

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TUMOUR LYSIS SYNDROME 1. Characteristic biochemical disturbances

K+
Uric acid PO 4 ++ Ca

Lactic acidosis

2. The likelihood of developing acute tumour lysis can be predicted by: Bulky disease Marked sensitivityu of tumour ro Rx modality Pre-existing renal impairment Raised LDH (pretreatment >1500) Raised uric acid Mild Allopurinol Moderate Allopurinol + Hydration PO4
Fluids+Diuretic Stop Alkalinization Dialysis

Severe Allopurinol + Hyperhydration K +

Monitor ECG Fluids + Diuretic Resonium/ Insulin glucose Ca Gluconate Alkalinization Dialysis

3. Corrective Action Uric acid

Alkalinization Dialysis

Fluid overload
Diuretic Dialysis

Allopurinol 300mg/day. May give loading dose of 600 mg daily for 2-3 days in high risk patients with normal renal function. Need dose reduction in renal impairment in relation to creatinine clearance. Hyper-hydration 3 litres /m2/day with NS or1/5 NS continued till the period of risk is over , as judged by stable biochemical indices and decrease in assessable disease. Aim to keep urine output > 100ml/hour Hydration 1.5 litres/m2/day orally or intravenously Alkalinization 50-100 Meq NaHCO3 /litre of hydration fluid, aiming for urine PH 7.0-8.0 (note: uric acid is 13x more soluble at PH 7 than PH 5 ); Yet alkalization can exacerbate nephrocalcinosis associated with hyperphosphataemia. Insulin - Glucose 10 units of Actrapid in 50 ml D50 over 30 minutes. Avoid if haemodialysis can be arranged within hour. Haemodialysis: For progressive renal failure or rapidly deteriorating metabolic disturbances
Reference: RC Chasty, JA Liu-yin. Acute tumour lysis syndrome Br J Hosp Med 1993;49:88-492

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SECTION TWO CHEMOTHERAPY PROTOCOLS

57

ANAL CANCER: Combined chemotherapy/radiotherapy Chemotherapy: Mitomycin C 5-Fluorouracil 10 mg/m2 IV day 1 only 800 mg/m2/day continuous infusion days 1-4 and 43-46

Radiotherapy: Initial phase 4 week 36 Gy 2 week break second phase 1/2 to 2 weeks (varies) 14.4-18 Gy (Some radiation oncologists do not have the break. In week 5, 5FU is infused)
References .TROG Guidelines 95.2, September 1995 Cummings BJ, Keane TJ, O'Sullivan B, Wong CS, Catton CN. Epidermoid anal cancer: treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C. Int J Radiat Oncol Biol Phys. 1991 Oct;21(5):1115-25.

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BILIARY CANCER Gemcitabine (Repeat every 28 days) 1250 mg/m2/day days 1, 8, 15

Reference: Verderame F, Mandina P, Abruzzo F, Scarpulla M, Di Leo R. Biliary tract cancer: our experience with gemcitabine treatment. Anticancer Drugs. 2000 Oct 11(9):707-8.

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BLADDER (Transitional Cell):

MVAC Methotrexate Vinblastine Doxorubicin Cisplatin 30mg/m2 IV bolus days 1,15,22 3mg/m2 IV bolus days 1,15,22 (vesicant) 30mg/m2 IV bolus day 2 (vesicant) 70mg/m2 IV over 2 hours day 2

(Repeat every 28 days) Restage every 3 cycles (Dose modification - For grade 4 myelosuppression omit days 15 and/or 22) hydration pre and post-cisplatin delayed emesis protocol ensure creatinine clearance > 60ml/min check magnesium and potassium levels note U&Es, LFT, CBE and diff caution using gentamicin concomitantly with cisplatin

Cisplatin/Gemcitabine (or substitute carboplatin) Reference: Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler
P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73.

(for patients unlikely to tolerate MVAC because of renal function, age or performance status) Cisplatin 70 mg/m2 day 1 Gemcitabine 1250 mg/m2 days 1+8 (Modified from ref which only uses 1000 mg/m2)
Reference: von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000 Sep;18(17):3068-77.

(or substitute carboplatin AUC 5)

Concomitant chemo/radiotherapy Cisplatin 20mg/m2/dailyx 5days with 1 litre N Saline hydration Cover during week 1 and 4 of radical radiation concomitantly
Reference: Utsunomiya M, Itoh H, Yoshioka T, Masaki N, Itatani H. Preliminary results of concurrent cisplatin and radiation therapy in locally advanced bladder cancer. Br J Urol. 1992 Oct;70(4):399-403.

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BRAIN: PCV Lomustine (CCNU) Vincristine Procarbazine 110mg/m2 oral day 1 (capsules are 100, 40, 10mg) 1.4mg/m2 ( max 2 mg) I.V. Day 1 60mg/m2 oral Days 8 to 21 (capsules are 50 mg) (repeat every 4 weeks)

References: Kim L, Hochberg FH, Thornton AF, Harsh GR 4th, Patel H, Finkelstein D, Louis DN. Procarbazine, lomustine, and vincristine (PCV) chemotherapy for grade III and grade IV oligoastrocytomas. J Neurosurg. 1996 Oct;85(4):602-7.

TEMOZOLAMIDE Temozolamide 200 mg/m2/day p.o. for 5 days every 4 weeks if no prior chemotherapy 150 mg/m2/day p.o. for 5 days every 4 weeks if prior chemotherapy

Reference: Brandes AA, Ermani M, Basso U, Amista P, Berti F, Scienza R, Rotilio A, Pinna G, Gardiman M, Monfardini S. Temozolomide as a second-line systemic regimen in recurrent high-grade glioma: a phase II study. Ann Oncol. 2001 Feb;12(2):255-7.

THALIDOMIDE (needs ethics committee and SA Govt issued license to prescribe) Thalidomide 100 mg/day starting dose, increase by 100 mg/day each week until 500 mg/day p.o. Can be given as a single agent or in combination with chemotherapy
Reference: Marx GM, McCowatt S, Boyle F, Pavlakis N, Levi JA, Bell DR, Freilich R, Cook R, Biggs M, Little N, Wheeler HR. Phase II study of thalidomide as an anti-angiogenic agent in the treatment of recurrent glioblastoma multiforme (GBM). Proc Am Soc Clin Oncol 2000, 19: 158a.

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BREAST CANCER: Adjuvant Therapy CMF: ALL I.V. CMF: 2 Cyclophosphamide 100mg/m PO days 1-14 Cyclophosphamide 750mg/m2 IV day 1 (or 150mg/day) Methotrexate 40mg/m2 IV days 1+8 Methotrexate 60mg/m2 IV day 1 5-Fluorouracil 600mg/m2 IV days 1+8 5-Fluorouracil 750mg/m2 IV day 1 (repeat every 4 weeks for 6 cycles) (repeat every 3 weeks) Give concomitant G-CSF to maintain dose intensity if neutropenia is dose limiting but better adminisgter with the all intravenous regimen See section 1 for precautions with methotrexate 3rd space collections e.g. pleural effusions, cause MTX accumulation avoid concomitant aspirin or nonsteroidal anti-inflammatory agents (see p.1.8-1.10) for o interactions) encourage oral fluids with 14 day cyclophosphamide for patients receiving concurrent radiotherapy give IV CMF on Fridays and omit the fraction of radiotherapy that day
Reference: Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995 Apr 6;332(14):901-6.

AC: Doxorubicin 60 mg/m2 Cyclophosphamide 600 mg/m2

Reference: Fisher B, Redmond C, Wickerham DL, Bowman D, Schipper H, Wolmark N, Sass R, Fisher ER, Jochimsen P, LegaultPoisson S, et al. Doxorubicin-containing regimens for the treatment of stage II breast cancer: The National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol. 1989 May;7(5):572-82.

For High Risk Patients: A.C: Doxorubicin 60mg/m2 (vesicant) Cyclophosphamide 600mg/m2 ( repeat every 3 weeks for 4 cycles) then; CMF for 3 cycles either oral or IV (every 4 weeks for 3 cycles) Modification of:
Reference : Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. Ten-year results. JAMA. 1995 Feb 15;273(7):542-7.

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Post menopausal Tamoxifen

20 mg PO daily

Reference: [No authors listed] Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists' Collaborative Group. Lancet. 1992 Jan 4;339(8784):1-15. Review.

Locally Advanced FAC 5 Fluorouracil 600 mg/m2 IV day 1 + 8 Doxorubicin 60mg/m2 IV day 1 (vesicant) Cyclophosphamide 600mg/m2 IV day 1 (repeat every 4 weeks)
Reference: Hortobagyi GN, Ames FC, Buzdar AU, Kau SW, McNeese MD, Paulus D, Hug V, Holmes FA, Romsdahl MM, Fraschini G, et al Management of stage III primary breast cancer with primary chemotherapy, surgery, and radiation therapy. Cancer. 1988 Dec 15;62(12):250 Review.

Stage IV: First line chemotherapy CMFP (oral or IV) (add prednisolone 40mg/m2 PO days 1-14 to CMF) Reassess every 3 courses Treat until maximum response Trastuzumab (Herceptin) and Taxanes (apply using HIC guidelines) Herceptin 4 mg/kg IV over 90 minutes then 2mg/kg/week over 30 minutes u progression (Premedication paracetamol 1 gm po and diphenhydramine 50 mg po just prior to dose) (Watch for hypersensitivity particularly with the first dose) WITH Docetaxel 75 mg/m2 IV over 1 hour every 3 weeks for 6 cycles (Premed: Dexamethasone 8 mg bid for 3 days starting 24 hours prior to the dose) OR Paclitaxel 90 mg/m2 IV over 60 minutes weekly Premedicate with Dexamethasone 20mg po 12hrs and 6 hrs prior to paclitaxel and Ranitidine 50mg IV 30-60mins prior to paclitaxel and Phenergan 25 mg IV (can substitute diphenhydramine 50 mg po)
Reference: Dieras V, Beuzeboc P, Laurence V, Pierga JY, Pouillart P. Interaction between Herceptin((R)) and Taxanes. Oncology. 2001 Oct;61 Suppl S2:43-9.

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Herceptin single agent (apply using HIC guidelines) Herceptin 4 mg/kg IV over 90 minutes then 2mg/kg/week over 30 minutes until progression (Premedication paracetamol 1 gm po and diphenhydramine 50 mg po just prior to dose) (Watch for hypersensitivity particularly with the first dose)
Reference: Baselga J. Phase I and II clinical trials of trastuzumab. Ann Oncol. 2001;12 Suppl 1:S49-55.

Second Line chemotherapy Doxorubicin 60mg/m2 IV day 1 (vesicant) (repeat every 3 weeks)
Reference: Joensuu H, Holli K, Heikkinen M, Suonio E, Aro AR, Hietanen P, Huovinen R. Combination chemotherapy versus singleagent therapy as first- and second-line treatment in metastatic breast cancer: a prospective randomized trial. J Clin Oncol. 1998 Dec;16(12):3720-30.

Third line chemotherapy: 75 mg/m2/day over 1 hour as starting dose can escalate to 100mg.m2/day IV over 1 hour In heavily pretreated patients or those with poor liver function can start at 60 mg/m2 (repeat every 3 weeks) Docetaxel (Premed: Dexamethasone 8 mg bid for 3 days starting 24 hours prior to the dose)
Reference: Ravdin PM, Burris HA 3rd, Cook G, Eisenberg P, Kane M, Bierman WA, Mortimer J, Genevois E, Bellet RE. Phase II trial of docetaxel in advanced anthracycline-resistant or anthracenedione-resistant breast cancer. J Clin Oncol. 1995 Dec;13(12):2879-85.

Docetaxel (weekly)

36 mg/m2/week over 1 hour for 6 weeks then 2 weeks off

(Premed dexamethasone 8 mg night before and 8 mg b.i.d. on the day of treatment)

Reference: Hainsworth JD, Burris HA 3rd, Yardley DA, Bradof JE, Grimaldi M, Kalman LA, Sullivan T, Baker M, Erland JB, Greco FA. Weekly docetaxel in the treatment of elderly patients with advanced breast cancer: a Minnie Pearl Cancer Research Network phase II trial. J Clin Oncol. 2001 Aug 1;19(15):3500-5.

Paclitaxel 175mg/m2/day over 3 hours IV (repeat every 3 weeks) Premedicate with Dexamethasone 20mg po 12hrs and 6 hrs prior to paclitaxel and Ranitidine 50mg IV 30-60mins prior to paclitaxel and Phenergan 25 mg IV (can substitute diphenhydramine 50 mg po)
Reference: Hortobagyi GN, Holmes FA. Single-agent paclitaxel for the treatment of breast cancer: an overview. Semin Oncol. 1996 Feb;23(1 Suppl 1):4-9. Review.

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Paclitaxel (weekly)

100 mg/m2 IV over 1 hour

Reference: Seidman AD, Hudis CA, Albanel J, Tong W, Tepler I, Currie V, Moynahan ME, Theodoulou M, Gollub M, Baselga J, Norton L. Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol. 1998 Oct;16(10):3353-61. Review.

Fourth line chemotherapy: Capecitabine 2500 mg/m2 divided into 2 doses daily po 2 weeks every 3 weeks

Reference: Cervantes G, Torrecillas L, Erazo AA, Delgadillo F, SuarezT, Leoner C, Cortes P, Cepeda F. Capecitabine (Xeloda) as treatment after failure of taxanes for metastatic breast cancer. Proc Am Soc Clin Oncol 2000, 19: 121a.

Mitomycin C Vinblastine

10mg/m2 IV Day 1 (vesicant) 5mg/m2 IV Day 1 and 15 (vesicant) (repeat every 4 weeks)

Reference: Garewal HS, Brooks RJ, Jones SE, Miller TP.Garewal HS, Brooks RJ, Jones SE, Miller TP. Treatment of advanced breast cancer mitomycin C combined with vinblastine or vindesine. J Clin Oncol. 1983 Dec;1(12):772-5.

Hormonal Therapy: Tamoxifen Anastrozole 20 mg. po daily 1mg po daily or

Reference: Costa SD, Kaufmann M. Is anastrozole superior to tamoxifen as first-line therapy for advanced breast cancer? J Clin Oncol. 2001 May 1;19(9):2580; discussion 2580-2.

Then Medroxyprogesterone acetate 500 mg po daily or Exemestane 25 mg/day

Reference: Hillner BE, Radice D. Cost-effectiveness analysis of exemestane compared with megestrol in patients with advanced breast carcinoma. Cancer. 2001 Feb 1;91(3):484-9.

Premenopausal Advanced Breast Cancer Zoladex Tamoxifen 3.6 mg SC every month 20 mg/day

Reference: Klijn JG, Blamey RW, Boccardo F, Tominaga T, Duchateau L, Sylvester R. Combined tamoxifen and luteinizing hormonereleasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol. 2001 Jan 15;19(2):343-53 .

Breast Cancer (Bone Predominant) Pamidronate 90mg IV over 2 hours (patients with bone predominant breast cancer where the major problem is skeletal events (pain, fracture) Pamidronate is available via Section 100
65

CERVIX CANCER: Single Agents Cisplatin (repeat every 3 weeks) 100mg/m2 day 1

hydration pre and post-cisplatin fluid balance chart ensure creatinine clearance > 60ml/min check magnesium and potassium levels note U&Es, LFT, CBE and diff caution using gentamicin concomitantly with cisplatin

Reference: Alberts DS, Garcia D, Mason-Liddil N. Cisplatin in advanced cancer of the cervix: an update. Semin Oncol. 1991 Feb;18(1 Suppl 3):11-24. Review.

Ifosfamide Mesna

5000 mg/m2 24 hour infusion day 1 with 5000 mg/m2

Reference: Sutton GP, Blessing JA, Adcock L, Webster KD, DeEulis T. Phase II study of ifosfamide and mesna in patients with previously-treated carcinoma of the cervix. A Gynecologic Oncology Group study. Invest New Drugs. 1989 Nov;7(4):341-3.

Combination Therapy Cisplatin 50 mg/m2 iv Ifosfamide 5000 mg/m2 25 hr infusion Mesna 5000 mg/m2
Reference: Omura GA, Blessing JA, Vaccarello L, Berman ML, Clarke-Pearson DL, Mutch DG, Anderson B. Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 1997 Jan;15(1):165-71.

Combined Chemoradiotherapy Cisplatin 70 mg/m2 iv 5-Fluorouracil 1000 mg/m2 iv cont inf 96 hours With RT repeat every 3 weeks
Reference: Peters WA 3rd, Liu PY, Barrett RJ 2nd, Stock RJ, Monk BJ, Berek JS, Souhami L, Grigsby P, Gordon W Jr, Alberts DS. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol. 2000 Apr;18(8):1606-13.

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COLORECTAL CANCER: Adjuvant for Dukes C Colon 5-FU/Leucovorin (Folinic Acid): 5-FU 370mg/m2 I.V. bolus Days 1-5 ( repeat every 28 days) If no toxicity increase 5-FU dose next cycle to 425mg/m2 Leucovorin (calcium folinate) IV 20mg/m2/day Days 1-5 given immediately prior to the 5-FU every 28 days.
Reference: Poon MA, O'Connell MJ, Moertel CG, Wieand HS, Cullinan SA, Everson LK, Krook JE, Mailliard JA, Laurie JA, Tschetter LK, et al. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol. 1989 Oct;7(10):1407-18. Review.

Adjuvant for rectal Leucovorin 500 mg/m2 IV 2 hour infusion 5 Fluorouracil 500 mg/m2 IV bolus weekly for 6 weeks then 2 weeks without drug. Chemotherapy is continued post RT for a total of 6 cycles or 1 year post commencement of treatment Radiotherapy To be given 3-5 weeks after the first dose of chemotherapy concomitantly with 5 Fluorouracil 225 mg/m2 continuous ambulatory infusion (modified from the original protocol)
Reference: Wolmark N, Wieand HS, Hyams DM, Colangelo L, Dimitrov NV, Romond EH, Wexler M, Prager D, Cruz AB Jr, Gordon PH, Petrelli NJ, Deutsch M, Mamounas E, Wickerham DL, Fisher ER, Rockette H, Fisher B. Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst. 2000 Mar 1;92(5):388-96.

Metastatic disease Saltz: Irinotecan/ 5 Fluoruracil/Leucovorin Irinotecan Leucovorin 5 Fluorouracil 125 mg/m2 IVover 90 minutes 20 mg/m2 IV bolus 500 mg/m2 IV bolus

Give once each week for 4 weeks every 6 weeks Need premed with atropine 0.4 mg for early onset diarrhoea For poor performance status patients use the weekly 5 Fluoruracil/Leucovorin without the Irinotecan, which can be used 2nd line at the above dose.
Reference: Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000 Sep 28;343(13):905-14.

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Alternative First Line or Relapsed Disease: Oxaliplatin 130 mg/m2 IV 2 hour infusion Repeat every 3 weeks (Avoid cold and cold fluids)
Reference: Bleiberg H. Oxaliplatin (L-OHP): a new reality in colorectal cancer. Br J Cancer. 1998 Jun;77 Suppl 4:1-3. Review.

Combination for Relapse (FOLFOX 7): Oxaliplatin Leucovorin 130 mg/m2 with 400 mg/m2

over 2 hours, day 1

5 Fluorouracil 400 mg/m2 bolus then 46 hour infusion 2400 mg/m2 Repeat every 2 weeks
Reference: Maindrault-Goebel F, de Gramont A, Louvet C, Andre T, Carola E, Mabro M, Artru P, Gilles V, Lotz JP, Izrael V, Krulik M. High-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX 7).Eur J Cancer. 2001 May;37(8):1000-5.

Capecitabine

2500 mg/m2/day po (divided into 2 doses) daily for 2 weeks followed by 1 weeks rest

Reference: Twelves C, Boyer M, Findlay M, Cassidy J, Weitzel C, Barker C, Osterwalder B, Jamieson C, Hieke K. Capecitabine (Xeloda) improves medical resource use compared with 5-fluorouracil plus leucovorin in a phase III trial conducted in patients with advanced colorectal carcinoma. Eur J Cancer. 2001 Mar;37(5):597-604.

Continuous ambulatory infusion 5-FU 300mg/m2/day continuous IV via portable pump. (Restage every 12 weeks)
Reference: Lokich JJ, Ahlgren JD, Gullo JJ, Philips JA, Fryer JG. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol. 1989 Apr;7(4):425-32.

Raltitrexid 3 mg/m2 IV (Repeat every 3 weeks) Can be used for patients who cannot tolerate 5 fluorouracil eg due to coronary artery spasm
Reference: Zalcberg JR, Cunningham D, Van Cutsem E, Francois E, Schornagel J, Adenis A, Green M, Iveson A, Azab M, Seymour I. ZD1694: A novel thymidylate synthase inhibitor with substantial activity in the treatment of patients with advanced colorectal cancer. Tomudex Colorectal Study Group. J Clin Oncol. 1996 Mar;14(3):716-21.

Liver only disease: Floxuridine (FUDR) 0.2mg/kg/day (esc. to 0.3) I/A via pump for 14 days Add Heparin 10,000u/s and Dexamethasone 8mg per bag (repeat every 28 days) (Floxuridine is in SAS from Dept of Health in Canberra or RAH delegate)
Reference: [No authors listed] Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. Meta-Analysis Group in Cancer. J Natl Cancer Inst. 1996 Mar 6;88(5):252-8.

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Chemo/radiotherapy: (Rectal or local colon recurrence or pre operative concomitant with rectal) Radiation 5 Fluorouracil 225 mg/m2/day continuous ambulatory infusion
Reference: Bauer TW, Spitz FR. Adjuvant and neoadjuvant chemoradiation therapy for primary colorectal cancer. Surg Oncol. 1998 Nov-Dec;7(3-4):175-81. Review.

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ENDOCRINE: Adrenocortical Carcinoma: 1.0. Mitotane gm/day) 4 gm/day (divide into QID and escalate to max tolerated (10 (requires SAS approval from Dept of Health in Canberra) Etoposide Doxorubicin Cisplatin 100 mg/m2 days 5,6,7 20 mg/m2 days 1 + 8 40 mg/m2days 1 + 9

Reference: Berruti A, Terzolo M, Pia A, Angeli A, Dogliotti L. Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Italian Group for the Study of Adrenal Cancer. Cancer. 1998 Nov 15;83(10):2194200.

2.0.

Carcinoid: (and Islet Cell Tumours) First Line: Streptozocin 500mg/m2 IV over 15 minutes (or extended to 1 hour if venous irritation) days 1-5 5-Fluorouracil 400mg/m2 IV over 10 mins days 1-5 (repeat every 4 weeks) (Streptozocin requires SAS approval from Dept. of Health in Canberra) fluid balance chart check for protein in urine check for BSL (hypoglycaemia)

Reference: Moertel CG, Hanley JA. Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Clin Trials. 1979 Winter;2(4):327-34.

Second Line (as for small cell lung cancer) Cisplatin 80mg/m2 IV over 2 hrs day 1 Etoposide 120mg/m2 IV over 1 hour days 1,2,3 (Repeat every 3 weeks) delayed emesis protocol for cisplatin hydration pre and post-cisplatin fluid balance chart ensure creatinine clearance > 60ml/min check magnesium and potassium levels note U&Es, LFT, CBE and diff caution using gentamicin concomitantly with cisplatin

Reference: Rougier P, Mitry E. Chemotherapy in the treatment of neuroendocrine malignant tumors. Digestion. 2000;62 Suppl 1:73-8. Review.

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Alternate Treatments: Interferon

3 million units S/C Mon,Wed,Fri (Continue until maximum response)

Reference: Basser RL, Lieschke GJ, Sheridan WP, Fox RM, Green MD. Recombinant alpha-2b interferon in patients with malignant carcinoid tumour. Aust N Z J Med. 1991 Dec;21(6):875-8.

50 micrograms bd day 1 100 micrograms bd day 2 150 micrograms tds thereafter For patients who are stable on S/C octreotide can use long acting Octreotide (Sandostatin LAR) 20 mg every 4 weeks deep intragluteal injection. If well controlled decrease to 10 mg after 3 months or if poorly controlled increase to 30 mg . Can supplement with subcutaneous at a dose used prior to long acting.
Reference: Oberg K, Norheim I, Theodorsson E. Treatment of malignant midgut carcinoid tumours with a long-acting somatostatin analogue octreotide. Acta Oncol. 1991;30(4):503-7.

Octreotide

MIBG - in situations where metastatic tumour takes up MIBG it may be appropriate to treat with I131 labelled MIBG
Reference: Pathirana AA, Vinjamuri S, Byrne C, Ghaneh P, Vora J, Poston GJ. (131)I-MIBG radionuclide therapy is safe and costeffective in the control of symptoms of the carcinoid syndrome. Eur J Surg Oncol. 2001 Jun;27(4):404-8.

For symptom control: Cyproheptadine 0.4 mg/kg in 3 divided doses (range usually 12-48 mg)
Reference: Moertel CG, Kvols LK, Rubin J. A study of cyproheptadine in the treatment of metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer. 1991 Jan 1;67(1):33-6.

3.0.

Thyroid: (If not iodophilic or after radioiodine) Doxorubicin 75 mg/m2 IV day 1 (vesicant) (Repeat every 3 weeks)

Reference: Ahuja S, Ernst H. Chemotherapy of thyroid carcinoma. J Endocrinol Invest. 1987 Jun;10(3):303-10.

Medullary Carcinoma of Thyroid No standard therapy. Refer to literature eg below

Reference: Nocera M, Baudin E, Pellegriti G, Cailleux AF, Mechelany-Corone C, Schlumberger M. Treatment of advanced medullary thyroid cancer with an alternating combination of doxorubicin-streptozocin and 5 FU dacarbazine. Groupe d'Etude des Tumeurs a Calcitonine (GETC). Br J Cancer. 2000 Sep;83(6):715-8.

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ENDOMETRIAL CANCER: (Recurrent disease after hormone therapy, or visceral disease) Doxorubicin 60mg/m2 IV day 1 (vesicant) (Repeat every 3 weeks)

bolus IV over 5 mins into fast running infusion

Reference: Moore TD, Phillips PH, Nerenstone SR, Cheson BD. Systemic treatment of advanced and recurrent endometrial carcinoma: current status and future directions. J Clin Oncol. 1991 Jun;9(6):1071-88. Review.

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GASTRIC CANCER: ECF: 50 mg/m2 IV day 1 every 3 weeks 60mg/m2 IV over 2 hours every 3 weeks 200mg/m2/day by continuous IV infusion until completion of treatment (Restage after 3 cycles) Can substitute doxorubicin for epirubicin Doxorubicin 40mg/m2 IV bolus every 3 weeks (vesicant) Epirubicin Cisplatin 5-FU delayed emesis protocol for cisplatin hydration pre and post-cisplatin fluid balance chart ensure creatinine clearance > 60ml/min check magnesium and potassium levels note U&Es, LFT, CBE and diff caution using gentamicin concomitantly with cisplatin

Reference: Zaniboni A, Barni S, Labianca R, Marini G, Pancera G, Giaccon G, Piazza E, Signaroldi A, Legnani W, Luporini G. Epirubicin, cisplatin, and continuous infusion 5-fluorouracil is an active and safe regimen for patients with advanced gastric cancer. An Italian Group for the Study of Digestive Tract Cancer (GISCAD) report. Cancer. 1995 Nov 15;76(10):1694-9.

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HEAD AND NECK CANCER (Squamous Cell) Locally advanced or metastatic (palliative): First Line: Cisplatin 100mg/m2 IV over 2 hrs 5-Fluorouracil 1000mg/m2/day continuous IV infusion x 5 days (in 2L) (Repeat every 3-4 weeks depending on myelosuppression) delayed emesis protocol for cisplatin hydration pre and post-cisplatin fluid balance chart ensure creatinine clearance > 60ml/min check magnesium and potassium levels note U&Es, LFT, CBE and diff caution using gentamicin concomitantly with cisplatin In patients with poor renal function substitute in place of cisplatin: Carboplatin AUC = 5 (see carboplatin dosage guidelines p1.5 ) ( repeat every 4 weeks)

Reference: Weaver A, Fleming S, Ensley J, Kish JA, Jacobs J, Kinzie J, Crissman J, Al-Sarraf M. Superior clinical response and survival rates with initial bolus of cisplatin and 120 hour infusion of 5-fluorouracil before definitive therapy for locally advanced head and neck cancer. Am J Surg. 1984 Oct;148(4):525-9.

Second Line: Methotrexate 40mg/m2 IV day 1 Repeat weekly (Can escalate until myelosuppression) If mucositis is dose limiting add calcium folinate 15mg every 6 hours x 4 doses starting 24 hours after chemotherapy class 2 antiemetics avoid concomitant aspirin or non-steroidal anti-inflammatory agents
Reference: DeConti RC, Schoenfeld D. A randomized prospective comparison of intermittent methotrexate, methotrexate with leucovorin, and a methotrexate combination in head and neck cancer. Cancer. 1981 Sep 1;48(5):1061-72.

Locally advanced - Radical treatment intent : Cisplatin 20mg/m2 I.V. days 1-5 weeks 1 and 5 concurrent with radiotherapy

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HODGKIN'S DISEASE: First Line: ABVD Doxorubicin Bleomycin Vinblastine Dacarbazine 25mg/m2 IV day 1+ 15 (vesicant) 10mg/m2 IV day 1+ 15 (hydrocortisone 100mg IV premed) 6mg/m2 IV day 1+ 15 (vesicant) 375mg/m2IV in 500ml over 1 hour day 1+ 15 (Repeat every 28 days)

Limit cumulative dose bleomycin to 300 mg If blood counts fall use G-CSF Day 2 for 10 days (may only need 5 days, alternate days if severe bone pain) Day 16 for 5-10 days (alternate days if bone pain)

Reference: Bonadonna G, Santoro A. ABVD chemotherapy in the treatment of Hodgkin's disease. Cancer Treat Rev. 1982 Mar;9(1):21-35. Review.

Second Line: ChlVPP (British MOPP) Chlorambucil Vinblastine Procarbazine Prednisolone 6 mg/m2 po Days 1-14 6 mg/m2 IV Days 1 + 8 100 mg/m2 po Days 1-14 40 mg/m2 po Days 1-14

Reference: McElwain TJ, Toy J, Smith E, Peckham MJ, Austin DE. A combination of chlorambucil, vinblastine, procarbazine and prednisolone for treatment of Hodgkin's disease. Br J Cancer. 1977 Aug;36(2):276-80.

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KAPOSI'S SARCOMA Pegylated Liposomal Doxorubicin (Repeat every 2 weeks) Or Bleomycin with:Hydrocortisone Vincristine Doxorubicin (Repeat every 2 weeks) Can use vincristine and bleomycin without the doxorubicin if toxicity is a problem
Reference: Northfelt DW, Dezube BJ, Thommes JA, Miller BJ, Fischl MA, Friedman-Kien A, Kaplan LD, Du Mond C, Mamelok RD, Henry DH. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: results of a randomized phase III clinical trial. J Clin Oncol. 1998 Jul;16(7):2445-51.

20 mg/m2 IV

10 u/m2 IV 100mg/IV 1.4mg/m2 (max 2mg) 20mg/m2 IVDay 1 (vesicant)

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LIVER CANCER: (PRIMARY) Unresectable: Doxorubicin 60mg/m2 day 1 (vesicant) (Repeat every 3 weeks)
Reference: Sciarrino E, Simonetti RG, Le Moli S, Pagliaro L. Adriamycin treatment for hepatocellular carcinoma. Experience with 109 patients. Cancer. 1985 Dec 15;56(12):2751-5.

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LUNG CANCER: SMALL CELL: Metastatic and Adjuvant (Also Merkel cell tumor) First Line: Cisplatin 80mg/m2 IV over 2 hrs day 1 Etoposide 120mg/m2 IV over 1 hour days 1,2,3 (Repeat every 3 weeks) delayed emesis protocol for cisplatin hydration pre and post-cisplatin fluid balance chart ensure creatinine clearance > 60ml/min check magnesium and potassium levels note U&Es, LFT, CBE and diff caution using gentamicin concomitantly with cisplatin Can substitute carboplatin AUC 5
Reference: Roth BJ, Johnson DH, Einhorn LH, Schacter LP, Cherng NC, Cohen HJ, Crawford J, Randolph JA, Goodlow JL, Broun GO, et al. Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol. 1992 Feb;10(2):282-91.

In Limited Disease: (a) Irradiate the site of bulk disease in the chest with course I (b) PCI after chemotherapy if achieve CR is optional Second Line: (Also for use of thymoma) Cyclophosphamide Doxorubicin Vincristine (Repeat every 3 weeks) 1g/m2 IV day 1 50mg/m2 IV day 1 (vesicant) 2mg IV day 1 (vesicant)

Reference: Greco FA, Richardson RL, Snell JD, Stroup SL, Oldham RK. Small cell lung cancer. Complete remission and improved survival. Am J Med. 1979 Apr;66(4):625-30.

NON SMALL CELL LUNG CANCER 1st line metastatic or induction for stage 111 Cisplatin Gemcitabine (repeat cycles every 21 days) Can substitute carboplatin AUC 5

100mg/m2 day 1 1250 mg/m2 day 1,8

Reference: Cardenal F, Lopez-Cabrerizo MP, Anton A, Alberola V, Massuti B, Carrato A, Barneto I, Lomas M, Garcia M, Lianes P, Montalar J, Vadell C, Gonzalez-Larriba JL, Nguyen B, Artal A, Rosell R. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 1999 Jan;17(1):12-8.

2nd line Docetaxel (repeat cycles every 21 days) 75 mg/m2

Premed: Dexamethasone 8 mg bid for 3 days starting 24 hours prior to the dose Reference: Shepherd FA, Fossella FV, Lynch T, Armand JP, Rigas JR, Kris MG. Docetaxel (Taxotere) shows survival and quality-oflife benefits in the second-line treatment of non-small cell lung cancer: a review of two phase III trials. Semin Oncol. 2001 Feb;28(1 Suppl 2):4-9. Review.

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LYMPHOMA (NON HODGKIN'S): LOW GRADE: First Line: Chlorambucil Prednisolone

16mg/m2/day PO days 1-5 (2mg tablets) 40mg/m2/day PO days 1-5 (Repeat every 28 days)

References: Cadman E, Drislane F, Waldron JA Jr, Farber L, Prosnitz L, Bertino JR. High-dose pulse chlorambucil: effective therapy for rapid remission induction in nodular lymphocytic poorly differentiated lymphoma. Cancer. 1982 Sep 15;50(6):1037-41.

Salvage: CVP Cyclophosphamide

400mg/m2/day PO days 1-5 (encourage fluids 2-3L/day) 50mg tablets)

Vincristine Prednisolone

1.4mg/m2/day IV [max 2mg] day 1 (vesicant) 100mg/day PO day 1-5 (Repeat every 21 days)

Reference: Bagley CM Jr, Devita VT Jr, Berard CW, Canellos GP. Advanced lymphosarcoma: intensive cyclical combination chemotherapy with cyclophosphamide, vincristine, and prednisone. Ann Intern Med. 1972 Feb;76(2):227-34.

Mabthera (Rituximab)

375 mg/m2 every week for 4 weeks (ADMIT for course 1)

Reference: McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33 .

INTERMEDIATE GRADE: 2. CHOP: Cyclophosphamide 750mg/m2 IV day 1 Doxorubicin 50mg/m2 IV day 1 (vesicant) Vincristine 1.4mg/m2 IV [max 2mg] day 1 (vesicant) Prednisolone 100mg/day PO days 1-5 (repeat every 3 weeks restage after course 4, ejection fraction pre treatment and after course 4) If achieve CR and patient had bone marrow involvement Give IT MTX 12 mg 2xweek for 3 weeks. For stage I disease give 3 cycles then local irradiation
Reference: Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP. A phase III comparison of CHOP vs. m-BACOD vs. ProMACE-CytaBOM vs. MACOP-B in patients with intermediate- or high-grade nonHodgkin's lymphoma: results of SWOG-8516 (Intergroup 0067), the National High-Priority Lymphoma Study. Ann Oncol. 1994;5 Suppl 2:91-5.

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Salvage therapy for CHOP failures (particularly pre high dose therapy and transplant) DHAP 1. Dexamethasone 40mg IV over 15 mins days 1-4 2 Cisplatin 100mg/m IV over 24 hours day 1 Cytarabine 2g/m2 in 500mls NS over 3 hours day 2 every 12 hours x 2 dose (repeat every 28 days)
Reference: Velasquez WS, Cabanillas F, Salvador P, McLaughlin P, Fridrik M, Tucker S, Jagannath S, Hagemeister FB, Redman JR, Swan F, et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood. 1988 Jan;71(1):117-22.

CEPP (B) Cyclophosphamide 600mg2 I.V.days 1+8 Etoposide 70mg/m2 I.V.days 1,2,3 Procarbazine 60mg/m2/day oral (50mg capsules) days 1-10 Prednisolone 60mg/m2 /day oral days 1-10 (repeat every 4 weeks if proceeding to transplant)
Reference: Chao NJ, Rosenberg SA, Horning SJ. CEPP(B): an effective and well-tolerated regimen in poor-risk, aggressive nonHodgkin's lymphoma. Blood. 1990 Oct 1;76(7):1293-8.

HIGH GRADE: Use Haematology Unit current protocol, including intrathecal therapy. e.g. COPADM
Reference: Michel G, Landman-Parker J, Auclerc MF, Mathey C, Leblanc T, Legall E, Bordigoni P, Lamagnere JP, Demeocq F, Perel Y, Auvrignon A, Berthou C, Bauduer F, Pautard B, Schneider P, Schaison G, Leverger G, Baruchel A. Use of recombinant human granulocyte colony-stimulating factor to increase chemotherapy dose-intensity: a randomized trial in very high-risk childhood acute lymphoblastic leukemia. J Clin Oncol. 2000 Apr;18(7):1517-24.

e.g. Cycle 1 COP Day 1 Cyclophosphmaide 300 mg/m2 IV 2 Day 1 Vincristine 1.4 mg/m max 2 mg) IV bid Days 1-7 Prednisolone 60 mg/m2/day po With IT MTX 15 mg and IT hydrocortisone 15 mg Cycles 2 + 3 + 6 COPADM Day 1 Vincristine 1.4 mg/m2 IV Days 2-4 Cyclophosphamide 500 mg/m2/day IV 2 Day 2 Doxorubicin 60 mg/m IV Day 1 HD Methotrexate 3gm/m2/3hrs IV (with hydration and alkalinisation) Folinic acid 15 mg/m2/dose every 6 hours Days 2-4 (starts 24 hours post start of MTX) IT Methotrexate + 15 mg IT Days 2 + 6 (12-24 hrs after start of MTX) IT Hydrocortisone 15 mg IT Days 2 + 6 bid Days 1-5 Prednisolone 60 mg/m2 po G-CSF 5 g/kg/day SC Day7 to recovery

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Cycles 4 + 5 CYM HD MTX 3 gm/m2/3hrs IV (with hydration and alkalisation) Folinic acid 15 mg/m2/dose every 6 hours IT Methotrexate 15 mg IT IT Hydrocortisone 15 mg IT Cytosine arabinoside 100 mg/m2/day (5 x 24 hour CI) IT Cytosine arabinoside 40 mg IT infusion) G-CSF 5 g/kg/day SC

Day 1 Day 1 Days 2 + 6 Days 2 + 6 Days 2-6 Day 7 (on completion of AraC Day 7 to recovery

CNS Lymphoma HD MTX Methotrexate 1 gm/m2 day 1 + 8 Follow by cranial irradiation on day 15 (45 Gy with 4.5 Gy boost) IT Therapy is given if the CSF contains lymphoma cells IT Methotrexate 12mg twice/week until CSF clears then once/week Or IT Cytosine Arabinoside 40 Mg
Reference: O'Brien P, Roos D, Pratt G, Liew K, Barton M, Poulsen M, Olver I, Trotter G. Phase II multicenter study of brief singleagent methotrexate followed by irradiation in primary CNS lymphoma. J Clin Oncol. 2000 Feb;18(3):519-

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MELANOMA: Advanced disease First Line: Dacarbazine (Repeat every 3 weeks) 850mg/m2 IV over 1 hour day 1

Reference: Legha SS. Current therapy for malignant melanoma. Semin Oncol. 1989 Feb;16(1 Suppl 1):34-44. Review.

Second Line: Lomustine (CCNU) (Repeat every 4 weeks)

80mg/m2 PO day 1 (10mg, 40mg and 100 mg capsules)

Reference: Wasserman TH, Slavik M, Carter SK. Methyl-CCNU inclinical cancer therapy. Cancer Treat Rev. 1974 Dec;1(4):251-69. Review.

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MERKEL CELL TUMOUR Same chemotherapy as small cell lung cancer

Reference: Tai PT, Yu E, Winquist E, Hammond A, Stitt L, Tonita J, Gilchrist J. Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases. J Clin Oncol. 2000 Jun;18(12):2493-9. Review.

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MESOTHELIOMA Cisplatin Gemcitabine 100 mg/m2 IV over 1 hour day 1 1000 mg/m2 IV days 1+8 (Repeat every 21 days) delayed emesis protocol for cisplatin hydration pre and post-cisplatin fluid balance chart ensure creatinine clearance > 60ml/min check magnesium and potassium levels note U&Es, LFT, CBE and diff caution using gentamicin concomitantly with cisplatin

Reference: Byrne MJ, Davidson JA, Musk AW, Dewar J, van Hazel G, Buck M, de Klerk NH, Robinson BW. Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study. J Clin Oncol. 1999 Jan;17(1):25-30.

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OESOPHAGEAL CANCER: Combined chemotherapy and radiotherapy or single dose pre op or palliative 80mg/m2 IV over 2 hrs day 1 5-Fluorouracil 800mg/m2/day IV continuous days 1-5

Cisplatin

When given as chemotherapy alone as palliative treatment give every 3 weeks When given with palliative radiotherapy give in first week of 3 weeks of RT When given with radical radiotherapy give weeks 1 and 5 delayed emesis protocol for cisplatin hydration pre and post-cisplatin fluid balance chart ensure creatinine clearance > 60ml/min check magnesium and potassium levels note U&Es, LFT, CBE and diff caution using gentamicin concomitantly with cisplatin

Reference: Burmeister BH, Denham JW, O'Brien M, Jamieson GG, Gill PG, Devitt P, Yeoh E, Hamilton CS, Ackland SP, Lamb DS, et al. Combined modality therapy for esophageal carcinoma: preliminary results from a large Australasian multicenter study. Int J Radiat Oncol Biol Phys. 1995 Jul 15;32(4):997-1006.

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OVARIAN CANCER: First Line: Carboplatin AUC 7.5 IV day 1 Paclitaxel 175 mg/m2 IV (3 hour infusion) day 1 Repeat every 3 weeks Or substitute cisplatin for carboplatin Cisplatin 75 mg/m2 IV day 1
Reference: ten Bokkel Huinink W, Veenhof C, Huizing M, Rodenhuis S, Helmerhorst T, Dubbelman R, Dalesio O, Beijnen J, Winograd B. Carboplatin and paclitaxel in patients with advanced ovarian cancer: a dose-finding study. Semin Oncol. 1997 Feb;24(1 Suppl 2):S2-31-S2-33.

If relapse occurs > 12 months post treatment a second treatment with a platinum regimen is warranted eg Carboplatin Salvage Regimens Topotecan 1.5 mg/m2/day IV (30 min infusion) Days 1-5 Repeat every 3 weeks Use tropisetron 5 mg and dexamethasone 4 mg as pre med AUC 7.5 IV day 1

Reference: Bookman MA, Malmstrom H, Bolis G, Gordon A, Lissoni A, Krebs JB, Fields SZ. Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. J Clin Oncol. 1998 Oct;16(10):3345-52.

Liposomal Doxorubicin 50 mg/m2 IV Repeat every 4 weeks

Reference: Muggia F, Hamilton A. Phase III data on Caelyx(R) in ovarian cancer. Eur J Cancer. 2001 Dec;37 Suppl 9:15-18.

If patients have received first line therapy with cisplatin 100 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks then consider 2nd line with Paclitaxel 175 mg/m2 IV over 3 hours Hexalen 50 mg/m2/day orally ( in 4 divided doses) daily for 14 days (Repeat every 28 days)
Reference: Olver I, Davy M, Luftner D, Park SH, Egorin M, Ellis A, Webster L. A phase I study of paclitaxel and altretamine as second-line therapy to cisplatin regimens for ovarian cancer. Cancer Chemother Pharmacol. 2001 Aug;48(2):109-14.

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PANCREAS : Inoperable locally advanced disease Combined chemo/radiotherapy Fluorouracil 225mg/m2/day continuous ambulatory infusion for the duration of the radiotherapy
Reference: Regine WF, John WJ, McGrath P, Strodel WE, Mohiuddin M.The feasibility of dose escalation using concurrent radiation and 5-fluorouracil therapy following pancreaticoduodenectomy for pancreatic carcinoma.J Hepatobiliary Pancreat Surg. 2000;7(1):537.

Metastatic Disease (Palliation): Gemcitabine 1250 mg/m2/week IV weekly for 3 weeks in every 4
Reference: Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD. Improvements in survival and clinical benefit with gemcitabine as firstline therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13.

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PNET TUMOURS: (See protocol for sarcomas, Ewings)

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RENAL CANCER: Interferon alpha 10 million units three times per week subcutaneously

Reference: Stebbing J, Gore M. The current status of interferon-alpha treatment in advanced renal cancer. BJU Int. 2001 May;87(7):599-601. Review. No abstract available.

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SARCOMA: Soft tissue metastatic: First Line: Doxorubicin: 75mg/m2 IV day 1 (vesicant) (Repeat every 21 days)

Reference: Santoro A, Tursz T, Mouridsen H, Verweij J, Steward W, Somers R, Buesa J, Casali P, Spooner D, Rankin E, et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol. 1995 Jul;13(7):1537-45.

Second Line: Ifosfamide: Mesna:

3750mg/m2 daily x 2 days 3750mg/m2 daily x 2 days Mesna to continue for 12 hours after completion of ifosfamide (2250mg/m2) (Repeat every 21 days)

Reference: Antman KH, Ryan L, Elias A, Sherman D, Grier HE. Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma.J Clin Oncol. 1989 Jan;7(1):126-31.

Or combination therapy: Ifosfamide Mesna Following Doxorubicin 5000 mg/m2 IV (24 hour infusion) day 1 with 2500 mg/m2 IV (24 hour infusion) day 1 50 mg/m2 IV day 1 (Repeat every 21 days)

Reference: Schutte J, Mouridsen HT, Stewart W, Santoro A, van Oosterom AT, Somers R, Blackledge G, Verweij J, Dombernowsky P, Thomas D, et al.Ifosfamide plus doxorubicin in previously untreated patients with advanced soft tissue sarcoma. The EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 1990;26(5):558-61.

Salvage: CYVADIC Cyclophosphamide 500 mg/m2 IV day 1 Vincristine 1 mg/m2 IV days 1-5 Doxorubicin 50 mg/m2 IV day 1 Dacarbazine 250 mg/m2 IV daily days 1-5 If no more doxorubicin can be used can substitute dactinomycin for doxorubicin Dactinomycin 0.3 mg/m2 IV days 3 and 4
References: Pinedo HM, Bramwell VH, Mouridsen HT, Somers R, Vendrik CP, Santoro A, Buesa J, Wagener T, van Oosterom AT, van Unnik JA, et al. Cyvadic in advanced soft tissue sarcoma: a randomized study comparing two schedules. A study of the EORTC Soft Tissue and Bone Sarcoma Group. Cancer. 1984 May 1;53(9):1825-32.

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SARCOMA: Ewing's (ANZ CCSG Protocol) (Use also for PNET Tumours) Vincristine Cyclophosphamide Doxorubicin Ifosfamide Etoposide Mesna 1.5mg/m2 IV Day 1, 22 1200mg/m2 IV Day 1, 22 30mg/m2 IV Day 1,2 22,23 (vesicant) 1.8gm/m2/day IV over 1 hour D 43,44,45,46,47 100mg/m2/day IV D 43,44,45,46,47 360mg/m2 IV over 1 hour combined with mesna, then 600mg/IL IV over 3 hours, then 400mg over 2 hours 400mg over 3 hours 400mg over 3 hours (Repeat every 9 weeks) After 2 or 3 cycles Give with concomitant radiotherapy Use vincristine and cyclophosphamide without doxorubicin then Ifos, Etoposide, Mena x 2 at 3 weekly intervals during the RT. SARCOMA: (Osteogenic) (Refer to Womens and Childrens for latest protocol) SARCOMA: (Rhabdomyosarcoma) (Refer to Womens and Childrens for latest protocol)

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SKIN CANCER (Non Melanoma): Cisplatin 5-Fluorouracil 100mg/m2/day IV over 2 hours 1g/m2/day continuous x 5 days (Repeat every 3 weeks)

delayed emesis protocol for cisplatin hydration pre and post-cisplatin fluid balance chart ensure creatinine clearance > 60ml/min check magnesium and potassium levels note U&Es, LFT, CBE and diff caution using gentamicin concomitantly with cisplatin

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TESTICULAR CANCER: First Line: PEB Cisplatin

Etoposide Bleomycin with steroid pre-med Restage every 2nd cycle Bleomycin can be given IM if given as outpatient See precautions with pulmonary toxicity - section 1.8. and also pulmonary function tests every 2 cycles delayed emesis protocol for cisplatin hydration pre and post-cisplatin fluid balance chart ensure creatinine clearance > 60ml/min check magnesium and potassium levels note U&Es, LFT, CBE and diff caution using gentamicin concomitantly with cisplatin Minimum 3 cycles first line If CR on radiology and normal markers, stop. If markers still elevated, then change to second line. If residual disease and normal markers, then surgical resection unless still responding after 4 cycles continue to 6. If persistent disease is found at surgery then further 2 cycles of second line chemotherapy should be given.
Reference: Einhorn LH, Williams SD, Loehrer PJ, Birch R, Drasga R, Omura G, Greco FA. Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol. J Clin Oncol. 1989 Mar;7(3):387-91.

100mg/m2 IV days 1 - ( repeat every 3 weeks) Or (20mg/m2 IV days 1-5 (an alternative way of giving the cisplatin) Give with 1 litre of saline 100mg/m2 IV over 1 hour days 1-5 (repeat every 3 weeks) 30u IV day 1 -( repeat weekly for 10 doses) i.e stop bleomycin at 300u

Second Line: V.I.P Cisplatin Vinblastine Ifosfamide Mesna

20mg/m2 IV days 1-5 6mg/m2 IV days 1,2 1.2g/m2 IV days 1-5 with 400mg/m2 day 1 (pre Ifosfamide) then 1.2g/m2 IV per day continuous for 5 days until 12 hours after ifosfamide has ceased. (repeat every 3 weeks)

Reference: Loehrer PJ Sr, Gonin R, Nichols CR, Weathers T, Einhorn LH. Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol. 1998 Jul;16(7):2500-4.

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(If vinblastine was used first line use Etoposide 75mg/m2 IV over 1 hour days 1-5)
Reference: Loehrer PJ Sr, Einhorn LH, Williams SD. VP-16 plus ifosfamide plus cisplatin as salvage therapy in refractory germ cell cancer. J Clin Oncol. 1986 Apr;4(4):528-36.

Neoadjuvant PEBx2 Vascular invasion Choriosarcoma Invasion beyond capsule Invasion of cord Extragonadal primary

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UNKNOWN PRIMARY: First Line: CAP Cyclophosphamide Doxorubicin Cisplatin Administer every 3 weeks 500 mg/m2 IV day 1 50 mg/m2 IV day 1 (vesicant) 60 mg/m2 IV day 1

Reference: Bedikian AY, Bodey GP, Valdivieso M, Burgess MA. Sequential chemotherapy for adenocarcinoma of unknown primary. Am J Clin Oncol. 1983 Apr;6(2):219-24.

Women with axillary nodes should be treated as breast cancer Young males should be treated with PEB as testicular cancer Women with peritoneal disease should be treated as ovarian cancer If a GI primary site is most likely consider 5FU/leucovorin 5 Fluorouracil Leucovorin Administer weekly 500 mg/m2 IV bolus 1 hour after 20 mg/m2 IV

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CLINICAL TRIALS SECTION THREE

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BLADDER: (1) Phase II Randomised trial of Gemcitabine and Docetaxel vs Gemcitabine and Carboplatin in recurrent or metastatic TCC of the Urothelium Gemcitabine and Docetaxel arm Gemcitabine 1,200mg/m2 on Day 1and 8 as a 30 minute infusion Docetaxel 85mg/m2 on day 8 as 1 hour infusion prior to gemcitabine Repeated every 21 days for a maximum of 8 cycles Gemcitabine and Carboplatin arm Gemcitabine 1,000mg/m2 on Day 1and 8 as a 30 minute infusion Carboplatin AUC5 given as a 1 hour infusion at AUC5 Repeated every 21 days for a maximum of 8 cycles

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BREAST: (Adjuvant) (1) A Multicenter Phase III Randomized Trial comparing Docetaxel in combination with Doxorubicin and Cyclophosphamide (TAC) versus Doxorubicin and Cyclophosphamide followed by Docetaxel (ACT) as Adjuvant Treatment of Operable Breast Cancer Her2neu Negative Patients with Positive Axillary Nodes (BCIRG 005) TAC regimen: Doxorubicin 50mg/m2 administered iv over 15 min Cyclophosphamide 500mg/m2 administered iv over 5 to 60 minutes Docetaxel 75mg/m2 administered iv over one hour Every 3 weeks for 6 cycles. ACT combination: Doxorubicin 60mg/m2 administered iv over 15 minutes. Cyclophosphamide 600mg/m2 administered iv over 5 minutes to 60 minutes Three weeks after the 4th cycle Docetaxel 100mg/m2 administered iv over 1 hour for another 4 cycles ie every 3 weeks. (2) Multicenter Phase III Randomised Trial comparing Doxorubicin and Cyclophosphamide followed by Docetaxel (ACT) with Doxorubicin and Cyclophosphamide followed by Docetaxel and Trastuzumab (ACTH) and with Docetaxel, Platinum salt and Trastuzumab (TCH) in the Adjuvant Treatment of Node Positive and High Risk Node Negative Patients with Operable Breast Cancer containing the Her2neu Alteration (BCIRG 006) ACT combination: Doxorubicin 60mg/m2 administered iv (intravenous, into the vein) over 15 minutes. Cyclophosphamide 600mg/m2 administered iv over 5 to 60 minutes Three weeks after the 4th cycle: Docetaxel 100mg/m2 administered iv over 1 hour for another 4 cycles ie every 3 weeks. ACTH combination: Doxorubicin 60mg/m2 administered iv (intravenous, into the vein) over 15 minutes. Cyclophosphamide 600mg/m2 administered iv over 5 to 60 minutes Three weeks after the 4th cycle patient receives the Docetaxel/ Trastuzumab (TH) segment: First cycle of TH: Day 1: Trastuzumab 4 mg/kg administered iv over 90 minutes. Day 2: Docetaxel 100 mg/m2 administered iv over 1 hour. Day 8: Trastuzumab 2 mg/kg administered iv over 30 minutes. Day 15: Trastuzumab 2 mg/kg administered iv over 30 minutes. Subsequent cycles: Day 1: Docetaxel 100 mg/m2 administered iv over 1 hour followed by Trastuzumab 2 mg/kg administered iv over 30 minutes. Day 8: Trastuzumab 2 mg/kg administered iv over 30 minutes. Day 15: Trastuzumab 2 mg/kg administered iv over 30 minutes.
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Following completion of the 4 cycles of TH, Trastuzumab will continue weekly for one years treatment, in total. TCH combination: First cycle of TCH: Trastuzumab 4 mg/kg administered iv over 90 minutes. Day 1: Docetaxel 75 mg/m2 administered iv over 1 hour followed immediately by either Day 2: carboplatin at target AUC = 6 mg/mL/min administered iv over 30-60 minutes Day 8: Trastuzumab 2 mg/kg administered iv over 30 minutes. Trastuzumab 2 mg/kg administered iv over 30 minutes. Day 15: Subsequent cycles: Docetaxel 75 mg/m2 administered iv over 1 hour followed immediately by Day 1: carboplatin at target AUC = 6 mg/mL/min administered iv over 30-60 minutes followed by Trastuzumab 2 mg/kg administered iv over 30 minutes. Trastuzumab 2 mg/kg administered iv over 30 minutes. Day 8: Trastuzumab 2 mg/kg administered iv over 30 minutes. Day 15: Following completion of the 6 cycles of TCH, Trastuzumab will continue weekly for one years treatment, in total. BREAST (Advanced) (1) A multicentre phase III randomised clinical trial comparing docetaxel (Taxotere) and trastuzumab (Herceptin) TH with docetaxel (Taxotere), platinum salt (cisplatin or carboplatin), and trastuzumab (Herceptin) TCH as first line chemotherapy for patients with advanced breast cancer containing the HER2 gene amplification. BCIRG 007 First cycle of TH Day 1: Herceptin 4 mg/kg IV over 90 minutes. Day 2: Taxotere 100 mg/m2 IV over 1 hour. Day 8: Herceptin 2 mg/kg IV over 30 minutes. Herceptin 2 mg/kg IV over 30 minutes. Day 15: Day 1 of Cycle 2 Day 22: Subsequent cycles (to start 3 weeks after Day 1 of 1st cycle) Day 1: Taxotere 100 mg/m2 IV over 1 hour on day 1 every 3 weeks, followed by Herceptin 2 mg/kg IV over 30 minutes Day 8: Herceptin 2 mg/kg IV over 30 minutes. Herceptin 2 mg/kg IV over 30 minutes. Day 15: Day 22: Day 1 of future cycles. Following completion of the 8 cycles of Taxotere, Herceptin will continue every 3 weeks at a dose of 6 mg/kg IV over 30 minutes. First cycle of TCH: Day 1: Herceptin 4 mg/kg IV over 90 minutes. Day 2: Taxotere 75 mg/m2 IV over 1 hour followed immediately by carboplatin at target AUC = 6 mg/mL/min IV over 30-60 minutes. Day 8: Herceptin 2 mg/kg IV over 30 minutes. Herceptin 2 mg/kg IV over 30 minutes. Day 15: Day 1 of Cycle 2. Day 22:
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Subsequent cycles (to start 3 weeks after Day 1 of 1st cycle): Taxotere 75 mg/m2 IV over 1 hour followed immediately by carboplatin at target Day 1: AUC = 6 mg/mL/min IV over 30-60 minutes followed by Herceptin 2 mg/kg IV over 30 minutes. Day 8: Herceptin 2 mg/kg IV over 30 minutes. Herceptin 2 mg/kg IV over 30 minutes. Day 15: Day 1 of future cycles. Day 22: Following completion of the 8 cycles of Taxotere/platinum salt, Herceptin will continue every 3 weeks at a dose of 6 mg/kg by IV over 30 minutes. (2) Assessment of Parameters of Response to combined modality treatment of locally advanced breast cancer: Chemotherapy ECF x 6 course 5-Fluorouracil 200 mg/m2 continuous ambulatory infusion via an infusaport and portable pump Epirubicin 50mg/m2 IV every 3 weeks Cisplatin 60mg/m2 IV every 3 weeks with IV hydration and mannitol Radiotherapy to follow within 1 month of chemotherapy Surgery to follow Evaluation pretreatment after 3 and 6 courses of chemotherapy then post radiotherapy are mammogram, breast ultrasound (including Doppler assessment) breast MRI with gadolinium enhancement and sesta-mibi scan. (3) A phase II study of prolonged ambulatory infusion 5-Fluorouracil as salvage therapy after previous intensive myelosuppressive chemotherapy for metastatic breast cancer. 5-Fluorouracil 300mg/m2/day Via a Cormed III infusion pump through an infusaport.

(4) Randomized Phase II Trial of Gemcitabine Combined with Taxane for Metastatic Breast Cancer Study B9E-MC-S197 Arm A: Paclitaxel as a 3 hour infusion at a dose of 175mg/m2 followed by Gemcitabine as a 30 minute infusion at a dose of 1250mg/m2 on Day 1 every 3 weeks Arm B: Paclitaxel as a 60 minute infusion at a dose of 100mg/m2 followed by Gemcitabine as a 30 minute infusion at a dose of 1000m2 on days 1 and 8 every 3 weeks. Arm C: Docetaxel as a 60 minute infusion at a dose of 40mg/m2 followed by Gemcitabine as a 30 minute infusion at a dose of 1000m2 on days 1 and 8 every 3 weeks.

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COLORECTAL (1) Pilot study of SIR-Spheres plus chemotherapy with either 5-fluorouracil, leucovorin and irinotecan, or irinotecan alone in patients with non-resectable liver metastases from primary adenocarcinoma of large bowel. The chemotherapy treatment regimen used will depend on whether patients either have, or have not, already received chemotherapy for established metastatic colorectal cancer. Adjuvant chemotherapy with FU/LV following resection of the primary colorectal cancer is not regarded as treatment of metastatic colorectal cancer, unless the diagnosis of metastatic colorectal cancer was made while the patient was either actively receiving, or had received within the previous 3 months, adjuvant FU/LV Protocol Chemotherapy for patients NOT PREVIOUSLY TREATED with FU/LV. Patients not previously treated with FU/LV for metastatic colorectal cancer should begin treatment as soon as possible, and not greater than 28 days after trial entry. The treatment regimen requires that patients will receive chemotherapy once per week for 4 weeks and repeated each 6 weeks. For the purposes of this protocol one chemotherapy cycle is defined as the administration of chemotherapy (either single or triple drug) during a six week period. GROUP ONE (3 PATIENTS) Chemotherapy Cycles; Patients will receive 5FU (500mg/m2 IV bolus) plus leucovorin (20mg/m2 IV bolus) plus irinotecan 25mg/m2 IV infused over a 90minute period weekly for 4 weeks and repeated every 6 weeks. From cycle three onwards, the irinotecan dose may be increased up to a maintenance dose of 100mg/m2 IV for 4 weeks every 6 weeks, provided the toxicity profile allows, and until an event as listed in 7.4.3 occurs. SIR-Spheres (at the calculated patient dose) are implanted 1 day after the first day of administration of chemotherapy in Cycle one. Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 CS C C C GROUP TWO (3 PATIENTS) Treatment of patients in Group Two will begin at not less than 4 weeks after the entry of the third patient in Group One. If the toxicity profile of the 3 patients treated in Group One is acceptable, then the treatment regimen for the 3 patients in Group Two will be as for Group One but with the dose of irinotecan increased to 50mg/m2. GROUP THREE (3 PATIENTS) Treatment of patients in Group Three will occur at not less than 4 weeks after the entry of the third patient in Group Two. If the toxicity profile of the 3 patients treated in Group Two is acceptable, then the treatment regimen for the 3 patients in Group Three will be as for Group One but with the dose of irinotecan increased to 75mg/m2. GROUP FOUR (3 PATIENTS) Treatment of patients in Group Four will occur at not less than 4 weeks after the entry of the third patient in Group Three. If the toxicity profile of the 3 patients treated in Group Three is acceptable, then the treatment regimen for the 3 patients in Group Four will be as for Group One but with the dose of irinotecan increased to 100mg/m2.
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Protocol Chemotherapy for patients PREVIOUSLY TREATED with FU/LV. Patients who have been previously treated with FU/LV for established metastatic disease and have failed treatment will be treated with irinotecan as the sole chemotherapy drug. Treatment should begin as soon as possible, and not greater than 28 days after trial entry. GROUP ONE (3 PATIENTS) Chemotherapy Cycles; Patients will receive irinotecan 50mg/m2 IV infused over a 90 minute period weekly for 4 weeks and repeated every 6 weeks. From cycle three onwards, the irinotecan dose may be increased up to a maintenance dose of 100mg/m2 IV for 4 weeks every 6 weeks, provided the toxicity profile allows, and until an event as listed in 7.4.3 occurs. SIR-Spheres (at the calculated patient dose) are implanted one day after the first day of administration of chemotherapy in Cycle one. Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 CS C C C GROUP TWO (3 PATIENTS) Treatment of patients in Group Two will occur at not less than 4 weeks after the entry of the third patient in Group One. If the toxicity profile of the 3 patients treated in Group One is acceptable, then the treatment regimen for the 3 patients in Group Two will be as for Group One but with the dose of irinotecan increased to 75mg/m2. GROUP THREE (3 PATIENTS) Treatment of patients in Group Three will occur at not less than 4 weeks after the entry of the third patient in Group Two. If the toxicity profile of the 3 patients treated in Group Two is acceptable, then the treatment regimen for the 3 patients in Group Three will be as for Group One but with the dose of irinotecan increased to 100mg/m2. Ancillary Protocol Treatment Patients will receive oral tabs of Zantac 150mg bd, or 300mg daily, for a period of four weeks after implantation of SIR-Spheres. This is recorded in the concomitant medication section of the CR (2) A clinical trial comparing 5-FU plus LV and oxaliplatin with 5-FU plus LV for the treatment of patients with stage II and III carcinoma of the colon 5-FU + LV (FL) LV 500 mg/m2 by IV infusion over 2 hours; 5-FU 500 mg/m2 will be given by IV bolus 1 hour after LV infusion has begun. Treatment will be given weekly for 6 weeks (on days 1, 8, 15, 22, 29, 36) followed by a rest period. Repeat treatment begins 21 days after the date of administration of the last administered dose of the previous cycle (one cycle = 8 weeks). A total of 3 cycles will be administered. Chemotherapy should begin within 1 week from randomization. 5-FU + LV and Oxaliplatin (FLOX) LV 500 mg/m2 by IV infusion over 2 hours; 5-FU 500 mg/m2 will be given by IV bolus 1 hour after LV infusion has begun. LV and 5-FU will be given weekly for 6 weeks (on days 1, 8, 15, 22, 29, 36) followed by a rest period. Oxaliplatin 85 mg/m2 will be given weeks 1, 3 and 5 (days 1, 15, and 29) as a 2-hour infusion before the LV and 5-FU infusion. Repeat treatment begins 21 days after
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the date of administration of the last administered dose of the previous cycle (one cycle = 8 weeks). A total of 3 cycles will be administered. Chemotherapy should begin within 1 week from randomization.

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HEAD AND NECK: (1) A phase II study of concurrent radiotherapy and prolonged ambulatory infusion carboplatin in squamous cell carcinoma of the head and neck RT 60-66 Gy CTD in 30-33 at 5 fractions per week with Carboplatin 28mg/m2/24 hours as a prolonged ambulatory infusion via an infusion pump commencing immediately prior to the first dose of radiation.

(2) TROG 98.02 Randomised Phase II study of Two different strategies for chemoradiation of advanced SCC of the head and neck Arm 1 Radical radiotherapy with Cisplatin 50 mg/m2 before radiotherapy on D1 of week 6 and 7 5FU 360mg/m2/day by continuous IV infusion from D1 D5 (120 hour infusion) of weeks 6 and 7. Arm 2 Cisplatin 75mg/m2 before radiotherapy on D2 of weeks 1, 4 and 7 Tirapazamine *290mg/m2 before each cisplatin dose *160mg/m2 before radiotherapy on D1, D3, D5 of weeks 2 and 3 (3) A Prospective, Single-Blinded Randomised Trial Of Radiation Therapy With Or Without Amifostine For Radiation-Induced Xerostomia In Patients With Head And Neck Cancer Arm 1: Amifostine 200 mg / m2 + Radiation Therapy (1.8-2.0gy) 5 days a week for 6-7 weeks Arm 2: Placebo (normal saline 200mg / m2 ) + Radiation Therapy (1.8-2.0gy) 5 days a week for 6-7 weeks

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LUNG: Non Small Cell: (1) An Open-Label, Multicentre, Randomised, Phase III Study Comparing Oral Topotecan to Intravenous Docetaxel in Patients with Pretreated Advanced Non-Small Cell Lung Cancer Topotecan PO 2.3mg/ m2 /day on days 1-5 every 3 weeks Or Docetaxel IV 75mg/ m2 /day on day 1 every 3 weeks

(2) A Randomized Placebo Controlled Study Of Osi-774 In Patients With Incurable Stage IIIB/IV Non-Small Cell Lung Cancer Who Have Failed Standard Therapy For Advanced Or Metastatic Disease OSI-774 150mg daily Or Placebo 150mg daily

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LYMPHOMA: (1) A Phase II study of Idarubicin Based Combined Modality therapy in Primary CNS Lymphoma Idarubicin 20mg/m2 on Day 1 and 22 Methotrexate 1gm/m2 on Day 15, 36 and 50

Radiotherapy commences on day 64 (30gy in 20 fractions)

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MELANOMA: (1) A Phase II Study Of IV Vinflunine In Patients With Chemotherapy Nave Metastatic Malignant Melanoma Vinflunine as a 10 minute infusion at a dose of 320mg/m2 every 3 weeks. Continued until disease progression.

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SUPPORTIVE CARE & MISCELLANEOUS

(1) MUCOSITIS: A study to investigate the onset, duration and severity of histological changes of oral mucositis in humans with cytotoxic chemotherapy for cancer.

(2) END OF LIFE ISSUES End of life issues: Assessing the views of patients with cancer in the final phase of their illness (3) BONE METASTASES A study to evaluate patient safety and preference following 3-4 weekly intravenous Zometa (zoledronic acid) administration in hospital clinics or at home in cancer patients commencing bisphosphonate treatment for osteolytic/osteoblastic metastases Zometa 4 mg as a 15-minute intravenous infusion every 3-4 weeks over a 48-50 week period in either the hospital clinic or home setting. One dose of Aredia 9Omg as a 2-4 hour infusion in the hospital clinic setting. (4) ZEST Study A double-blind, placebo-controlled trial of Zolofts effects on symptoms and survival time in advanced cancer ARM A. Sertraline 50mg tablets One tablet once a day by mouth. ARM B. Placebo One sertraline placebo once a day by mouth.

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UNKNOWN PRIMARY (1) A Phase II Study Of Gemcitabine And Carboplatin As Treatment For Patients With Metastatic Carcinoma Of Unknown Primary Site Gemcitabine 1 gm m2 as a 30 minute infusion on days 1 and 8, with Carboplatin administered in a AUC5 over one hour on day 8, with treatment repeated on a three weekly basis.

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PHARMACOKINETIC SAMPLING Collect 10ml (or volume required) in tube supplied by Data Manager or as a general rule, heparinised green top tube without separator gel for plasma, white top tube for serum. Centrifuge immediately or if kept on ice within 30 minutes. Ensure centrifuge is turned on, place tube in machine. Always remember to counteract weight with another tube place in the opposite position. Close lid to centrifuge. Set speed to 70 and turn time to 10 minutes. Remove tube when centrifuge has completely stopped. Using the pipette supplied, tilt tube and while avoiding red cells carefully transfer plasma or serum into plain Nunc freezer tube (supplied by Data manager). Label Nunc tube thoroughly (i.e. Initials, date and time and protocol number) then freeze. Labels will be provided by Data Manager. The labels will be less likely to fall off the frozen tubes if they are able to overlap when wrapped around the tube and/or covered with a piece of clear adhesive tape that runs completely around the tube. All samples stored in -80 freezer ( in plastic bag provided)

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SERIOUS ADVERSE EVENTS All serious adverse events whether causally related to treatment or not, must be notified immediately. The investigator is obligated to report any serious adverse event within 24 hours and to submit a written report within 72 hours to the sponsoring drug company and also to the RAH Research Ethics committee. Serious events include:1. All deaths 2. Life threatening events 3. Events which are disabling or incapacitating 4. Events which require or prolong hospitalisation. 5. Any congenital anormaly of cancer or drug overdose 6. Serious laboratory abnormality directly associated with relevant clinical signs or symptoms. In the event of any of the above please notify the Data Managers Office on Ext 24765, 25637 or 24358. The Data Manager will then initiate the appropriate notification. Clinical Trials patient casenotes are readily identified by the pink sticker on the left hand corner.

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