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Hodgkin lymphoma ABVD (DOXOrubicin bleomycin vinBLASTine dacarbazine) advanced stage

Patients with lymphoma should be considered for inclusion into clinical trials. Link to ALLG website, ANZCTR website and Lymphoma Australia website.

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Cycle 1 to 6

Drug Dose Route Day
DOXOrubicin 25 mg/m2 IV 1 and 15
vinBLASTine 6 mg/m2 IV 1 and 15
Dacarbazine 375 mg/m2 IV infusion 1 and 15
Bleomycin 10,000 International Units/m2 IV 1 and 15
Frequency:
28 days 
Cycles:
6. Unless disease progression or unacceptable toxicity.
Notes:
  • Do not delay treatment, irrespective of blood count as keeping to the protocol schedule and maintaining dose intensity is very important for treatment outcome.r
  • DOSE EQUIVALENCE: 1,500 International Units of bleomycin are equivalent to 1.5 USP units and approximately equivalent to 1.5 mg (by potency) or 1 mg (by weight).r
  • Protocols that give bleomycin in mg or mg/m2 refer to mg potency not mg weight.r
  • Growth factor support is not routinely required unless there are treatment delays (due to sepsis etc.), because it may increase the risk of bleomycin induced pulmonary toxicity. Monitor patients closely for signs of pulmonary toxicity if the combination is used.r
  • Bleomycin can be omitted in patients who are PET 2 negative (at the discretion of the treating physician).r
  • There is an increased risk of bleomycin toxicity in patients > 60yrs of age and careful monitoring and early cessation should be considered for this group.
Drug status:

Doxorubicin, bleomycin and vinblastine are on the PBS general schedule

Dacarbazine is TGA approved but not PBS reimbursed

Cost:
~ $550 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes antineoplastic drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many antineoplastic drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 to 6

Day 1
Netupitant 300 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with palonosetron) 
Palonosetron 0.5 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone 12 mg (PO) 60 minutes before chemotherapy
DOXOrubicin 25 mg/m2 (IV) over 5 to 15 minutes
vinBLASTine 6 mg/m2 (IV) in 50 mL sodium chloride 0.9% over 5 to 10 minutes
Dacarbazine 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 60 minutes
Bleomycin 10,000 International Units/m2 (IV) in 5 mL to 10 mL sodium chloride 0.9% over 10 minutes
Day 2 to 4
Dexamethasone 8 mg (PO) ONCE a day with or after food (or in divided doses). Note: dexamethasone 8mg doses may not be required and may be reduced or omitted at the clinician's discretion. *
Day 15
Netupitant 300 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with palonosetron) 
Palonosetron 0.5 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone 12 mg (PO) 60 minutes before chemotherapy
DOXOrubicin 25 mg/m2 (IV) over 5 to 15 minutes
vinBLASTine 6 mg/m2 (IV) in 50 mL sodium chloride 0.9% over 5 to 10 minutes
Dacarbazine 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 60 minutes
Bleomycin 10,000 International Units/m2 (IV) in 5 mL to 10 mL sodium chloride 0.9% over 10 minutes
Day 16 to 18
Dexamethasone 8 mg (PO) ONCE a day with or after food (or in divided doses). Note: dexamethasone 8mg doses may not be required and may be reduced or omitted at the clinician's discretion. *

* Link to ID 7 Prevention of chemotherapy induced nausea and vomiting.

Notes:

  • Do not delay treatment, irrespective of blood count as keeping to the protocol schedule and maintaining dose intensity is very important for treatment outcome.r
  • Bleomycin can be omitted in patients who are PET 2 negative (at the discretion of the treating physician).r
  • There is an increased risk of bleomycin toxicity in patients > 60yrs of age and careful monitoring and early cessation should be considered for this group.

Frequency:
28 days 
Cycles:
6. Unless disease progression or unacceptable toxicity.

Cycle 1 to 6

Drug Dose Route Day
DOXOrubicin 25 mg/m2 IV 1 and 15
vinBLASTine 6 mg/m2 IV 1 and 15
Dacarbazine 375 mg/m2 IV infusion 1 and 15
Bleomycin 10,000 International Units/m2 IV 1 and 15
Frequency:
28 days 
Cycles:
6. Unless disease progression or unacceptable toxicity.
Notes:
  • Do not delay treatment, irrespective of blood count as keeping to the protocol schedule and maintaining dose intensity is very important for treatment outcome.r
  • DOSE EQUIVALENCE: 1,500 International Units of bleomycin are equivalent to 1.5 USP units and approximately equivalent to 1.5 mg (by potency) or 1 mg (by weight).r
  • Protocols that give bleomycin in mg or mg/m2 refer to mg potency not mg weight.r
  • Growth factor support is not routinely required unless there are treatment delays (due to sepsis etc.), because it may increase the risk of bleomycin induced pulmonary toxicity. Monitor patients closely for signs of pulmonary toxicity if the combination is used.r
  • Bleomycin can be omitted in patients who are PET 2 negative (at the discretion of the treating physician).r
  • There is an increased risk of bleomycin toxicity in patients > 60yrs of age and careful monitoring and early cessation should be considered for this group.
Drug status:

Doxorubicin, bleomycin and vinblastine are on the PBS general schedule

Dacarbazine is TGA approved but not PBS reimbursed

Cost:
~ $550 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes antineoplastic drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many antineoplastic drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 to 6

Day 1
Netupitant 300 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with palonosetron) 
Palonosetron 0.5 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone 12 mg (PO) 60 minutes before chemotherapy
DOXOrubicin 25 mg/m2 (IV) over 5 to 15 minutes
vinBLASTine 6 mg/m2 (IV) in 50 mL sodium chloride 0.9% over 5 to 10 minutes
Dacarbazine 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 60 minutes
Bleomycin 10,000 International Units/m2 (IV) in 5 mL to 10 mL sodium chloride 0.9% over 10 minutes
Day 2 to 4
Dexamethasone 8 mg (PO) ONCE a day with or after food (or in divided doses). Note: dexamethasone 8mg doses may not be required and may be reduced or omitted at the clinician's discretion. *
Day 15
Netupitant 300 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with palonosetron) 
Palonosetron 0.5 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone 12 mg (PO) 60 minutes before chemotherapy
DOXOrubicin 25 mg/m2 (IV) over 5 to 15 minutes
vinBLASTine 6 mg/m2 (IV) in 50 mL sodium chloride 0.9% over 5 to 10 minutes
Dacarbazine 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 60 minutes
Bleomycin 10,000 International Units/m2 (IV) in 5 mL to 10 mL sodium chloride 0.9% over 10 minutes
Day 16 to 18
Dexamethasone 8 mg (PO) ONCE a day with or after food (or in divided doses). Note: dexamethasone 8mg doses may not be required and may be reduced or omitted at the clinician's discretion. *

* Link to ID 7 Prevention of chemotherapy induced nausea and vomiting.

Notes:

  • Do not delay treatment, irrespective of blood count as keeping to the protocol schedule and maintaining dose intensity is very important for treatment outcome.r
  • Bleomycin can be omitted in patients who are PET 2 negative (at the discretion of the treating physician).r
  • There is an increased risk of bleomycin toxicity in patients > 60yrs of age and careful monitoring and early cessation should be considered for this group.

Frequency:
28 days 
Cycles:
6. Unless disease progression or unacceptable toxicity.
Venous access required

IV cannula (IVC) or central venous access device (CVAD) is required to administer this treatment.

Read more about central venous access device line selection
Hypersensitivity/infusion related reaction

High risk with bleomycin.

Note: a hypersensitivity reaction can occur with any dose of bleomycin, regardless of whether a test dose has been performed. The manufacturer recommends a test dose of bleomycin 1,000 to 5,000 International Units prior to the first and second bleomycin doses in all lymphoma patients.
Premedication

A corticosteroid may reduce severity of fever/chills related to bleomycin (note: dexamethasone/prednisolone is included as an antiemetic in this protocol); paracetamol may be used to reduce fever.
Emetogenicity HIGH

Suggested default antiemetics have been added to the treatment schedule, and may be substituted to reflect institutional policy.

Ensure that patients also have sufficient antiemetics for breakthrough emesis:

Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR

Prochlorperazine 10 mg PO or 12.5 mg IV every 6 hours when necessary.

Read more about preventing antineoplastic induced nausea and vomiting
Cumulative lifetime dose of doxorubicin

The total cumulative lifetime dose of doxorubicin is 450 to 500 mg/m2.

Reduce the total cumulative lifetime dose to 400 to 450 mg/m2 if elderly, prior mediastinal radiation, hypertensive cardiomegaly, concurrent therapy with high dose cyclophosphamide and some other cytotoxic drugs (e.g. dacarbazine, dactinomycin, etoposide, mitomycin, melphalan, vincristine and bleomycin).

Baseline clinical assessment, echocardiogram (ECHO) or gated heart pool scan (GHPS) and electrocardiogram (ECG) evaluation. Patients with normal baseline cardiac function (left ventricular ejection fraction (LVEF) > 50%) and low risk patients require LVEF monitoring when greater than 70% of anthracycline threshold is reached or if patient displays symptoms of cardiac impairment.

Read more about cardiac toxicity associated with anthracyclines
Pulmonary toxicity

Bleomycin has been associated with severe and life threatening respiratory complications. The total cumulative dose of bleomycin should NOT exceed 400,000 international units. The risk of pulmonary toxicity increases beyond a cumulative dose of 300,000 international units. Check the cumulative dose prior to each treatment.

The approach to pulmonary screening with bleomycin is variable and inconsistent. The Haematology Reference Committee recommends baseline pulmonary function assessment, then monitor as clinically appropriate. If significant or severe reduction in pulmonary function at baseline, it may be appropriate to reconsider the use of bleomycin.

Read more about pulmonary toxicity associated with antineoplastic drugs.
Growth factor support

Growth factor support is not routinely required unless there are treatment delays (due to sepsis etc.), because it may increase the risk of bleomycin induced pulmonary toxicity. Monitor patients closely for signs of pulmonary toxicity if the combination is used. 

G-CSF (short or long acting) is available on the PBS for chemotherapy induced neutropenia depending on patient factors and/or neutropenia risk. 

Access the PBS website
Peripheral neuropathy

Assess prior to each treatment. If a patient experiences grade 2 or greater peripheral neuropathy, a dose reduction, delay, or omission of treatment may be required; review by medical officer before commencing treatment.

Read more about peripheral neuropathy

Link to chemotherapy-induced peripheral neuropathy screening tool
Constipation

Prescribe prophylactic laxatives to prevent constipation related to the use of vinca alkaloids.
Tumour lysis risk

Assess patient for risk of developing tumour lysis syndrome.

Read more about prevention and management of tumour lysis syndrome.
Pneumocystis jiroveci pneumonia (PJP) prophylaxis

­

Read more about prophylaxis of pneumocystis jiroveci (carinii) in cancer patients
Antiviral prophylaxis

­

Read more about antiviral prophylaxis drugs and doses
Irradiated blood components

Irradiation of blood components is recommended.

Read more about the indications for the use of irradiated blood components
Blood tests

FBC, EUC, calcium, magnesium, phosphate, LDH and LFTs at baseline, and prior to each treatment or as clinically indicated.
Hepatitis B screening and prophylaxis

Routine screening for HBsAg and anti-HBc is recommended prior to initiation of treatment. Prophylaxis should be determined according to individual institutional policy.

Read more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy
Vaccinations

Live vaccines, including BCG, MMR, zoster and varicella vaccines, are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease.

Refer to the recommended schedule of vaccination for immunocompromised patients, as outlined in the Australian Immunisation Handbook.
Effects of cancer treatment on fertility

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive age prior to commencing treatment.

Read more about the effect of cancer treatment on fertility
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the antineoplastic regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences. Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Note: All dose reductions are calculated as a percentage of the starting dose

Haematological toxicity
ANC x 109/L (pre-treatment blood test)
0.5 to less than 1.0 Grade 3 to 4 haematological toxicity or sepsis is not an indication for dose reduction. Keeping to the protocol schedule and maintaining dose intensity is very important for treatment outcome.

Growth factor support is not routinely required unless there are treatment delays due to sepsis etc., only then consider support with G-CSF (filgrastim, lenograstim, lipegfilgrastim or pegfilgrastim) for subsequent cycles.
 
less than 0.5
Renal impairment
Creatinine clearance (mL/min)
30 to 50 Reduce bleomycin by 25%
less than 30 Consider omitting bleomycin
Hepatic impairment
Hepatic dysfunction
Mild Reduce doxorubicin and vinblastine by 25%
Moderate Reduce doxorubicin and vinblastine by 50% : dose reduction of dacarbazine may be required
Severe Omit doxorubicin, vinblastine and dacarbazine
Pulmonary toxicity
Bleomycin should be stopped if there is clinical evidence of pulmonary toxicity (cough, dyspnoea, basal crepitation) or when the DLCO is less than 30 to 35% of the pre-treatment value
Peripheral neuropathy
Grade 2 or more which is present at the start of the next cycle Dose reduce or omit vinblastine

References & Disclaimer

Bleomycin
  Interaction Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, contrast dye, frusemide, NSAIDs) Bleomycin toxicity may result from delayed clearance due to induced renal dysfunction; including when low doses used Avoid combination or monitor renal function and for increased bleomycin toxicity.
Administer bleomycin before cisplatin in regimens using the combination
Oxygen during anaesthesia Bleomycin causes sensitisation of lung tissue to oxygen If oxygen is required, the use of low concentration (e.g. 25%) is recommended.
Fluid replacement should be carefully monitored, with emphasis on administration of colloid rather than crystalloid, to avoid interstitial pulmonary oedema
Colony stimulating factors May increase the risk of bleomycin induced pulmonary toxicity, especially at higher doses; this has not been confirmed in clinical trials Monitor patients closely for signs of pulmonary toxicity if the combination is used
Dacarbazine
  Interaction Clinical management
CYP1A2 and 2E1 inducers (e.g. phenytoin, rifampicin etc.) Increased toxicity of dacarbazine metabolite possible due to hastened and/or higher percentage of dacarbazine activation Avoid combination or monitor closely for increased toxicity of dacarbazine metabolite
CYP1A2 and 2E1 inhibitors (e.g. abiraterone, amiodarone, ciprofloxacin, fluvoxamine, vemurafenib etc.) Reduced efficacy of dacarbazine possible due to inhibition of the conversion of dacarbazine to its active metabolite (which may also result in reduced clearance of dacarbazine as the parent compound) Avoid combination or monitor closely for decreased clinical response to dacarbazine; also, monitor for increased toxicity of dacarbazine as the parent compound
Sorafenib Increased toxicity of dacarbazine metabolite possible due to increased serum concentration (mechanism uncertain) Avoid combination or monitor closely for increased toxicity of dacarbazine metabolite
Fotemustine Fatal adult respiratory distress syndrome (ARDS) if administered sequentially An interval of one week should elapse between the last dose of fotemustine and the first day of dacarbazine treatment
Azathioprine, mercaptopurine Increased toxicity of these drugs possible due to inhibition of xanthine oxidase by dacarbazine Avoid combination or monitor closely for increased toxicity of azathioprine, mercaptopurine
Levodopa Reduced response to levodopa in treating parkinsonism (mechanism unknown) Adjust levodopa dose accordingly
Doxorubicin
  Interaction Clinical management
Cardiotoxic drugs (eg. bevacizumab, calcium channel blockers, propranolol, trastuzumab) Increased risk of doxorubicin-induced cardiotoxicity Avoid combination or monitor closely for cardiotoxicity
Cyclophosphamide Sensitises the heart to the cardiotoxic effects of doxorubicin; also, doxorubicin may exacerbate cyclophosphamide induced cystitis Monitor closely for cardiotoxicity and ensure adequate prophylaxis for haemorrhagic cystitis when combination is used
Glucosamine Reduced efficacy of doxorubicin (due to induction of glucose-regulated stress proteins resulting in decreased expression of topoisomerase II in vitro) The clinical effect of glucosamine taken orally is unknown. Avoid combination or monitor for decreased clinical response to doxorubicin
CYP2D6 inhibitors (e.g. SSRIs (esp. paroxetine), perhexiline, cinacalcet, doxepin, flecainide, quinine, terbinafine) Increased toxicity of doxorubicin possible due to reduced clearance Monitor for doxorubicin toxicity
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of doxorubicin possible due to reduced clearance Monitor for doxorubicin toxicity
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John's wort etc.) Reduced efficacy of doxorubicin possible due to increased clearance Monitor for decreased clinical response to doxorubicin
NK-1 antagonist e.g. aprepitant, fosaprepitant, netupitant
  Interaction Clinical management
Dexamethasone Increased effects/toxicity of dexamethasone due to inhibition of its metabolism via CYP3A4

Reduce dose of antiemetic dexamethasone by approximately 50% when adding a NK-1 antagonist. For protocols that already recommend a NK-1 antagonist, the dose reduction of antiemetic dexamethasone has already been taken into account.

If dexamethasone is part of the chemotherapy protocol, dose reduction as per the product information is not routinely recommended in clinical practice and no additional dexamethasone is required for antiemetic cover. 
Warfarin

Reduced anticoagulant efficacy of warfarin due to increased clearance (aprepitant induces CYP2C9). *Note interaction only applicable to aprepitant/ fosaprepitant

INR should be monitored in the 2 week period, particularly at 7 to 10 days following the administration of aprepitant/ fosaprepitant
Combined oral contraceptive Reduced contraceptive efficacy due to increased clearance. *Note interaction only applicable to aprepitant/ fosaprepitant Alternative non-hormonal methods should be used during and for 1 month after stopping aprepitant/ fosaprepitant
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of NK-1 antagonist possible due to increased clearance Avoid combination or monitor for decreased antiemetic effect. Consider using an alternative antiemetic regimen
CYP3A4 inhibitors (e.g. azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of NK-1 antagonist possible due to reduced clearance Avoid combination or monitor for increased adverse effects of NK-1 antagonist (e.g. headache, hiccups, constipation)
Drugs metabolised by CYP3A4 (e.g. etoposide, imatinib, irinotecan, midazolam, paclitaxel, vinblastine, vincristine etc.) Increased effects/toxicity of these drugs possible due to inhibition of CYP3A4 by NK-1 antagonist Avoid combination or monitor for increased toxicity especially with orally administered drugs
Vinblastine
  Interaction Clinical management
CYP3A4 and P-gp inhibitors (e.g. amiodarone, aprepitant, azole-antifungals, ritonavir, lapatinib, nilotinib, sorafenib, macrolides, ciclosporin, grapefruit juice etc.) Increased toxicity of vinblastine possible due to reduced clearance Monitor for vinblastine toxicity (esp. neurotoxicity, adynamic ileus)
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of vinblastine possible due to increased clearance Monitor for decreased clinical response to vinblastine
Drugs undergoing P-gp-mediated elimination (e.g. dabigatran, loperamide, phenytoin etc.) Reduced efficacy of these drugs possible due to induction of P-gp by vinblastine resulting in increased clearance Avoid combination or monitor for decreased clinical response to interacting drugs
Mitomycin Increased risk of pulmonary toxicity when vinblastine administered following or concomitantly with mitomycin Avoid combination or monitor closely for pulmonary toxicity (i.e. interstitial infiltrates, pleural effusion resulting in respiratory distress and cough)
Ototoxic drugs (e.g. cisplatin, aminoglycosides, frusemide, NSAIDs) Additive ototoxicity (as reported with other vinca alkaloids) Avoid combination or perform regular audiometric testing
General
  Interaction Clinical management
Warfarin Antineoplastic agents may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

Interaction with both CYP3A4 and P-gp inhibitors /inducers.

DOAC and antineoplastic levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).

Apixaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. If treating VTE, avoid use with strong CYP3A4 and P‑gp inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 and P‑gp  inhibitors.

Dabigatran: avoid combination with strong P‑gp inducers and inhibitors.

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin Antineoplastic agents can damage the lining of the intestine; affecting the absorption of digoxin. Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics Both altered antiepileptic and antineoplastic levels may occur, possibly leading to loss of efficacy or toxicity. Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the antineoplastic therapy.
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia. Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update
Vaccines Diminished response to vaccines and increased risk of infection with live vaccines. Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Day 1 and 15

Approximate treatment time: 3 hours

General patient assessment prior to each day of treatment.

Peripheral neuropathy assessment tool

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

Prime IV line(s).

Insert IV cannula or access port or CVC.

  • weigh patient before each treatment 

Hydration if prescribed.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Doxorubicin

Administer doxorubicin (vesicant):
  • over 5 to 15 minutes
    • via a minibag OR
    • by IV bolus via a side port of a freely flowing IV infusion
  • ensure vein is patent and monitor for signs of extravasation throughout administration
  • flush with ~150 mL of sodium chloride 0.9%
  • potential for flare reaction during administration of doxorubicin (facial flushing and red streaking along the vein) stop infusion and exclude extravasation before continuing at a slower rate of infusion.

Although rare, cardiac arrhythmias may occur during or immediately after doxorubicin administration. If sudden onset of dyspnoea, palpitations or irregular pulse occurs, stop administration immediately and obtain urgent medical officer review.

Vinblastine

Administer vinblastine (vesicant):
  • over 5 to 10 minutes
    • via a minibag OR
    • by IV bolus via a side port of a freely flowing IV infusion
  • ensure vein is patent and monitor for signs of extravasation throughout administration
  • flush with ~150 mL of sodium chloride 0.9%.

Dacarbazine

Administer dacarbazine (irritant):
  • via IV infusion over 60 minutes
  • protect from light
  • flush with ~100 mL of sodium chloride 0.9%.

Too rapid an infusion of dacarbazine can lead to pain at the infusion site:

  • stop the infusion
  • ensure the drug has not extravasated
  • when patency has been confirmed, continue infusion at a slower rate and commence a concurrent infusion of 500 mL of sodium chloride 0.9%
  • consider administering dose in 1000 mL sodium chloride 0.9% for subsequent doses or insertion of a CVAD if severe pain persists.

Bleomycin 

Prior to administration:
  • test dose is recommended in lymphoma patients for the first two treatments. However, the usefulness of a test dose for predicting hypersensitivity reactions remains controversial. Refer to local policy for administration details 
  • premedication: if prescribed.
Administer bleomycin:
  • over 10 minutes
    • via a minibag OR
    • by IV bolus via a side port of a freely flowing IV infusion
  • flush with ~ 50 mL of sodium chloride 0.9%
  • hypersensitivity reaction can occur with any dose of bleomycin regardless of whether a test dose has been administered.

Remove IV cannula and/or deaccess port or CVC.

Continue safe handling precautions until 7 days after completion of drug(s)

Discharge information

Antiemetics
  • Antiemetics as prescribed.
Laxatives
  • Ensure patient has prophylactic laxatives.
Growth factor support
  • Arrangements for administration if prescribed.
Prophylaxis medications
  • Prophylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antivirals.
Patient information
  • Ensure patient receives patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Extravasation, tissue or vein injury

The unintentional instillation or leakage of a drug or substance out of a blood vessel into surrounding tissue. This has the potential to cause damage to affected tissue.

Read more about extravasation management
Flare reaction

Anthracycline flare reaction is caused by a localised allergic reaction. It is characterised by erythematous vein streaking, urticaria and pruritus which may occur during drug administration and is often associated with too rapid an infusion. Extravasation must be ruled out if flare occurs.
Red-orange discolouration of urine

Pink/red/orange discolouration of the urine. This can last for up to 48 hours after some anthracycline drugs.
Taste and smell alteration

Read more about taste and smell changes
Headache
Flu-like symptoms

Early (onset days to weeks)
Neutropenia

Abnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. 

Read more about neutropenia
Thrombocytopenia

A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding.  

Read more about thrombocytopenia
Oral mucositis

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following chemotherapy, radiotherapy to the head, neck or oesophagus, and high dose chemotherapy followed by a blood and marrow transplant (BMT).

Read more about oral mucositis
Constipation
Fatigue

Read more about fatigue
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Photosensitivity

Increased sensitivity to ultraviolet (UV) light resulting in an exaggerated sunburn-like reaction accompanied by stinging sensations and urticaria.
Peripheral neuropathy

Typically symmetrical sensory neuropathy, affecting the fingers and toes, sometimes progressing to the hands and feet.  It is associated with several classes of antineoplastic agents. These include taxanes, platinum-based compounds, vinca alkaloids and some drugs used to treat multiple myeloma.

Read more about peripheral neuropathy
Skin rash

Antineoplastic agents can cause a number of changes in the skin with maculo-papular rash the most common type of drug-induced skin reaction. 

Read more about skin rash

Late (onset weeks to months)
Anaemia

Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. 

Read more about anaemia
Cognitive changes (chemo fog)

Changes in cognition characterised by memory loss, forgetfulness and feeling vague. This is also referred to as 'chemo brain' or 'chemo fog'.

Read more about cognitive changes (chemo fog) 
Alopecia

Hair loss may occur from all parts of the body. Patients can also experience mild to moderate discomfort of the hair follicles, and rarely pain as the hair is falling out.

Read more about alopecia
Nail changes

Hyperpigmentation, paronychia, onycholysis, splinter haemorrhage, pyogenic granuloma formation, subungal haematoma and subungal hyperkeratosis are some of the nail changes associated with antineoplastic treatment.   

Read more about nail toxicities
Pulmonary toxicity

Pulmonary toxicity may include damage to the lungs, airways, pleura and pulmonary circulation.

Delayed (onset months to years)
Cardiotoxicity

Anthracyclines are the most frequently implicated antineoplastic agents associated with cardiotoxicity, which typically manifests as a reduction in left ventricular ejection fraction (LVEF), cardiomyopathy, or symptomatic CHF. Anthracycline induced cardiotoxicity has been categorised into acute, early-onset chronic progressive and late-onset chronic progressive and is usually not reversible. The risk of clinical cardiotoxicity increases with a number of risk factors including higher total cumulative doses. 

Read more about cardiac toxicity associated with anthracyclines

The combination of doxorubicin, bleomycin, vinblastine and dacarbazine for treatment of advanced Hodgkin lymphoma was first reported by Bonadonna et al.r ABVD was shown to be superior to the previous standard regimen, MOPP, alonerrr and less toxic than the MOPP/ABVD combination, with minimal infertility and reduced rates of secondary malignancy compared with radiation therapy (RT) or MOPP.r

A Cochrane meta-analysis in 2017r concluded that based on “moderate- to high-quality evidence that adult patients between 16 and 60 years of age with early unfavourable and advanced stage HL benefit regarding OS and PFS from first-line chemotherapy including escalated BEACOPP. The proven benefit in OS for patients with advanced HL is a new finding of this updated review due to the inclusion of the results from the EORTC 20012 trial. Furthermore, there is only low-quality evidence of a difference in the total number of secondary malignancies, as the follow-up period might be too short to detect meaningful differences. Low-quality evidence also suggests that people treated with escalated BEACOPP may have a higher risk to develop secondary AML or MDS. Due to the availability of only very low-quality evidence available, we are unable to come to a conclusion in terms of infertility. This review does, for the first time suggest a survival benefit. However, it is clear from this review that escalated BEACOPP may be more toxic than ABVD, and very important long-term side effects of second malignancies and infertility have not been sufficiently analysed yet".

Of note that studies using PET directed therapy were not included in the Cochrane review. Two important studies were published recently. In the RATHL study, 1129 patients have underwent interim PET-CT after 2 cycles of ABVD chemotherapyr. PET negative patients were randomised to ABVD or AVD, while PET positive patients were treated with 4 cycles of either BEACOPP-14 or escBEACOPP. Updated results presented at ICL-14r conference in 2017 showed that following a negative PET2, 952 pts were randomised to continue ABVD or AVD. With a median follow‐up of 52 months, PFS at 3 years for ABVD was 85.4% and for AVD 84.0%. Among 172 pts with a positive PET2, 5 year PFS was 65.7% and 5 year OS 85.1%. The primary outcome measure was the PFS rate among patients who were randomly assigned to continue or stop bleomycin after negative findings on an interim PET-CT scan; the aim was to exclude a difference of 5 percentage points at 3 years. The observed upper boundary of the 95% confidence interval (5.3 percentage points) was just over this margin, and this is probably due to the lower-than-expected 3-year PFS rate of 85.7% in the ABVD group, which would require more events to exclude a 5-percentage-point difference. The inclusion of bleomycin in the first two cycles may still make a positive contribution to the control of disease, but its omission after negative findings on an interim PET-CT scan carries a minimal risk of treatment failure, estimated in our trial to be 1.6%, and there was no significant difference in survival between the randomised groups. 

Efficacy

Evidence of the efficacy of ABVD in advanced stage Hodgkin lymphoma comes from several RCTs comparing ABVD with other regimens (see table). In these studies, complete remission (CR) rates range from 76-89% with 5 year overall survival (OS) 73-90%.

Study Trial Design Results for ABVD arm
n = CR FFS @ 5yrs PFS @ 5yrs OS @ 5yrs
Canellos (1992)r 6-8 x ABVD vs MOPP vs MOPP/ABVD; no RT 115 82% 61% - 73%
Chisesi (2002)r 6 x ABVD vs MEC vs Stanford V; ± RT 98 89.7% 81.4%* 91.5%* 94.7%*
Duggan (2003)r 8-10 x ABVD vs MOPP/ABV; no RT 433 76% 63% - 82%
Johnson (2005)r 6-8 x ABVD vs multidrug regimens; ± RT 262 68% - 75%* 90%*
Gobbi (2005)r 6 x ABVD vs mod Stanford V vs MOPPEBVCAD; ± RT 122 89% 78% 85% 90%
Federico (2009)r 6 x ABVD vs BEACOPP vs CEC; ± RT 99 84% 65% 68% 84%
Hoskin (2009)r 6-8 x ABVD vs Stanford V; ± RT 261 92%** - 76% 90%

* outcome percentages are at 3 years, not 5 years as the other studies summarised here
** overall response rate (CR + PR)

NB:
MOPP= mechlorethamine + vincristine + procarbazine + prednisone
Stanford V= doxorubicin + vinblastine + mechlorethamine + vincristine + bleomycin + etoposide + prednisone
MOPPEBVCAD= mechlorethamine + vincristine + procarbazine + prednisone + epidoxirubicin + bleomycin + vinblastine + lomustine + doxorubicin + vindesine
CEC (COPPEBVCAD)= cyclophosphamide + lomustine + vindesine + melphalan + prednisone + epidoxirubicin + vincristine + procarbazine + vinblastine + bleomycin
BEACOPP= bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone

ABVD is one of the two main international standard treatments for advanced stage Hodgkin lymphoma, the other being escalated BEACOPP (see link). 

Toxicity

ABVD causes Grade 3-4 neutropenia in 30-34% of patientsrr Despite this rates of significant infections are low (1-2% Grade 3-4).rr Evens et al demonstrated that G-CSF support is not required to maintain near 100% dose intensity during ABVD treatment.r In their study 58% of 658 ABVD treatments were administered with an ANC <1.0 x 109/L without an increase in infection (incidence rate, 0.44%) when compared with those given G-CSF (incidence rate, 0.78%). Other Grade 3-4 early toxicities include alopecia (24-30%),rr nausea and vomiting (6-13%)rr and pulmonary (6-10%).rr

Fertility is relatively preserved after ABVD. 30-54% of males experience transient oligo/azospermia however most fully recover.rr Transient amenorrhoea occurs in around one third of women of reproductive age (<45 years) but permanent amenorrhoea secondary to ABVD alone is uncommon.r Furthermore, female Hodgkin lymphoma survivors attempting pregnancy after ABVD had fertility comparable with case controls with a 12 month pregnancy rate of 70%.r

Although second malignancies occur in patients post-ABVD (6% at 6-10 years follow up) rates of secondary MDS/AML are very low and do not appear to be significantly increased.rrr Other long term toxicities include bleomycin-induced lung injury (link to Pulmonary toxicity associated with antineoplastic agents) and doxorubicin-related cardiac toxicity (link to Cardiac toxicity associated with anthracyclines). 

In the most recent Cochrane reviewr, authors concluded that: “The risk of secondary acute myeloid leukaemia and myelodysplastic syndrome (AML/MDS) is increased but efficacy is improved among patients treated with intensified chemotherapy protocols. Treatment decisions must be tailored for individual patients. Consolidating radiotherapy is associated with an increased rate of secondary malignancies; therefore it appears important to define which patients can safely be treated without radiotherapy after chemotherapy, both for early and advanced stages. For early stages, treatment optimisation methods such as use of fewer chemotherapy cycles and reduced field or reduced-dose radiotherapy did not appear to markedly affect efficacy or secondary malignancy risk. Due to the limited amount of long-term follow-up in this meta-analysis, further long-term investigations of late events are needed, particularly with respect to secondary solid tumours. Since many older studies have been included, possible improvement of radiotherapy techniques must be considered when interpreting these results.

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Version 6

Date Summary of changes
27/03/2020

Protocol presented and reviewed at the March 2020 Haematology Reference Committee meeting. 

  • Updated to 6 cycles, as standard practice
  • Notes added regarding bleomycin 
  • Evidence section updated

Version 5

Date Summary of changes
19/10/2006 Clarification of bleomycin equivalence doses
07/12/2007 Further clarification of bleomycin equivalence
20/05/2008 Clarification of belomycin administration; Review and addition of information to increase the comprehensiveness of the protocol
26/06/2008 Re-wording of administration of vesicants to the standardised format
25/01/2010 Removed recommendation to apply heat along vein to relieve pain caused by dacarbazine infusion as literature supports the use of both heat and cold.
25/01/2010 Review of dose modifications and transferred to eviQ
26/11/2010 Reviewed at Reference Committee meeting (RCM)
15/11/2011 New format to allow for export of protocol information
Protocol version number changed to V.2
Antiemetics and premedications added to the treatment schedule
Additional Clinical Information, Key Prescribing table and Key Administration table combined into new section titled Clinical Considerations
Drug specific information placed behind the drug name link
14/11/2011 PHC view added
18/12/2012 Old evidence removed, note added in the evidence section. Changes made as per RCM November 2010. 
18/12/2012 Republished on eviQ
11/10/2013

Reviewed at Haematology Reference Committee meeting (HRCM).
Evidence updated.
Emend changed from 125mg on day 1 and 80mg on day 2 & 3 to 165mg on day 1.
Protocol version number changed to V.3
PHC view removed
11/09/2015

Reviewed at HRCM: no major changes - links to HL Radiotherapy protocols and IPS document made.
09/03/2016 PJP prophylaxis preclin added to clinical considerations.
24/05/2016 Changed the order of Bleomycin and Dacarbazine in the treatment schedule and nursing admin sections to be in line with the correct order of administration.
29/08/2016 Changed the order of drugs in the treatment schedule summary and patient information sheet as per the ABVD acronym.
15/09/2016 Updated the volume of vinblastine to 50 mL in the treatment schedule.

31/05/2017

Transferred to new eviQ website. Version number changed to V.4.

Antiemetic change: Netupitant/palonosetron combination has replaced aprepitant and a 5HT3 receptor antagonist in combination with dexamethasone for all highly emetogenic regimens.
03/07/2018

Protocol reviewed and presented at the May 2018 eviQ Lymphoma and CLL Reference Committee meeting. Discussion continued over email and document approved for publication with the following changes: 

  • Removal of urinalysis in the administration section. 
  • Evidence section updated. 
  • Version change to V.5. 
11/07/2019

Potential drug interaction of bleomycin and G-CSF added to footnote under the treatment schedule and G-CSF clinical information block. 

Lung damage with bleomycin information reiterated in "Other information about your treatment" section of the patient information page. 

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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28 May 2020