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Hodgkin lymphoma BEACOPP escalated dose (bleomycin etoposide DOXOrubicin CYCLOPHOSPHamide vinCRISTine procarbazine prednisolone)

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

The anticancer drug(s) in this protocol may have been included in the ADDIKD guideline. Dose recommendations in kidney dysfunction have yet to be updated to align with the ADDIKD guideline. Recommendations will be updated once the individual protocol has been evaluated by the reference committee. For further information refer to the ADDIKD guideline. To assist with calculations, use the eviQ Estimated Glomerular Filtration Rate (eGFR) calculator.

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Cycle 1 to 6

Drug Dose Route Day
Prednisolone 40 mg/m2 ONCE a day PO 1 to 14
Procarbazine 100 mg/m2 ONCE a day PO 1 to 7
DOXOrubicin 35 mg/m2 IV 1
CYCLOPHOSPHamide 1,250 mg/m2 IV infusion 1
Etoposide * 200 mg/m2 IV infusion 1 to 3
Pegfilgrastim ** 6 mg Subcut 4
vinCRISTine 1.4 mg/m2 (Cap dose at 2 mg) IV infusion 8
Bleomycin 10,000 International Units/m2 IV 8

* Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg. Doses in this protocol are expressed as etoposide.

**Pegfilgrastim or equivalent G-CSF can be used. Monitor patients closely for signs of pulmonary toxicity as the combination of bleomycin and G-CSF may increase the risk of bleomycin induced pulmonary toxicity. 

Frequency:
21 days 
Cycles:
2 to 6
Notes:
  • 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
  • In the HD15 trial doses were capped at a BSA of 2.1 m2.
  • In the HD15/18 trial a steroid prephase (e.g. dexamethasone 40 mg daily) was given for 4 days prior to treatment in patients greater than age 40 and up to 7 days of steroids in younger patients was used to bridge the time to commencement of treatment.
  • It is the consensus of the Haematology reference committee that as treatment related mortality is more likely in the initial cycle consideration should be given to admission to hospital for the first cycle. If treatment is given in the ambulatory setting close monitoring is required.
  • Link to Dose de-escalation scheme for subsequent cycles.
  • PET-adapted approaches may be considered at the discretion of the treating haematologist.r See evidence section for more information.rrrr
Drug status:

Doxorubicin, cyclophosphamide, etoposide, bleomycin and prednisolone are on the PBS general schedule

Procarbazine: TGA registered for this indication but not PBS reimbursed

Pegfilgrastim: (PBS authority)

Procarbazine is available as 50mg capsules
Prednisolone is available as 25 mg, 5 mg and 1 mg tablets

Cost:
~ $1,340 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 anti-cancer 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 anti-cancer 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
Prednisolone 40 mg/m2 (PO) ONCE a day on days 1 to 14. Take in the morning with food.
Procarbazine 100 mg/m2 (PO) ONCE a day on days 1 to 7
DOXOrubicin 35 mg/m2 (IV) over 5 to 15 minutes
CYCLOPHOSPHamide 1,250 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
Etoposide 200 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 30 to 60 minutes
Day 2 and 3
Prednisolone 40 mg/m2 (PO) ONCE a day on days 1 to 14. Take in the morning with food.
Procarbazine 100 mg/m2 (PO) ONCE a day on days 1 to 7
Etoposide 200 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 30 to 60 minutes
Day 4
Prednisolone 40 mg/m2 (PO) ONCE a day on days 1 to 14. Take in the morning with food.
Procarbazine 100 mg/m2 (PO) ONCE a day on days 1 to 7
Pegfilgrastim 6 mg (Subcut) inject subcutaneously on day 4 at least 24 hours after day 3 IV etoposide administration.
Day 5 to 7
Prednisolone 40 mg/m2 (PO) ONCE a day on days 1 to 14. Take in the morning with food.
Procarbazine 100 mg/m2 (PO) ONCE a day on days 1 to 7
Day 8
Prednisolone 40 mg/m2 (PO) ONCE a day on days 1 to 14. Take in the morning with food.
vinCRISTine 1.4 mg/m2 (IV infusion) (Cap dose at 2 mg) in 50 mL sodium chloride 0.9% over 5 to 10 minutes

via minibag
Bleomycin 10,000 International Units/m2 (IV) in 5 to 10 mL sodium chloride 0.9% over ~ 10 minutes
Day 9 to 14
Prednisolone 40 mg/m2 (PO) ONCE a day on days 1 to 14. Take in the morning with food.

  • Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg. Doses in this protocol are expressed as etoposide. 
  • Pegfilgrastim or equivalent G-CSF can be used. 

Frequency:
21 days 
Cycles:
2 to 6

Cycle 1 to 6

Drug Dose Route Day
Prednisolone 40 mg/m2 ONCE a day PO 1 to 14
Procarbazine 100 mg/m2 ONCE a day PO 1 to 7
DOXOrubicin 35 mg/m2 IV 1
CYCLOPHOSPHamide 1,250 mg/m2 IV infusion 1
Etoposide * 200 mg/m2 IV infusion 1 to 3
Pegfilgrastim ** 6 mg Subcut 4
vinCRISTine 1.4 mg/m2 (Cap dose at 2 mg) IV infusion 8
Bleomycin 10,000 International Units/m2 IV 8

* Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg. Doses in this protocol are expressed as etoposide.

**Pegfilgrastim or equivalent G-CSF can be used. Monitor patients closely for signs of pulmonary toxicity as the combination of bleomycin and G-CSF may increase the risk of bleomycin induced pulmonary toxicity. 

Frequency:
21 days 
Cycles:
2 to 6
Notes:
  • 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
  • In the HD15 trial doses were capped at a BSA of 2.1 m2.
  • In the HD15/18 trial a steroid prephase (e.g. dexamethasone 40 mg daily) was given for 4 days prior to treatment in patients greater than age 40 and up to 7 days of steroids in younger patients was used to bridge the time to commencement of treatment.
  • It is the consensus of the Haematology reference committee that as treatment related mortality is more likely in the initial cycle consideration should be given to admission to hospital for the first cycle. If treatment is given in the ambulatory setting close monitoring is required.
  • Link to Dose de-escalation scheme for subsequent cycles.
  • PET-adapted approaches may be considered at the discretion of the treating haematologist.r See evidence section for more information.rrrr
Drug status:

Doxorubicin, cyclophosphamide, etoposide, bleomycin and prednisolone are on the PBS general schedule

Procarbazine: TGA registered for this indication but not PBS reimbursed

Pegfilgrastim: (PBS authority)

Procarbazine is available as 50mg capsules
Prednisolone is available as 25 mg, 5 mg and 1 mg tablets

Cost:
~ $1,340 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 anti-cancer 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 anti-cancer 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
Prednisolone 40 mg/m2 (PO) ONCE a day on days 1 to 14. Take in the morning with food.
Procarbazine 100 mg/m2 (PO) ONCE a day on days 1 to 7
DOXOrubicin 35 mg/m2 (IV) over 5 to 15 minutes
CYCLOPHOSPHamide 1,250 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
Etoposide 200 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 30 to 60 minutes
Day 2 and 3
Prednisolone 40 mg/m2 (PO) ONCE a day on days 1 to 14. Take in the morning with food.
Procarbazine 100 mg/m2 (PO) ONCE a day on days 1 to 7
Etoposide 200 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 30 to 60 minutes
Day 4
Prednisolone 40 mg/m2 (PO) ONCE a day on days 1 to 14. Take in the morning with food.
Procarbazine 100 mg/m2 (PO) ONCE a day on days 1 to 7
Pegfilgrastim 6 mg (Subcut) inject subcutaneously on day 4 at least 24 hours after day 3 IV etoposide administration.
Day 5 to 7
Prednisolone 40 mg/m2 (PO) ONCE a day on days 1 to 14. Take in the morning with food.
Procarbazine 100 mg/m2 (PO) ONCE a day on days 1 to 7
Day 8
Prednisolone 40 mg/m2 (PO) ONCE a day on days 1 to 14. Take in the morning with food.
vinCRISTine 1.4 mg/m2 (IV infusion) (Cap dose at 2 mg) in 50 mL sodium chloride 0.9% over 5 to 10 minutes

via minibag
Bleomycin 10,000 International Units/m2 (IV) in 5 to 10 mL sodium chloride 0.9% over ~ 10 minutes
Day 9 to 14
Prednisolone 40 mg/m2 (PO) ONCE a day on days 1 to 14. Take in the morning with food.

  • Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg. Doses in this protocol are expressed as etoposide. 
  • Pegfilgrastim or equivalent G-CSF can be used. 

Frequency:
21 days 
Cycles:
2 to 6
Safety alert vincristine administration

For safe administration of vincristine refer to the safety alert issued by the Australian Commission on Safety and Quality in Health Care
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
Caution with oral anti-cancer drugs

Select links for information on the safe prescribing, dispensing and administration of orally administered anti-cancer drugs. 

Read more about the COSA guidelines and oral anti-cancer therapy
Procarbazine oral administration

Procarbazine is a weak monoamine oxidase inhibitor (MAOI) and has the potential to interact with certain medications, alcohol and food. For further information see Interactions section of the protocol.
Hypersensitivity/infusion related reaction

High risk with bleomycin and etoposide.

Note: a hypersensitivity reaction can occur with any dose of bleomycin, regardless of whether a test dose has been performed.
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.
Antiemetics for multi-day protocols

Antiemetic therapy should be administered throughout the duration of the chemotherapy protocol and to cover delayed nausea. The acute and delayed emetic risk of multi-day chemotherapy protocols will overlap depending on the individual drugs and their sequence of administration. More or less antiemetic cover may be required. 

As a steroid has been included as part of this protocol, additional antiemetic steroids are not required.

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 every 6 hours when necessary.

Read more about preventing anti-cancer therapy induced nausea and vomiting
Cumulative lifetime dose of anthracyclines

Cumulative doses should take into account all previous anthracyclines received during a patient’s lifetime (i.e. daunorubicin, doxorubicin, epirubicin, idarubicin and mitoxantrone). 

Criteria for reducing the total anthracycline cumulative lifetime dose include:

  • patient is elderly
  • prior mediastinal radiation
  • hypertensive cardiomegaly
  • concurrent therapy with high dose cyclophosphamide and some other cytotoxic drugs (e.g. bleomycin, dacarbazine, dactinomycin, etoposide, melphalan, mitomycin and vincristine).

Baseline clinical assessments include 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 the anthracycline threshold is reached or if the patient displays symptoms of cardiac impairment. Post-treatment cardiac monitoring is recommended for patients who have received high levels of total cumulative doses of anthracyclines at the clinician's discretion.

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. Bleomycin should be stopped if there is clinical evidence of pulmonary toxicity (cough, dyspnoea, basal crepitation) or when the diffusing capacity for carbon monoxide (DLCO) is less than 30 to 35% of the pre-treatment value.

Read more about pulmonary toxicity associated with anti-cancer drugs.
Biosimilar drug

Read more about biosimilar drugs on the Biosimilar Awareness Initiative page
Peripheral neuropathy

Assess prior to each treatment. Based on clinical findings, temporary omission, dose reduction or cessation of the vinca alkaloid may be indicated; 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.
Etoposide conversion factor

Note: Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg.
Doses in this protocol are expressed as etoposide.
Corticosteroids

Diabetic patients should monitor their blood glucose levels closely. To minimise gastric irritation, advise patient to take immediately after food. Consider the use of a H2 antagonist or proton pump inhibitor if appropriate.

Read more about acute short term effects from corticosteroids
Tumour lysis risk

Assess patient for risk of developing tumour lysis syndrome.

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

­

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

­

Read more about antiviral prophylaxis drugs and doses
Growth factor support

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

Monitor patients closely for signs of pulmonary toxicity as the combination of bleomycin and G-CSF may increase the risk of bleomycin induced pulmonary toxicity. 

Access the PBS website
Irradiated blood components

The use of irradiated of blood components is recommended for patients receiving this treatment.

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

FBC, EUC, LFTs, LDH and BSL baseline, repeat FBC 2 to 3 times weekly during days 8 to 15 (expected nadir) and until recovery. Repeat EUC, LFTs, LDH and BSL regularly throughout treatment.
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 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.

Read more about COVID-19 vaccines and cancer.
Fertility, pregnancy and lactation

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive potential prior to commencing treatment. There is a risk of foetal harm in pregnant women. A pregnancy test should be considered prior to initiating treatment in females of reproductive potential if sexually active. It is important that all patients of reproductive potential use effective contraception whilst on therapy and after treatment finishes. Effective contraception methods and adequate contraception timeframe should be discussed with all patients of reproductive potential. Possibility of infant risk should be discussed with breastfeeding patients.

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 anti-cancer 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, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. 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.
The dose recommendations in kidney dysfunction (i.e.renal impairment) displayed may not reflect those in the ADDIKD guideline and have been included for historical reference only. Recommendations will be updated once the individual protocol has been evaluated by the reference committee, with this version of the protocol then being archived. Clinicians are expected to refer to the ADDIKD guideline prior to prescribing in kidney dysfunction.
International Consensus Guideline for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).

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

Haematological toxicity
  • The next cycle is not commenced unless the white cells are greater than 2.5 x 109/L or neutrophils greater than 1.5 x 109/L AND platelets greater than 80 x 109/L prior to restarting therapy.
  • If the critical values are not reached on the planned day of treatment continuation, therapy is postponed, and blood values should be tested again after 3, 7, 10 and 14 days.
  • Bleomycin and vincristine were to be administered even if leucopenia was observed on Day 8. However, if non-haematological events occur, consider omitting Day 8.
Dose de-escalation scheme

Link to Dose de-escalation scheme 

The dose de-escalation scheme is based upon the occurrence of toxic events in previous cycles. The dose in all following cycles will be reduced by one dose level should one or more toxic events occur in a given cycle.

Toxic events include:

  • leucopenia WHO Grade 4 for more than 4 days (leucocytes less than 1.0 x 109/L)
  • thrombocytopenia WHO Grade 4 on one or more days (platelets less than 25 x 109/L)
  • infection WHO Grade 4
  • other toxicity WHO Grade 4, e.g. mucositis
  • postponement of treatment for more than 2 weeks due to inadequate recovery of blood values.

If any toxic event occurs in 2 successive cycles, the following cycle is administered at baseline dose. Note: no reduction is made for treatment postponement of up to 2 weeks
  Dose (mg/m2)
Level Cyclophosphamide (Day 1) Doxorubicin (Day 1) Etoposide (Day 1 to 3)
4 (starting level) 1250 35 200
3 1100 35 175
2 950 35 150
1 800 35 125
Baseline 650 25 100
Renal impairment
Creatinine clearance (mL/min)
30 to 50 Reduce bleomycin by 25%
less than 30 Reduce bleomycin by 50% and cyclophosphamide by 25%; consider dose reduction of procarbazine
Hepatic impairment
Hepatic dysfunction
Mild Reduce doxorubicin and vincristine by 25%
Moderate Reduce doxorubicin and vincristine by 50%
Severe Omit doxorubicin and vincristine
Peripheral neuropathy
Grade 2 which is present at the start of the next cycle Reduce vincristine by 50%
Grade 3 Omit vincristine
Pulmonary Toxicity
Bleomycin should be stopped if there is clinical evidence of pulmonary toxicity (cough, dyspnoea, basal crepitation) or when the diffusing capacity for carbon monoxide (DLCO) is less than 30 to 35% of the pre-treatment value

Drug interactions in eviQ protocols are under review and being updated to align with current literature. Further site-wide updates and changes will occur in due course. References & Disclaimer

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources:  

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
Cyclophosphamide
  Interaction Clinical management
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Increased toxicity of cyclophosphamide possible due to increased conversion to active (and inactive) metabolites Avoid combination or monitor for cyclophosphamide toxicity
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Reduced efficacy of cyclophosphamide possible due to decreased conversion to active (and inactive) metabolites Avoid combination or monitor for decreased clinical response to cyclophosphamide
Amiodarone Possible additive pulmonary toxicity with high-dose cyclophosphamide (i.e. doses used prior to stem cell transplant; 60 mg/kg daily or 120 to 270 mg/kg over a few days) Avoid combination or monitor closely for pulmonary toxicity
Allopurinol, hydrochlorothiazide, indapamide Delayed effect. Increased risk of bone marrow depression; probably due to reduced clearance of active metabolites of cyclophosphamide Avoid combination, consider alternative antihypertensive therapy or monitor for myelosuppression
Ciclosporin Reduced efficacy of ciclosporin due to reduced serum concentration Monitor ciclosporin levels; adjust dosage as appropriate; monitor response to ciclosporin
Suxamethonium Prolonged apnoea due to marked and persistent inhibition of cholinesterase by cyclophosphamide Alert the anaesthetist if a patient has been treated with cyclophosphamide within ten days of planned general anaesthesia
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
Etoposide and Etoposide Phosphate
  Interaction Clinical management
CYP3A4 and P-gp inhibitors (e.g. amiodarone, aprepitant, azole-antifungals, ritonavir, lapatinib, nilotinib, sorafenib, macrolides, ciclosporin etc.) Increased toxicity of etoposide possible due to reduced clearance Avoid combination or monitor for etoposide toxicity
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of etoposide possible due to increased clearance Avoid combination or monitor for decreased clinical response to etoposide
Glucosamine Reduced efficacy of etoposide (due to induction of glucose-regulated stress proteins resulting in decreased expression of topoisomerase II) Avoid combination or monitor for decreased clinical response to etoposide
Grapefruit juice Reduced efficacy of oral etoposide possible due to possible alteration of P-gp mediated intestinal transport of etoposide Avoid combination or monitor for decreased clinical response to etoposide
Prednisolone
  Interaction Clinical management
Antidiabetic agents (e.g. insulin, glibenclamide, glicazide, metformin, pioglitazone, etc) The efficacy of antidiabetic agents may be decreased Use with caution and monitor blood glucose
Azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, posaconazole) Increased toxicity of prednisolone possible due to reduced clearance Avoid combination or monitor for prednisolone toxicity
Oestrogens (e.g. oral contraceptives) Increased toxicity of prednisolone possible due to reduced clearance Avoid combination or monitor for prednisolone toxicity. Dose reduction of prednisolone may be required
Ritonavir Increased toxicity of prednisolone possible due to reduced clearance Avoid combination or monitor for prednisolone toxicity
Procarbazine
  Interaction Clinical management
CNS depressants (including opiates, opioids, phenothiazines) Additive CNS depressant effects (e.g. drowsiness, ataxia) Avoid combination or monitor for excessive CNS depression
Alcohol Disulfiram-like reaction (can include copious vomiting, dyspnoea, syncope) and increased sedation Patients should abstain from alcohol during and for one week after completing treatment with procarbazine
Anti-depressants (including SSRIs, tricyclics, monoamine oxidase inhibitors (MAO-Is)), other MAO-Is (e.g. linezolid, selegiline), serotonergic agents (e.g. 'triptans', tramadol, pethidine, St John's wort) Serotonin syndrome (hypertension, hyperthermia, agitation, hallucinations, rigidity, hyperreflexia, diaphoresis, tremor etc.) may be precipitated due to weak monoamine oxidase inhibition by procarbazine Avoid combination
Sympathomimetic agents (e.g. pseudoephedrine and other cold and flu medications, stimulants such as guarana, some appetite suppressants) Hypertensive crisis (headache, hyperpyrexia, hypertension) may be precipitated due to weak monoamine oxidase inhibition by procarbazine Avoid combination
Tyramine-rich foods (e.g. aged cheeses, yoghurt, cured meats, liver, pickled herrings, over-ripe bananas, avocados and yeast extracts such as Vegemite® and Marmite®) Hypertensive crisis (headache, hyperpyrexia, hypertension) may be precipitated due to weak monoamine oxidase inhibition by procarbazine Patients should be advised to avoid excessive consumption of tyramine-rich foods while taking procarbazine; total abstinence is not considered necessary
Oral hypoglycaemics Hypoglycaemia

(MAO-Is can stimulate insulin secretion; procarbazine is a weak MAO-I)		 Monitor blood glucose levels. Adjustment of the dose of antidiabetic medication may be required
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Increased risk of hypersensitivity reactions due to increased production of the reactive metabolite of procarbazine thought to be responsible Avoid combination; select alternative antiepileptic (e.g. clonazepam, diazepam, lorazepam) or monitor for hypersensitivity reaction
Vincristine
  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 vincristine possible due to reduced clearance Monitor for vincristine toxicity (esp. neurotoxicity, paralytic ileus)
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of vincristine possible due to increased clearance Monitor for decreased clinical response to vincristine
Mitomycin Acute shortness of breath and severe bronchospasm has occurred following use of vincristine in patients who had received mitomycin simultaneously or within 2 weeks Use combination with caution
Ototoxic drugs (e.g. cisplatin, aminoglycosides, frusemide, NSAIDs) Additive ototoxicity Avoid combination or perform regular audiometric testing
General
  Interaction Clinical management
Warfarin Anti-cancer drugs 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 anti-cancer drug 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 Anti-cancer drugs 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 anti-cancer drug 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 anti-cancer 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

eviQ provides safe and effective instructions on how to administer cancer treatments. However, eviQ does not provide every treatment delivery option, and is unable to provide a comprehensive list of cancer treatment agents and their required IV line giving set/filter. There may be alternative methods of treatment administration, and alternative supportive treatments that are also appropriate. Please refer to the individual product information monographs via the TGA website for further information.

Day 1

Approximate treatment time: 3 hours

General patient assessment prior to each day of treatment.

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 TIVAD or CVAD.

Hydration if prescribed.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Prednisolone

  • administer orally ONCE a day on days 1 to 14
  • to be taken in the morning with or after food

Note: if a dose is forgotten or vomited, contact treating team.

Procarbazine

  • administer orally ONCE daily on days 1 to 7
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • can be taken with food or on an empty stomach.

Note: missed doses should not be replaced, if a capsule is forgotten or vomited, consult treating team. If treating team unavailable, advise patient that normal dosing should be resumed at the next scheduled dose.

Patients should be advised to avoid alcohol and large amounts of tyramine-rich foods  (e.g. aged cheeses, cured meats, yeast extracts such as Vegemite® etc) while taking procarbazine.

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.

Cyclophosphamide

Administer cyclophosphamide:
  • via IV infusion over 30 to 60 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%
  • rapid infusion can cause dizziness, rhinitis, nausea and perioral numbness. If symptoms develop, slow infusion rate.

Etoposide

Administer etoposide (irritant):
  • via IV infusion over 30 to 60 minutes
  • rapid infusion may cause hypotension
  • observe for hypersensitivity
  • flush with ~ 100 mL sodium chloride 0.9%
  • if using etoposide phosphate administer in ~ 50 mL sodium chloride 0.9% or glucose 5% over ~15 minutes.
Stop infusion at first sign of reaction:
  • if symptoms are mild and resolve when infusion is stopped, consider recommencing infusion after review by medical officer at a slower rate.
  • for severe reactions seek medical assistance immediately and do not restart infusion.

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

Days 2 and 3

Approximate treatment time: 2 hours

General patient assessment prior to each day of treatment.

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

Hydration if prescribed.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Prednisolone

  • administer orally ONCE a day on days 1 to 14
  • to be taken in the morning with or after food

Note: if a dose is forgotten or vomited, contact treating team.

Procarbazine

  • administer orally ONCE daily on days 1 to 7
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • can be taken with food or on an empty stomach.

Note: missed doses should not be replaced, if a capsule is forgotten or vomited, consult treating team. If treating team unavailable, advise patient that normal dosing should be resumed at the next scheduled dose.

Patients should be advised to avoid alcohol and large amounts of tyramine-rich foods  (e.g. aged cheeses, cured meats, yeast extracts such as Vegemite® etc) while taking procarbazine.

Etoposide

Administer etoposide (irritant):
  • via IV infusion over 30 to 60 minutes
  • rapid infusion may cause hypotension
  • observe for hypersensitivity
  • flush with ~ 100 mL sodium chloride 0.9%
  • if using etoposide phosphate administer in ~ 50 mL sodium chloride 0.9% or glucose 5% over ~15 minutes.
Stop infusion at first sign of reaction:
  • if symptoms are mild and resolve when infusion is stopped, consider recommencing infusion after review by medical officer at a slower rate.
  • for severe reactions seek medical assistance immediately and do not restart infusion.

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

Day 4

General patient assessment prior to each day of treatment.

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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Prednisolone

  • administer orally ONCE a day on days 1 to 14
  • to be taken in the morning with or after food

Note: if a dose is forgotten or vomited, contact treating team.

Procarbazine

  • administer orally ONCE daily on days 1 to 7
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • can be taken with food or on an empty stomach.

Note: missed doses should not be replaced, if a capsule is forgotten or vomited, consult treating team. If treating team unavailable, advise patient that normal dosing should be resumed at the next scheduled dose.

Patients should be advised to avoid alcohol and large amounts of tyramine-rich foods  (e.g. aged cheeses, cured meats, yeast extracts such as Vegemite® etc) while taking procarbazine.

Pegfilgrastim

  • administer subcutaneously; or ensure arrangements have been made for administration

Note: Pegfilgrastim or equivalent growth factor support can be used. 

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

Days 5 to 7

This is an oral treatment

General patient assessment prior to each day of treatment.

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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Prednisolone

  • administer orally ONCE a day on days 1 to 14
  • to be taken in the morning with or after food

Note: if a dose is forgotten or vomited, contact treating team.

Procarbazine

  • administer orally ONCE daily on days 1 to 7
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • can be taken with food or on an empty stomach.

Note: missed doses should not be replaced, if a capsule is forgotten or vomited, consult treating team. If treating team unavailable, advise patient that normal dosing should be resumed at the next scheduled dose.

Patients should be advised to avoid alcohol and large amounts of tyramine-rich foods  (e.g. aged cheeses, cured meats, yeast extracts such as Vegemite® etc) while taking procarbazine.

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

Day 8

Approximate treatment time: 30 minutes

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 TIVAD or CVAD.

Hydration if prescribed.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Prednisolone

  • administer orally ONCE a day on days 1 to 14
  • to be taken in the morning with or after food

Note: if a dose is forgotten or vomited, contact treating team.

Vincristine

Administer vincristine (vesicant)
  • via a minibag over 5 to 10 minutes
  • ensure vein is patent and monitor for signs of extravasation throughout administration
  • flush with ~150 mL of sodium chloride 0.9%.

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 (irritant):
  • 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 TIVAD or CVAD. 

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

Days 9 to 14

This is an oral treatment

General patient assessment prior to each day of treatment.

Prednisolone

  • administer orally ONCE a day on days 1 to 14
  • to be taken in the morning with or after food

Note: if a dose is forgotten or vomited, contact treating team.

Discharge information

Procarbazine capsules and prednisolone tablets
  • Procarbazine capsules and prednisolone tablets with written instructions on how to take them.
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)
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.
Flu-like symptoms
Headache
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
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

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 immediate management of neutropenic fever
Thrombocytopenia

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

Read more about thrombocytopenia
Constipation
Fatigue

Read more about fatigue
Hyperglycaemia

High blood sugar, an excess of glucose in the blood stream.
Oral mucositis

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

Read more about oral mucositis
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 anti-cancer drugs. These include taxanes, platinum-based compounds, vinca alkaloids and some drugs used to treat multiple myeloma.

Read more about peripheral neuropathy
Photosensitivity

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

Erythematous or inflammatory skin reaction resembling severe sunburn at sites previously treated with radiation therapy can occur with certain anti-cancer drugs. Symptoms include vesiculation, desquamation and ulceration of the skin.

Read more about radiation recall
Side effects of corticosteroids

Insomnia, oedema, increased risk of infection e.g. oral thrush, gastric irritation, worsening of peptic ulcer disease, increased blood sugar levels, loss of diabetic control, mood and behavioural changes - including anxiety, euphoria, depression, mood swings, increased appetite and weight gain, osteoporosis and fractures (long term use), bruising and skin fragility are associated with corticosteroid use.
Skin rash

Anti-cancer drugs 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
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 anti-cancer drugs.   

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 anti-cancer drugs 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

BEACOPP escalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone)(BE) is an established treatment in patients under the age of 60. BE provides a survival advantage over treatment with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) alone in advanced Hodgkin lymphoma (HL) (defined as stage 2B with large mediastinal mass or extranodal lesions or stage 3 or 4).rr However, because of BE's short and long-term toxicity relative to ABVD, strategies to reduce the number of cycles given to patients have been developed, largely based on interim positron emission tomography (PET) scanning conducted after 2 cycles of chemotherapy. rrrr

The HD9 Trialr, a phase 3 multicentre international randomised trial involving 1201 patients, compared BE with standard BEACOPP (SB) and a COPP-ABVD (cyclophosphamide, vincristine, procarbazine and prednisone) hybrid in patients with advanced-stage HL (stages IIB to IV). Between 1993 and 1998, patients were randomised to receive 8 cycles of BE (466 patients), SB (469 patients) or the COPP-ABVD hybrid (260 patients) at the doses in table 1. 

Table 1: Planned regimens of COPP-ABVD and BEACOPPr

©NEJM 2003

A 2017 Cochrane meta-analysisr concluded that, based on “moderate- to high-quality evidence", adult patients between 16 and 60 years of age with early unfavourable and advanced-stage HL benefit regarding overall survival (OS) and progression-free survival (PFS) from first-line chemotherapy, including BE. 

Efficacy

The 10-year follow-up of HD9r demonstrated significant improvement in long-term freedom from treatment failure (FFTF) and OS for BE in advanced-stage HL. OS was 86%, 80% and 75% for BE, SB and COPP-ABVD, respectively, with P=0.01 for BE versus COPP-ABVD. Complete remission (CR) was achieved in 96% of patients with BE, 88% SB, and 85% with COPP/ABVD, as noted in table 2.

Table 2: Outcome of Treatment and Survival Rates in HD9r

©JCO 2009

Image 1: Kaplan-Meier analysis of the probability of (A) freedom from treatment failure and (B) overall survival in each treatment arm.r

©JCO 2009

Image 2: Forest plot of comparison: Analysis of Overall Survivalr

Image 3: Forest plot of comparison: Analysis of Progression Free Survivalr

©Cochrane Library 2017

In the RATHL studyr, 1129 patients with stage IIB-IV or IIA with adverse features, underwent interim PET-CT after 2 cycles of ABVD chemotherapy. PET-negative patients were randomised to ABVD or AVD, (doxorubicin, vinblastine and dacarbazine), while PET-positive patients were treated with 4 cycles of BE (or 6 cycles of BEACOPP-14). This study demonstrated that in those who were PET-positive (n=172) and had their treatment intensified to BEACOPP, 5-year progression-free survival (PFS) was 65% which is superior compared with historical data of continuing with ABVD. Similar results were achieved with escalation to BE in the SWOG 0816 studyr for patients who were interim PET-positive after 2 cycles of ABVD. 

In AHL2011r, a randomised, non-inferiority phase 3 multicentre study for newly diagnosed stage III, IV or IIB HL, patients received standard therapy (6 cycles of BE) or PET-driven therapy (2 cycles of BE, followed by PET-2). Patients who were PET-2-negative de-escalated to 4 cycles of ABVD, while PET-2 positive patients continued with initial therapy followed by PET-4 to assess response for consideration of salvage therapy. 5-year PFS was 86% in the standard treatment group versus 85·7% in the PET-driven treatment group.

The HD18 study investigated giving fewer chemotherapy cycles to patients with advanced HL who achieved a complete metabolic remission after 2 cycles of BE, while rituximab was added to treatment in patients with positive PET-2. Rituximab had no impact on survival in PET-2 positive patients: 5-year PFS 89.7% vs 88.1%. In the PET-2 negative patients, the study demonstrated non-inferiority of 4 vs 6 cycles of BE, with 5-year PFS at 92 and 91%, respectively. 

Toxicity

Table 3: Acute Adverse Effects of Chemotherapy.r

©NEJM 2003

Males treated with BEACOPP regimens are at high risk of infertility, with rates of azoospermia of approximately 90%.r Low birth rates are observed in women who have been treated for advanced-stage HL with a BEACOPP regimen, and 34% of females over the age of 30 will undergo menopause.r In the 10 year follow up of HD9 (COPP-ABVD versus SB versus BE) overall secondary malignancy rates were 5.7%, 6.6%, and 6.0%, with no significant difference between the arms. If acute myeloid leukaemia alone was considered, the rates were 0.4% (COPP-ABVD), 1.5% (SB), and 3.0% (BE) for the three arms.

A review of 3,412 patients treated with BE on the German HD9, HD12 and HD15r studies showed an overall treatment-related mortality (TRM) of 1.9%. One-third of these deaths occurred in the first cycle. TRM by age group was 0.7% for patients less than 30 years, 2.5% for ages 40 to 49, 3.8% for ages 50 to 59, and 14.3% for patients aged greater than 60 years.

In AHL2011r study, grade 3 to 4 adverse events were 92% vs 95%, neutropenia 87% vs 90%, anaemia 69% vs 28% and thrombocytopenia 66% vs 40%. Serious adverse events were in 192 (47%) patients in the standard therapy group versus 114 (28%) patients in the PET-driven group. 6 deaths (1%) occurred in the standard therapy arm (2 from septic shock, 2 from pneumonia, 1 from cardiac failure and 1 from AML). 2 deaths (<1%) occurred in the PET-driven group (1 from septic shock and 1 from AML).

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Version 7

Date Summary of changes
22/10/2021 Protocol reviewed at the Haematology Reference Committee meeting and the following changes made:
  • Number of cycles updated to 2 to 6 and note included regarding PET-adaptive therapy.
  • Antiemetics removed from treatment schedule.
  • Evidence reformatted and updated to include HD18 and AHL2011.
  • Review in 4 years.
31/08/2022 Bleomycin extravasation category updated to align with extravasation clinical resources update.

Version 6

Date Summary of changes
22/09/2020 Biosimilar drug added to clinical information. Version number changed to V.6

Version 5

Date Summary of changes
11/10/2006 Information added about bleomycin dose equivalence.
07/12/2007 Further clarification about bleomycin doe equivalence.
10/12/2007 Additional side effects added and additional information bleomycin test dosing.
26/06/2008 Changes to wording of the administration on vincristine to reflect the Australian Council for Safety and Quality in Health Care safety alert and the NSW Health safety alert.
10/11/2008 Revision and reformatting, added new evidence.
05/02/2010 Review; dose modifications reviewed, updated and standardised across all BEACOPP protocols; transferred to eviQ.
12/07/2010 Addition of pegfilgrastim on day 9 to treatment schedule instead of filgrastim, as per consensus of Haematology Reference Committee. See Notes section.
08/10/2010 Capping of bleomycin dose removed after discussion at September 2010 Haematology Reference Committee meeting (HRCM).
25/02/2013 Transferred to OMIS format.
11/10/2013 Reviewed at HRCM
13/11/2013 Changes made to evidence, number of cycles changed to 6 checked and republished.
20/03/2014 Pulmonary function monitoring changed to be the same as ABVD.
11/09/2015

Reviewed at HRCM: no major changes made.

31/05/2017

Transferred to new eviQ website. Version number change to V.4. Other changes include:

  • Diluent volume of vincristine changed from ‘50 to 100 mL’ to ‘50 mL’ as per Australian Injectable Handbook Sixth Edition.
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: 

  • Pegfilgrastim administration changed to Day 4 as per the HD-18 trial.
  • Inclusion of note that enables clinicians to use alternative growth factor supports to pegfilgrastim (e.g. filgrastim, lenograstim or lipegfilgrastim).
  • Removal of note on procarbazine dose escalation as not mentioned in the HD-15 or HD-18 trial and reference committee consensus that this is not reflective of clinical practice. 
  • Inclusion of PJP prophylaxis. 
  • Removal of Haemorrhagic cystitis as an early side effect as the dose of cyclophosphamide is too small to warrant  prophylaxis measures for urothelial toxicity. 
  • Evidence section updated. 
  • Version change to V.5. 
25/07/2019

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. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/1461

31 May 2023