BEACOPP-14/ Escalated BEACOPP

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Indication
Advanced stage Hodgkin Lymphoma where escalated therapy is indicated.

Early Stage Classical Hodgkin Lymphoma with positive interim PET-CT (Deauville 3 or more).

Patients must have WHO performance status 0-2, be aged ≤ 60 years with adequate cardiac function (e.g. LVEF >
50%) and adequate pulmonary function (e.g. transfer factor [TLCO/KCO] within 25% of normal predicted value).

Treatment should be discussed and agreed at a lymphoma MDT prior to initiation.

ICD-10
Codes with a prefix C81.

Regimen details
BEACOPP 14:
Day Drug Dose Route
1 Doxorubicin 25mg/m2 IV bolus
1 Cyclophosphamide 650mg/m2 IV bolus
1 to 3 Etoposide 100mg/m2 IV infusion
1 to 7 Procarbazine 100mg/m2 (to nearest 50mg) PO
1 to 7 Prednisolone 80mg/m2 PO
8 Vincristine 1.4mg/m2 (max 2mg) IV infusion
8 Bleomycin 10,000units/m2 IV infusion
9 to 13 G-CSF (as per local policy) SC

Escalated BEACOPP:
Day Drug Dose Route
1 Doxorubicin 35mg/m2 IV bolus
2
1 Mesna 1000mg/m prior to cyclophosphamide IV infusion
1 Cyclophosphamide 1250mg/m2 IV infusion
2
1 Mesna 1000mg/m 4 hours post cyclophosphamide IV infusion
1 to 3 Etoposide 200mg/m2 IV infusion
2
1 to 7 Procarbazine 100mg/m (to nearest 50mg) PO
1 to 14 Prednisolone 40mg/m2 PO
2
8 Vincristine 1.4mg/m (max 2mg) IV infusion
8 Bleomycin 10,000units/m2 IV infusion
9 to 13 G-CSF (as per local policy) SC
If bulky disease consider pre-hydration with 0.9% sodium chloride over 4-6 hours. Assess risk of tumour lysis
syndrome. Patients should drink 3L of fluid on the day of cyclophosphamide treatment.

Cycle frequency
BEACOPP 14: 14 days
Escalated BEACOPP: 21 days

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Number of cycles
BEACOPP 14: Up to 8 cycles (see below).
Escalated BEACOPP: Up to 6 cycles.

In advanced stage disease, when used after ABVD with a positive interim PET-CT (PET2), a further PET-CT is advised
after 4 cycles of BEACOPP 14 or 3 cycles of escalated BEACOPP. If the further PET-CT (PET3) is negative
recommend a further 2 cycles of BEACOPP14 or 1 cycle of escalated BEACOPP. Optimal timing for interim PET-CT
is day 12 (day 9-13) from the start of a cycle.
Escalated BEACOPP may be used as first line therapy for advanced Hodgkin lymphoma and 6 cycles given when
interim PET scan is not recommended, however one should be carried out at the end of the treatment to assess
the need for radiotherapy.

Alternatively escalated BEACOPP may be given for two cycles then PET-CT performed to assess response with PET
negative cases treated to a total of 4 cycles and PET positive to 6 cycles with end of therapy PET-CT to assess the
need for radiotherapy.

Administration
Consider placement of a PICC or central line.

Doxorubicin is administered by slow IV bolus into the arm of a fast running drip of sodium chloride 0.9%.

Mesna is administered in 100mL sodium chloride 0.9% over 15 minutes. The first dose is given prior to
cyclophosphamide and a second dose is given 4 hours after the cyclophosphamide.

Cyclophosphamide is administered as an IV bolus or as an IV infusion in 250-500mL sodium chloride 0.9% over 30

minutes.

Etoposide is administered in 1000mL-2000mL (concentration dependent) sodium chloride 0.9% over 60 minutes.

Procarbazine is available as 50mg capsules. Capsules should be swallowed whole with a glass of water.

Prednisolone is available as 5mg and 25mg tablets. The dose should be taken each morning with or after food.

Vincristine is administered in 50mL sodium chloride 0.9% over 10 minutes, as per national guidance. Nurse to
remain with patient throughout infusion.

Bleomycin is administered in 100mL sodium chloride 0.9% over 30 minutes.

Pre-medication
Hydrocortisone 100mg IV prior to each bleomycin dose.

Emetogenicity
This regimen has high emetic potential on day 1, moderate emetic potential on days 2-7 and mild emetic potential
on day 8.

Additional supportive medication

Allopurinol 300mg OD (or 100mg OD if creatinine clearance <20mL/min) for the first cycle.
H2 antagonist or proton-pump inhibitor as per local policy.
Antiemetics as per local policy.
Mouth care as per local policy.
PCP prophylaxis e.g. co-trimoxazole as per local policy to continue until 6 months after treatment stops.

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Antiviral prophylaxis
Antifungal (fluconazole) and antibiotic cover (ciprofloxacin) as per local policy may be appropriate during periods
while neutrophils < 0.5 x109/L.

Extravasation
Vincristine and doxorubicin are vesicant (group 5).
Cyclophosphamide and bleomycin neutral (group 1).
Etoposide is an irritant (group 3).

Investigations – pre first cycle

Investigation Validity period
FBC 7 days
U+Es (including creatinine) 7 days
LFTs 7 days
Calcium 7 days
Magnesium 7 days
Pulmonary Functions Tests (including transfer factor) 28 days

Hepatitis B core antibody and hepatitis BsAg, hepatitis C antibody, HIV 1+2 serology must be tested prior to
commencing treatment.

ECG and consider echocardiogram if cardiac history. Patients with significant history of ischaemic heart disease or
hypertension must have an acceptable LVEF ≥ 50%.

Prior to commencing treatment with unmodified drug doses patients must meet the following parameters,
however first cycle doses are usually not modified for cytopenias:

Investigation Limit
Neutrophils * ≥ 1.5 x 109/L
Platelets* ≥ 100 x 109/L
Calculated CrCl ≥ 60ml/min
Bilirubin ≤ 1.0 x ULN
ALT/AST ≤ 1.0 x ULN
* unless due to bone marrow infiltration

Investigations – pre subsequent cycles

Investigation Validity period
FBC 72 hours and prior to day 8
U+E (including creatinine) 72 hours and prior to day 8
LFTS 72 hours and prior to day 8

Standard limits in subsequent cycles for day 1 administration to go ahead

If blood results not within range, authorisation to administer must be given by prescriber/ consultant
Investigation Limit
WBC ≥ 2.5 x 109/L
Platelets ≥ 80 x 109/L
Calculated CrCl ≥ 60mL/min
Bilirubin ≤ 1.0 x ULN
ALT/AST ≤ 1.0 x ULN

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Dose modifications
 Haematological toxicity
BEACOPP 14
Day 1:
Cycle 1: proceed with full dose therapy, particularly when there are known lymphoma infiltrates in the marrow.
Cycle 2 onwards:
WBC (x109/L) Platelets (x109/L) Dose modification
≥ 2.5 and ≥ 80 100% doses
Delay 1 week or until recovery
< 2.5 or < 80
Adjust dose as per table below

Delay in white cell count or platelet recovery Dose modification

< 1 week Once counts recovered continue with 100% doses
1-2 weeks Once counts recovered 75% doses of cyclophosphamide,
doxorubicin, etoposide and procarbazine
> 2 weeks Once counts recovered 50% doses of cyclophosphamide,
doxorubicin, etoposide and procarbazine

Day 8 drugs should be given on schedule and dose irrespective of FBC.

Escalated BEACOPP:
Day 1:
Cycle 1: proceed with full dose therapy, particularly when there are known lymphoma infiltrates in the marrow.
Cycle 2 onwards: If WBC ≥ 2.5 x109/L and platelets > 80 x109/L treatment should continue with 100% doses. Doses
should be reduced as per the table below if any of the following occur:
- Grade 4 leucopenia (WBC < 1.0 x109/L) for more than 4 days
- Grade 4 thrombocytopenia (platelets < 25 x109/L)
- Grade 4 infection
- Grade 4 mucositis
- Any adverse event that required a 2 week treatment delay
After each of these adverse events the doses of cyclophosphamide and etopside should be reduced by one level
from escalated to standard doses on the scale in the table below:

Drug Level 1- Level 2 Level 3 Level 4 Level 5 –

escalated standard
Cyclophosphamide 1250mg/m2 1100 mg/m2 950 mg/m2 800 mg/m2 650 mg/m2
Etoposide 200 mg/m2 175 mg/m2 150 mg/m2 125 mg/m2 100 mg/m2

If adverse effects occur in 2 successive cycles, standard doses (i.e. level 5) should be used for all subsequent doses.

Day 8 drugs should be given on schedule and dose irrespective of FBC findings.

 Renal impairment
Creatinine clearance (mL/min) Cyclophosphamide dose Bleomycin dose
≥ 50 100% 100%
10-50 75% 75%
< 10 50% 50% - discuss with consultant

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 Creatinine clearance (mL/min) Etoposide dose
≥ 60 100%
30-59 85%
15-29 75%
< 15 Consider 50% - discuss with consultant

Doxorubicin - no dose adjustment required, consultant decision if severe renal impairment.

Procarbazine - if CrCl 30-45 mL/min consider 50% dose, if < 30mL/min consultant decision whether to discontinue.

Vincristine - consultant decision if CrCl < 30mL/min.

 Hepatic impairment
Bilirubin (x ULN) AST/ALT (x ULN) Doxorubicin dose
≤ 1.0 and < 2 x ULN 100%
> 1.0 - 2.5 or 2-3 x ULN 50%
> 2.5 - 4.0 25%
> 4.0 Omit

Bilirubin (x ULN) AST/ALT (x ULN) Etoposide dose Vincristine dose

≤ 1.25 and < 1.0 100% 100%
> 1.25 - 2.5 or > 1.0 - 3.0 50% 50%
> 2.5 or > 3.0 Discuss with consultant - consider Consider omitting
25% or omit

Bilirubin (x ULN) Procarbazine dose

≤ 2.0 100%
> 2.0 50%
> 5.0 or AST/ALT > 3.5 ULN Consider omission (discuss with consultant)

Cyclophosphamide – if bilirubin > 2.5 x ULN consider dose reduction consultant decision
Bleomycin - No specific advice regarding use in hepatic impairment, consultant decision.

Other toxicities
For patients who develop ≥ grade 3 ileus, delay treatment until ≤ grade 1 and then continue with 75% vincristine. If
≥ grade 3 ileus recurs, vincristine should be discontinued.

Neurotoxicity
Toxicity Definition Dose adjustment
Neuropathy Grade 2 (moderate symptoms) Consider reducing procarbazine to 75%
or/and
Reduce vincristine to 50%
Grade 3+ (severe symptoms, limiting self-care) Discontinue treatment

Pulmonary toxicity
All patients reporting cough or shortness of breath should have a chest X-ray and pulmonary function tests prior to
administration of bleomycin. Bleomycin should be discontinued if any clinical signs or CXR evidence of pulmonary
infiltration/fibrosis develop, or if the transfer factor is <50% of the predicted value.

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Pulmonary fibrosis is a greater risk in smokers, prior radiation to the thorax, the elderly and a cumulative dose >
400,000IU.

High concentrations of oxygen (>30%) should be avoided unless absolutely necessary. Patients should be warned
that if they have future general anaesthetics they must inform the anaesthetist that they have received bleomycin.
They should be advised against scuba diving.

Cardiac toxicity
Further doxorubicin is contraindicated in patients already treated with the maximum cumulative dose of
doxorubicin of 450mg/m2 or other anthracyclines.
Patients with a baseline ejection fraction < 50%, consider withholding doxorubicin / monitoring cardiac function; if,
> 20% reduction on repeat ECHO they should not receive further anthracyclines.

Skin toxicity
Particularly of the hands and feet is seen with bleomycin. Bleomycin should be discontinued only if it restricts
activity.

Adverse effects - for full details consult product literature/ reference texts
 Serious side effects
Treatment-related mortality (4-5%)
Myelosuppression
Cardiotoxicity
Pulmonary fibrosis
Aseptic osteonecrosis of the hip
Myelodysplastic syndrome and AML, secondary malignancy
Infertility
Anaphylaxis

 Frequently occurring side effects

Insomnia
Alopecia
Ovarian failure, amenorrhoea, sterility,
Nausea and vomiting
Stomatitis, ulceration,
Diarrhoea, constipation
Abdominal pain
Mucositis

 Other side effects

Discolouration of urine, haemorrhagic cystitis
CNS depression
Rash
Muscle weakness
Respiratory: tachypnoea, rales, acute or chronic interstitial pneumonitis and pulmonary fibrosis
Nasal congestion, epistaxis

Significant drug interactions – for full details consult product literature/ reference texts
Coumarin-derived anticoagulants such as warfarin: patients established on warfarin should either be changed to
low molecular weight heparin or have weekly monitoring of INR. Patients who are initiated on anti-coagulation
should remain on low molecular weight heparin until completion of the course of chemotherapy.
Phenytoin and fosphenytoin: close monitoring and/or alternative agents are recommended if co-prescribed with
this regimen. Phenytoin serum levels may be decreased, possibly as a result of decreased absorption and/or
increased metabolism.

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Alcohol: Procarbazine has a weak disulfiram-like effect and can lead to alcohol intolerance.
MAO inhibition: Procarbazine is a weak inhibitor of MAO and can cause CNS side-effects. Care should be taken
when co-prescribing antihypertensives, CNS depressants or tricyclic antidepressants. Interactions with tyramine-
containing foodstuffs must be borne in mind.
Barbiturates: Phenobarbital can lead to a reduced anti-tumour effect of lomustine due to induction of hepatic
enzymes and increased elimination. Barbiturates can cause increased CNS depression with procarbazine.

Vincristine
Avoid itraconazole, voriconazole or posaconazole within a week of treatment because of increased risk of
neuropathy with co-administration.

Additional comments
Encourage patients who smoke to stop – offer referral to smoking cessation services.

Cardiotoxicity has been associated with anthracyclines, with adverse events being more common in patients with a
prior history of coronary artery disease. Caution must be taken in patients with a history of significant cardiac
disease, arrhythmias or angina pectoris.

Doxorubicin has a life time maximum cumulative dose of 450mg/m2, less if prior/other anthracycline exposure.

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References  Summary of Product Characteristics Etoposide (Hospira) accessed 13 June 2018 via
www.medicines.org.uk
 Summary of Product Characteristics Bleomycin (Kyowa) accessed 13 June 2018
via www.medicines.org.uk
 Summary of Product Characteristics Cyclophosphamide (Sandoz) accessed 13 June
2018 via www.medicines.org.uk Summary of Product Characteristics Doxorubicin
(Hospira) accessed 13 June 2018 via www.medicines.org.uk
 Skoetz N et al. Comparison of first-line chemotherapy including escalated BEACOPP
versus chemotherapy including ABVD for people with early unfavourable or
advanced stage Hodgkin lymphoma. Cochrane Database Syst Rev. 2017 May
25;5:CD007941. doi: 10.1002/14651858.CD007941.pub3.
 Skoetz N, Will A, Monsef I, et al: Eight cycles of escalated-dose BEACOPP compared
with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose
BEACOPP with or without radiotherapy in patients with advanced-stage Hodgkin’s
lymphoma: Final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin
Oncol 29:4234-4242, 2011.
 Engert A, Haverkamp H, Kobe C et al. Reduced-intensity chemotherapy and PET-
guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15
trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet. 2012 May
12;379(9828).
 Borchmann P, Goergen H, Kobe C et al. PET-guided treatment in patients with
advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label,
international, randomised phase 3 trial by the German Hodgkin Study Group. Lancet.
 Sieber M, et al 14-day variant of the bleomycin, etoposide, doxorubicin,
cyclophosphamide, vincristine, procarbazine, and prednisone regimen in advanced-
stage Hodgkin's lymphoma: results of a pilot study of the German Hodgkin's
Lymphoma Study Group. J Clin Oncol. 2003 May 1;21(9):1734-9.
 André MP, et al. Early Positron Emission Tomography Response-Adapted Treatment
in Stage I and II Hodgkin Lymphoma: Final Results of the Randomized
EORTC/LYSA/FIL H10 Trial. J Clin Oncol. 2017 Mar 14:JCO201668639

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  BCSH Guidelines for the First Line Management of Classical Hodgkin Lymphoma.
Final Version Feb 2014.
 RATHL trial protocol v5.1; 20 September 2013.

Written/reviewed by: Dr A Whiteway (Consultant Haematologist, North Bristol NHS Trust), Claire Burney
(Consultant Haematologist, UHBristol NHS Trust)

Checked by: Sarah Murdoch (Senior Oncology/Haematology Pharmacist, SW Clinical Network)

Authorised by: Dr J Braybrooke (Consultant Oncologist, UHBristol NHS Trust, SW Clinical Network)

Date: July 2018

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