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Non-Hodgkin lymphoma DA-R-EPOCH (dose adjusted rituximab etoposide prednisolone vinCRISTine CYCLOPHOSPHamide DOXOrubicin)

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 8

Drug Dose Route Day
Prednisolone 60 mg/m2 TWICE a day PO 1 to 5
Rituximab 375 mg/m2 IV infusion * 1
DOXOrubicin 10 mg/m2 CIV over 24 hours (loaded with etoposide and vinCRISTine) 1 to 4
vinCRISTine 0.4 mg/m2 CIV over 24 hours (loaded with etoposide and DOXOrubicin) 1 to 4
Etoposide 50 mg/m2 CIV over 24 hours (loaded with DOXOrubicin and vinCRISTine) 1 to 4
CYCLOPHOSPHamide 750 mg/m2 IV infusion 5
Filgrastim 5 micrograms/kg Subcut 6 and continue daily until neutrophil recovery

* From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. For more information see the Non-Hodgkin lymphoma subcutaneous rituximab document.

Note: The treatment schedule shows doses for cycle 1 only. Subsequent cycles may require dose adjustments. The doses for each cycle are determined by the ANC nadir of the previous cycle. Please see dose-adjustment paradigm in the Dose modifications section below.

Frequency:
21 days 
Cycles:
6 minimum and 8 maximum cycles. 2 cycles to be given beyond complete remission or stable disease.
Notes:
  • CNS prophylaxis should be considered on a case by case basis for patients with high grade lymphoma who are at an increased risk of CNS relapse. Please see evidence section for more details.
  • There are various ways of administering doxorubicin, vincristine and etoposide/etoposide phosphate. e.g. vincristine and doxorubicin as an admixture and etoposide alone or as an admixture containing all three drugs; administration in the outpatient setting is feasible.
  • Etoposide phosphate is more stable than etoposide in combination with doxorubicin and vincristine.r
  • Doxorubicin, vincristine and etoposide phosphate as an admixture is compatible and stable for up to 124 hours.r
  • Doxorubicin, vincristine and etoposide as an admixture is compatible and stable for up to 72 hours.r
Drug status:

Rituximab and filgrastim: (PBS authority)

Rituximab SC: TGA registered but not PBS listed.

All other drugs in this protocol are on the PBS general schedule

Prednisolone is available as 25 mg, 5 mg and 1 mg tablets

Cost:
~ $1,130 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 8

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Prednisolone 60 mg/m2 (PO) TWICE a day on days 1 to 5.* Take with food.
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate **
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
DOXOrubicin 10 mg/m2 (CIV over 24 hours) loaded with vinCRISTine and etoposide in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours
vinCRISTine 0.4 mg/m2 (CIV over 24 hours) loaded with DOXOrubicin and etoposide in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours
Etoposide 50 mg/m2 (CIV over 24 hours) loaded with DOXOrubicin and vinCRISTine in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours
Day 2 to 4
Prednisolone 60 mg/m2 (PO) TWICE a day on days 1 to 5.* Take with food.
DOXOrubicin 10 mg/m2 (CIV over 24 hours) loaded with vinCRISTine and etoposide in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours
vinCRISTine 0.4 mg/m2 (CIV over 24 hours) loaded with DOXOrubicin and etoposide in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours
Etoposide 50 mg/m2 (CIV over 24 hours) loaded with DOXOrubicin and vinCRISTine in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours
Day 5
Prednisolone 60 mg/m2 (PO) TWICE a day on days 1 to 5.* Take with food.
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
CYCLOPHOSPHamide 750 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
Day 6
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously once daily starting day 6 and continue until neutrophils are 0.5 x 10 ^9/L above nadir

* One of the doses on day 1 should be taken 60 minutes before rituximab infusion.

** From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. For more information see the Non-Hodgkin lymphoma subcutaneous rituximab document.

Note: The treatment schedule shows doses for cycle 1 only. Subsequent cycles may require dose adjustments. The doses for each cycle are determined by the ANC nadir of the previous cycle. Please see dose-adjustment paradigm in the Dose modifications section below.

Frequency:
21 days 
Cycles:
6 minimum and 8 maximum cycles. 2 cycles to be given beyond complete remission or stable disease.

Cycle 1 to 8

Drug Dose Route Day
Prednisolone 60 mg/m2 TWICE a day PO 1 to 5
Rituximab 375 mg/m2 IV infusion * 1
DOXOrubicin 10 mg/m2 CIV over 24 hours (loaded with etoposide and vinCRISTine) 1 to 4
vinCRISTine 0.4 mg/m2 CIV over 24 hours (loaded with etoposide and DOXOrubicin) 1 to 4
Etoposide 50 mg/m2 CIV over 24 hours (loaded with DOXOrubicin and vinCRISTine) 1 to 4
CYCLOPHOSPHamide 750 mg/m2 IV infusion 5
Filgrastim 5 micrograms/kg Subcut 6 and continue daily until neutrophil recovery

* From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. For more information see the Non-Hodgkin lymphoma subcutaneous rituximab document.

Note: The treatment schedule shows doses for cycle 1 only. Subsequent cycles may require dose adjustments. The doses for each cycle are determined by the ANC nadir of the previous cycle. Please see dose-adjustment paradigm in the Dose modifications section below.

Frequency:
21 days 
Cycles:
6 minimum and 8 maximum cycles. 2 cycles to be given beyond complete remission or stable disease.
Notes:
  • CNS prophylaxis should be considered on a case by case basis for patients with high grade lymphoma who are at an increased risk of CNS relapse. Please see evidence section for more details.
  • There are various ways of administering doxorubicin, vincristine and etoposide/etoposide phosphate. e.g. vincristine and doxorubicin as an admixture and etoposide alone or as an admixture containing all three drugs; administration in the outpatient setting is feasible.
  • Etoposide phosphate is more stable than etoposide in combination with doxorubicin and vincristine.r
  • Doxorubicin, vincristine and etoposide phosphate as an admixture is compatible and stable for up to 124 hours.r
  • Doxorubicin, vincristine and etoposide as an admixture is compatible and stable for up to 72 hours.r
Drug status:

Rituximab and filgrastim: (PBS authority)

Rituximab SC: TGA registered but not PBS listed.

All other drugs in this protocol are on the PBS general schedule

Prednisolone is available as 25 mg, 5 mg and 1 mg tablets

Cost:
~ $1,130 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 8

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Prednisolone 60 mg/m2 (PO) TWICE a day on days 1 to 5.* Take with food.
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate **
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
DOXOrubicin 10 mg/m2 (CIV over 24 hours) loaded with vinCRISTine and etoposide in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours
vinCRISTine 0.4 mg/m2 (CIV over 24 hours) loaded with DOXOrubicin and etoposide in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours
Etoposide 50 mg/m2 (CIV over 24 hours) loaded with DOXOrubicin and vinCRISTine in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours
Day 2 to 4
Prednisolone 60 mg/m2 (PO) TWICE a day on days 1 to 5.* Take with food.
DOXOrubicin 10 mg/m2 (CIV over 24 hours) loaded with vinCRISTine and etoposide in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours
vinCRISTine 0.4 mg/m2 (CIV over 24 hours) loaded with DOXOrubicin and etoposide in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours
Etoposide 50 mg/m2 (CIV over 24 hours) loaded with DOXOrubicin and vinCRISTine in 500 mL sodium chloride 0.9% as a continuous infusion for 24 hours
Day 5
Prednisolone 60 mg/m2 (PO) TWICE a day on days 1 to 5.* Take with food.
Palonosetron 0.25 mg (IV bolus) 30 minutes before chemotherapy
CYCLOPHOSPHamide 750 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
Day 6
Filgrastim 5 micrograms/kg (Subcut) inject subcutaneously once daily starting day 6 and continue until neutrophils are 0.5 x 10 ^9/L above nadir

* One of the doses on day 1 should be taken 60 minutes before rituximab infusion.

** From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. For more information see the Non-Hodgkin lymphoma subcutaneous rituximab document.

Note: The treatment schedule shows doses for cycle 1 only. Subsequent cycles may require dose adjustments. The doses for each cycle are determined by the ANC nadir of the previous cycle. Please see dose-adjustment paradigm in the Dose modifications section below.

Frequency:
21 days 
Cycles:
6 minimum and 8 maximum cycles. 2 cycles to be given beyond complete remission or stable disease.
  • High grade B-cell lymphoma (including DLBCL) with MYC and BCL-2 or BCL-6 translocations 
  • Primary mediastinal Diffuse Large B-cell lymphoma (DLBCL)
  • Aggressive non-Hodgkin lymphoma in HIV infected individuals
  • Burkitt lymphoma
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

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 etoposide and rituximab.
Premedication

The product information states that premedication is required for this treatment.

Please refer to the treatment schedule for suggested premedication regimen. This may be substituted to reflect institutional policy.
Emetogenicity MODERATE

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

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

For patients with a prior episode of chemotherapy induced nausea or vomiting, a NK1 receptor antagonist may be available on the PBS in combination with a 5HT3 antagonist and steroid.

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
Rituximab rapid infusion

This regimen is not in line with the product monograph, however published literature indicates that it can be completed safely.

Read more about the rapid infusion of rituximab
Subcutaneous rituximab

Please note that subcutaneous rituximab is no longer subsidised by the Pharmaceutical Benefit Scheme and is currently unavailable in Australia.

All patients must always receive their first dose of rituximab by intravenous administration. Subcutaneous (SC) rituximab must only be given at the second or subsequent doses. From dose 2 onwards, rituximab may be administered subcutaneously as a flat dose of 1,400 mg. If patient was not able to receive one full rituximab intravenous infusion dose, they should continue the subsequent dose with intravenous rituximab until a full IV dose is successfully administered.

Premedication consisting of an analgesic/antipyretic and an antihistamine should always be administered before each dose of rituximab SC. Premedication with glucocorticoids should also be considered, particularly if rituximab SC is not given in combination with steroid-containing chemotherapy.

 Read more about Non-Hodgkin lymphoma subcutaneous rituximab 
Progressive multifocal leukoencephalopathy

Use of monoclonal antibodies may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal opportunistic viral infection of the brain. Patients must be monitored for any new or worsening neurological symptoms.

Read more about progressive multifocal leukoencephalopathy and the Therapeutic Goods Administration Medicines Safety update on progressive multifocal leukoencephalopathy from the Australian Government, Department of Health.
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
Central nervous system (CNS) prophylaxis

Consider CNS relapse assessment in patients with high grade lymphoma. 

Read more about CNS prophylaxis in diffuse large cell lymphoma
Tumour lysis risk

Patients are at high risk of developing tumour lysis syndrome, prophylaxis is recommended.

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

PJP prophylaxis is recommended e.g. trimethoprim/sulfamethoxazole 160/800 mg PO one tablet twice daily, twice weekly (e.g. on Mondays and Thursdays) OR one tablet three times weekly (e.g. on Mondays, Wednesdays and Fridays).

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 clinical indication and/or febrile neutropenia risk.  

Access the PBS website
Biosimilar drug

Read more about biosimilar drugs on the Biosimilar Awareness Initiative page
Blood tests

FBC, EUC, LFTs, LDH and BSL baseline, and prior to each treatment. Repeat FBC twice weekly (3 days apart) to determine dose for next cycle. 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.
  • If ANC 1.0 x 109/L or higher and platelets 100 x 109/L or higher on day 21, begin treatment.
  • Dose modifications based on 2019 study by Bartlett et alr, eviQ standard recommendations and product information.
Dose adjustment paradigm
  • Dose adjustments above starting dose level (Level 1) apply to etoposide, doxorubicin and cyclophosphamide
  • Dose adjustments below starting dose level (Level 1) apply to cyclophosphamide only
  • Measurement of ANC nadir based on twice weekly FBC only (3 days apart). Only use twice weekly FBC for dose-adjustment even if additional FBCs are obtained.

Drugs (mg/m2/day)		 Drug doses per dose level
-3 -2 -1 1* 2 3 4 5 6
Doxorubicin 10 10 10 10 12 14.4 17.3 20.7 24.8
Etoposide 50 50 50 50 60 72 86.4 103.7 124.4
Cyclophosphamide 384 480 600 750 900 1080 1296 1555 1866

*Starting dose level 

Drug doses are based on previous cycle ANC and platelet nadirs:
ANC x 109/L (nadir)
0.5 or higher on all measurements Increase 1 dose level above last cycle
less than 0.5 on 1 or 2 measurements Same dose level as last cycle
less than 0.5 on 3 or more measurements Reduce 1 dose level below last cycle
Platelets x 109/L (nadir)
less than 25 Reduce 1 dose level below last cycle

If ANC 1.0 x 109/L or higher and platelets 100 x 109/L or higher on day 21, begin treatment.

If ANC less than 1.0 x 109/L or platelets less than 100 x 109/L on day 21, delay up to 2 weeks.

G-CSF may be started and stopped 24 hours before treatment. If counts still low after 1 week delay and reduce 1 dose level below last cycle.

Renal impairment
Creatinine clearance (mL/min)
15 to 50 Reduce etoposide by 25%
less than 10 Reduce cyclophosphamide by 25% and etoposide by 50%
Hepatic impairment
Bilirubin (micromol/L)
20 to 50 Reduce doxorubicin dose by 50% and vincristine dose by 25%. Consider dose reducing etoposide.
51 to 85 Reduce doxorubicin dose by 75% and vincristine dose by 50%. Consider dose reducing etoposide.
greater than 85 Omit doxorubicin and etoposide
Peripheral neuropathy
Motor neuropathy
Grade 2 Reduce vincristine dose by 25%
Grade 3 Reduce vincristine dose by 50%
Grade 4 Omit vincristine
Sensory neuropathy
Grade 3 Reduce vincristine dose by 25%
Grade 4 Omit vincristine

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:  

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
Rituximab
  Interaction Clinical management
Antihypertensives Additive hypotensive effect Consider withholding antihypertensive medications 12 hours prior to the rituximab infusion
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

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).

Access TIVAD or CVAD.

Note: A large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

  • baseline weight
  • baseline urinalysis
  • strict fluid balance input and output

Hydration if prescribed

Prednisolone

  • administer orally TWICE a day (morning and midday) on scheduled days
  • to be taken with or after food
  • prednisolone can cause sleep disturbance, if this occurs a daily morning dose is recommended.

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

Rituximab

Prior to administration:
  • check baseline observations
  • check for previous adverse events during previous infusions
  • verify premedication has been taken. If not, administer 30 to 60 minutes prior to rituximab administration:
    • paracetamol 1000 mg orally AND
    • loratadine 10 mg orally (or similar antihistamine)
    • a steroid may also be included as a premed according to local guidelines: prednisolone orally 60 mg/m2 (part of this protocol) or hydrocortisone 100 mg IV
Initial infusion:
  • commence rituximab infusion at 50 mg/hr for 30 minutes
  • repeat observations prior to each rate increase
  • increase rate by 50 mg/hr every 30 minutes, up to a maximum of 400 mg/hr if observations are stable
  • flush with ~ 100 mL of sodium chloride 0.9%

If an infusion reaction occurs, temporarily discontinue the infusion and notify medical officer

  • when symptoms have completely resolved, recommence the infusion at half the rate prior to the reaction
  • for severe reactions stop infusion and manage as per emergency

Transient hypotension may occur. Consider withholding antihypertensive medication for 12 hours before and during infusion.

Subsequent infusions:

If an adverse event was experienced with initial infusion recommence infusion at the same rate as initial infusion

If no adverse event experienced with initial infusion:

  • commence rituximab infusion at 100 mg/hr
  • repeat observations prior to each rate increase
  • increase rate by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr if observations are stable
  • flush with ~ 100 mL of sodium chloride 0.9%

If an infusion reaction occurs, temporarily discontinue the infusion and notify medical officer

  • when symptoms have resolved, recommence the infusion at half the rate prior to the reaction
  • for severe reactions stop infusion and manage as per emergency

Read more about rapid infusion rituximab

Read more about subcutaneous rituximab

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Doxorubicin, vincristine and etoposide 

Administer doxorubicin, vincristine and etoposide (vesicant):
  • via IV infusion over 24 hours
  • via one line attached to one lumen of the CVAD
  • these drugs are mixed together (by the pharmacy department) in the same bag, check the amount in the bag is the amount prescribed for a 24 hour period only
  • verify the correct rate of infusion via the ambulatory infusion pump
  • read more information about the different ambulatory infusion pumps.

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

Days 2 to 4

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.

Note: A large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

  • daily weight
  • daily urinalysis
  • strict fluid balance input and output

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Prednisolone

  • administer orally TWICE a day (morning and midday) on scheduled days
  • to be taken with or after food
  • prednisolone can cause sleep disturbance, if this occurs a daily morning dose is recommended.

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

Doxorubicin, vincristine and etoposide 

Administer doxorubicin, vincristine and etoposide (vesicant):
  • via IV infusion over 24 hours
  • via one line attached to one lumen of the CVAD
  • these drugs are mixed together (by the pharmacy department) in the same bag, check the amount in the bag is the amount prescribed for a 24 hour period only
  • verify the correct rate of infusion via the ambulatory infusion pump
  • read more information about the different ambulatory infusion pumps.

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

Day 5

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.

Note: A large volume of intravenous fluid may be given with this protocol. If weight increases by more than 1 kg from baseline or fluid balance becomes positive by one litre or any other signs of fluid overload are present, review by medical officer (diuretics may be required).

  • daily weight
  • daily urinalysis
  • strict fluid balance input and output

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Prednisolone

  • administer orally TWICE a day (morning and midday) on scheduled days
  • to be taken with or after food
  • prednisolone can cause sleep disturbance, if this occurs a daily morning dose is recommended.

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

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.

Deaccess TIVAD or CVAD.

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

Day 6

General patient assessment prior to each day of treatment.

Filgrastim

  • administer filgrastim by subcutaneous injection once daily at least 24 hours after last dose of chemotherapy and continue until neutrophil recovery

Discharge information

Prednisolone tablets
  • 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, antifungals, 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
Bone pain

Bone pain, usually in the lower back or pelvis, associated with G-CSF.
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
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
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Constipation
Diarrhoea

Read more about treatment induced diarrhoea
Fatigue

Read more about fatigue
Haemorrhagic cystitis

An inflammatory process, characterised by diffuse mucosal inflammation with haemorrhage involving the entire bladder. Patients are at risk following treatment with cyclophosphamide, ifosfamide and radiation therapy. 

Read more about haemorrhagic cystitis
Injection-site reaction

Inflammation of or damage to the tissue surrounding the area where a drug was injected.
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
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.

Late (onset weeks to months)
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
Anaemia

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

Read more about anaemia
Progressive multifocal leukoencephalopathy (PML)

A rare opportunistic viral infection of the brain, usually leading to death or severe disability, can occur with monoclonal antibodies (e.g. rituximab, obinutuzumab, ofatumumab, brentuximab vedotin) and other targeted therapies (e.g. ibrutinib, ruxolitinib, idelalisib). Onset may occur up to months after the final dose.  

Read more about progressive multifocal leukoencephalopathy (PML)

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
Menopausal symptoms

Irregular or absent periods, hot flushes, mood swings, sleep disturbance, night sweats, vaginal dryness, decreased libido and dyspareunia. This is caused by ovarian failure and may be temporary or permanent.
Pulmonary toxicity

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

Read more about pulmonary toxicity associated with anti-cancer drugs

DA-R-EPOCH was developed to attempt to improve efficacy above that of R-CHOP through dose-intensification strategy and the addition of etoposide. The use of an infusional strategy, as opposed to the bolus dosing used in R-CHOP, was also hypothesised to assist in overcoming kinetic resistance in highly proliferative tumours due to utilisation of prolonged continuous exposure of tumour cells to chemotherapeutic agent.rr Infusional regimens also have the advantage of lower toxicity than equivalent bolus ​dosing.

DA-R-EPOCH was prospectively compared to R-CHOP for unselected diffuse large B-cell lymphoma (DLBCL) patients in a CALGB trial.r This prospective Phase III study of 491 patients showed more early discontinuations in the DA-R-EPOCH arm with increased toxicity and no difference in either progression-free survival (PFS) (hazard ratio, 0.93; 95% CI, 0.68 to 1.27; P = 0.65) or overall survival (OS) (2-year 86.5% versus 85.7%).  Factors such as MYC, BCL2 and BCL6 expression or rearrangement on fluorescence in situ hybridization (FISH) were not included prospectively and only analysed on a subset of patients, with only three identified cases of double-hit lymphoma (DHL) found. 35 patients with Primary Mediastinal B cell lymphoma were included in the analysis.r

As our understanding of the biology of DLBCL has increased, it is apparent that it is a genetically heterogeneous disease. Based on gene expression profiling, the putative cell of origin has been used to subclassify cases into germinal centre B-cell (GCB) and non-GCB (ABC or unclassified) categories, with the latter showing poorer response to therapy and inferior survival. Several studies have looked at dose intensification utilising DA-R-EPOCH as a means of improving outcomes in patients with non-GCB tumours.

Wilson et al.r looked at 69 patients with previously untreated DLBCL, who received DA-R-EPOCH, and compared outcomes between different prognostic groups according to international prognostic index (IPI) and to germinal centre (GC) vs non-GC phenotype. High risk by IPI had 54% event-free survival (EFS) at 62 months compared with 92% and 87% in the high-intermediate and low-intermediate groups respectively. EFS was 94% vs 58% for GC vs non-GC phenotype respectively.

Outcomes in GCB type DLBCL over two trials show 100% EFS at 5 years in HIV negative GCB DLBCL,r and 95% EFS at 5 years in HIV positive GCB DLBCL. A modification of the DA-EPOCH regime substituting high dose dexamethasone for prednisolone, and administering cycles at 14-day intervals, also achieved encouraging PFS and OS rates, especially in high-risk disease.r

While these single-arm studies to date have shown some promising results compared to historical controls, prospective data is lacking, and the failure to identify a survival advantage in all-comers means that there is insufficient evidence to recommend dose intensification in this group at this time.  Of note, other agents are currently being studied to try to improve outcomes in this group.

At present, there is no evidence to support the routine use of DA-R-EPOCH in patients with DLBCL, either GCB or non-GCB, without demonstrated MYC rearrangements.r

Currently, some of the main areas of interest include (1) improvement of cure rates in poorer prognosis disease, (2) improving outcomes in primary mediastinal B cell lymphoma (3) the treatment of Burkitt lymphoma (4) the treatment of aggressive NHL in HIV-infected individuals.

Treatment of Burkitt lymphoma

In a Phase II single-arm study of 19 HIV negative patients with Burkitt lymphoma, DA-R-EPOCH achieved 95% freedom from progression and 100% EFS.r A modified (reduced-intensity chemotherapy with double-dose Rituximab) "short course" regimen was given to 11 HIV patients, achieving 100% freedom from progression (FFP) and 90% OS. Patients received 2 cycles following complete response (CR), for a total of 6-8 cycles. It should be noted that this study involved small numbers of patients with CNS disease, and these patients received IT methotrexate.

Aggressive NHL in HIV infected individuals

A recent pooled analysis of aggressive lymphomas in the HIV population compared treatment using DA-R-EPOCH with R-CHOP,r and found improved EFS and OS with DA-R-EPOCH (hazard ratios 0.4 [95% CI 0.23-0.69] and 0.38 [95%CI 0.21-0.69] respectively). CD4 counts of < 50/µL or aaIPI (age-adjusted International Prognostic Index) were markers of poor outcome.

Earlier studiesr evaluated DA-EPOCH in this setting. This prospective single-arm trial evaluated DA-EPOCH in 39 patients with newly diagnosed AIDS-related lymphoma (80% DLBCL). ART was deferred until completion of chemotherapy.  Results showed CR in 74% and at median follow-up. 53 months, estimated PFS was 73% and OS 60%.  5 year OS for patients with CD4 counts >100/microL and ≤100/micro were 87 and 16% respectively.

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase II trials Wilson et al. 2002r Yes No Does not include rituximab
Jermann et al. 2004r Yes No Rituximab 375 mg/m2 day 1, doxorubicin 15 mg/m2 + etoposide 65 mg/m2 + vincristine 0.5 mg as a continuous i.v. infusion days 2-4, cyclophosphamide 750 mg/m2 day 5 and prednisone 60 mg/m2 orally days 1-14.

Garcia-Suarez et al. 2007r

 Yes Yes Prednisone 60 mg/m2 daily
Purroy et al. 2015r Yes - -

Wilson et al. 2012r

 Yes Yes -
Garcia-Suarez et al. 2013r Yes - -

Dunleavy et al. 2013r

 Yes Yes -

Barta et al. 2012r

 Yes No Rituximab 375 mg/m2 given day -2, cyclophosphamide is dose-escalated up to 750 mg/m2, prednisone 60 mg/m2 PO daily days 1-5
Phase III trials  CALGB/Alliance 50303. Wilson et al. 2016r

Yes 

 Yes 

Active Comparator Arm A - R-CHOP 

Experimental Arm B - DA-EPOCH-R

Retrospective studies 

 Petrich et al. 2014r Yes  N/A N/A
Oki et al. 2014r Yes  N/A R-CHOP v R-EPOCH v R-HyperCVAD in patients with double hit lymphoma (DHL) 

Case studies 

 Friedberg 2017r Yes  N/A - 
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN V4. May 2018 Yes Yes  - 
BCCA May 2018 Yes Yes  -
CCO March 2018 Yes  Yes  -

Efficacy

High-grade B-cell lymphoma (including DLBCL) with MYC and BCL-2 or BCL-6 translocations (WHO 2016) 

Garcia-Suarez et al.r studied 33 patients with poor prognosis previously untreated DLBCL who received DA-R-EPOCH. All patients had at least 2 adverse prognostic factors on the IPI (International Prognostic Index). 24% had bulky disease. Overall response rate (ORR) was 97%, with CR 81% and partial response (PR) 16%. Long-term follow up of this study demonstrated 10-year EFS and OS rates of 47.8% and 63.6% respectively.r Patients with bcl6 rearrangement had an OS of 100%, with the authors postulating that the addition of etoposide may downregulate bcl6 expression.

Friedbergr summarises the treatment of Double and Triple Hit Lymphomas (DHL/THL) in this manuscript.  The utility of “aggressive” chemoimmunotherapy regimens is broadly supported in view of the poor outcomes of such patients with R-CHOP alone.  There were insufficient numbers of DHL/THLs for post-hoc subset analysis in the CALGB study to assess superiority of DA-R-EPOCH over R-CHOP for unselected DLBCL,r however, there are some datar to suggest superior response rates (improved PFS) of “intensive” immunochemotherapy regimens over R-CHOP.  These retrospective, pooled data appears to support a more intensive regimen, however, utility of one (DA-R-EPOCH, HyperCVAD/MA, R-CODOX-M/IVAC) regimen over others is not suggested, and difference in results may be attributed to other issues studied, e.g. patient population.  Consolidation with AutoSCT appears not to improve survival in the de novo setting. 

Dunleavy et al. have recently published a Phase II, multicentre prospective study of DA-R-EPOCH in 53 patients with MYC rearranged DLBCL.r Of these, 19 patients had sole rearrangement of MYC, and 24 had additional rearrangement of BCL2, BCL6 or both. There were 3 treatment-related deaths. The 48-month EFS and OS were 71% and 76.7% respectively.

Oki et al.r.have published the largest case series of DHL.  This included retrospective analysis of 129 patients with DHL confirmed by FISH.  Similar to the Petrichr data, there is a suggestion that DA-R-EPOCH is a superior regimen to R-CHOP for DHL, certainly with respect to EFS, (see below) however, this is retrospective data, and relevant biases need to be therefore considered.  CNS relapse occurred in 10 - 15%, highlighting the need for CNS prophylaxis with DHL.  

Howlett et al. published a systematic review and meta-analysis of the use of R-CHOP, DA-R-EPOCH and intensive dose chemotherapy protocols such as CODOX-M/R-IVAC, R-HyperCVAD/R-M/C. They included 394 patients from 11 studies in the analysis of which 180 received R-CHOP, 91 received DA-R-EPOCH and 123 received dose-intensive protocols. The median PFS for the groups was 12.1, 22.2 and 18.9 months respectively, with a significant improvement in PFS with DA-R-EPOCH compared to R-CHOP, however, there was no significant improvement in OS.r

Of note, on immunohistochemistry, tumours may demonstrate high levels of expression of MYC, BCL-6 and BCL-2. While in many cases this corresponds to findings of gene rearrangements on FISH analysis, this is not always the case. Whether the use of dose escalation in these so-called double- or triple-expressors also confers an advantage is the source of interest, however the studies to date have failed to clearly demonstrate an advantage, and recommendations therefore remain to dose escalate in the case demonstrated MYC, BCL2 and/or BCL6 rearrangements only.

CNS prophylaxis

CNS disease poses a particular challenge in patients with DLBCL, including patients with CNS involvement at the time of presentation, as well as the risk of CNS relapse. Patients who experience CNS relapse have very poor prognosis, however, the risk of CNS relapse is less than that seen in other types of high-grade lymphoma such as Burkitt Lymphoma.r Higher risk patients include those with a greater burden of extranodal disease, increased age, high LDH and unfavourable tumour biology, including double and triple hit disease.r Of note, DA-R-EPOCH does not have good CNS penetration, and so patients with CNS involvement, or deemed to be at high risk of CNS involvement, require additional measures to be taken. Several strategies have been explored, including use of intrathecal methotrexate incorporated into the DA-R-EPOCH protocol, and use of high dose methotrexate given in between cycles.rrr

When considering addition of CNS prophylaxis, the toxicity of the approaches needs to be considered, particularly for patients with other co-morbidities, such as baseline renal dysfunction, who may be at increased risk of toxicity due to reduced clearance. Furthermore, protocols incorporating high dose methotrexate are usually given as an inpatient and therefore require planned admissions for administration, hydration and monitoring of clearance. It is of note that investigations into the use of intrathecal methotrexate have shown variability in CSF concentrations, and appear to have sufficient dose concentration in the leptomeninges, but do not appear to have sufficient penetration for parenchymal disease. This is of particular importance given that, in the rituximab era, the majority of CNS relapses are intraparenchymal.rr Conversely, use of systemic methotrexate requires a sufficient dose concentration to ensure appropriate CNS penetration, requiring rapid infusions at sufficient doses.r

There is a paucity of prospective randomised control trials looking at CNS prophylaxis in DLBCL, particularly looking at IT methotrexate vs systemic therapy. Several retrospective and prospective studies have been done looking at various strategies, although many of these used combined modalities. 

CNS prophylaxis with high dose methotrexate is supported by several studies, showing decreased risk of CNS relapse albeit at the expense of increased toxicity. Ferreri et al. showed a risk of relapse in high-risk patients treated with high dose methotrexate of 2.5% vs 12% in those either not receiving CNS prophylaxis, or receiving intrathecal therapy alone.r There is minimal evidence to suggest safety of DA-R-EPOCH with intravenous methotrexate to date. A small case series of 5 patients  looked at the use of a combination of DA-R-EPOCH and high dose methotrexate with no treatment-related deaths.r

(A) Progression-free and (B) overall survival curves estimated from the meta-analysis r

                   

© British Journal of Haematology 2015

Primary mediastinal diffuse large B cell lymphoma.

A single-arm, Phase II study showed excellent outcomes using DA-R-EPOCH for 51 patients with newly diagnosed primary mediastinal B cell lymphoma, with the aim of being able to omit adjuvant mediastinal radiation therapy. OS was 97% at 5 years, with 1 death due to secondary acute myeloid leukaemia. EFS was 93%. Only 2 patients did not achieve CR, and these subsequently entered CR after receiving radiation therapy.r

A subsequent multicentre, retrospective analysis with propensity scoring of 56 patients receiving R-CHOP and 76 receiving DA-R-EPOCH revealed similar 2-year OS (89% vs 91%). Fewer patients receiving DA-R-EPOCH were given consolidative radiation therapy (13.2% versus 58.9% for R-CHOP, p<0.001).r

A randomised, open-label, multicentre trial to assess the role of radiation therapy in patients achieving a PET CR post at least 6 cycles of chemoimmunotherapy (R-CHOP, DA-R-EPOCH and others) is ongoing (Clinicaltrials.gov NCT01599559).  The potential to omit radiation therapy is appealing, particularly in younger female patients.

Treatment of Burkitt lymphoma

DA-R-EPOCH has been utilised in the treatment of Burkitt lymphoma in both HIV positive and HIV negative patients. Compared to many other Burkitt lymphoma protocols, DA-R-EPOCH is less toxic and shows excellent response rates regardless of HIV status, age or disseminated disease. A single-arm Phase II study by Dunleavy et al. of 19 HIV negative patients using DA-R-EPOCH demonstrated 95% FFP and 100% EFS.r

CNS disease is of concern in Burkitt given a high risk of CNS relapse, even in those with negative findings at time of diagnosis. There have been various strategies for managing this. The Roschewski trial did not use CNS prophylaxis in patients who were classified as having low-risk disease, and no patients had progression. Other strategies have included the use of CNS prophylaxis with IT methotrexate at varying frequencies, however, this remains an area requiring more study.r

PFS, OS and PFS by subset in the Phase III Intergroup Trial Alliance/CALGB 50303r

@Journal of Clinical Oncology 2019

Toxicity

DA-R-EPOCH is generally well tolerated, with the major toxicities being neutropenia, febrile neutropenia and thrombocytopenia. Toxic deaths have been rarely reported, and secondary AML has also been rarely reported, usually in pre-treated patients.r

© British Journal of Haematology 2007

In the Phase III trial comparing upfront R-CHOP versus DA-R-EPOCH in unselected patients with DLBCL, there was a significant increase in grade 3-4 toxicities including haematological, infective and neuropathy in those assigned to DA-R-EPOCH.r

© Journal of Clinical Oncology 2019

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Version 6

Date Summary of changes
16/03/2021 Dose modifications section updated. Link to dose adjustment paradigm under treatment schedule removed. Version number changed to v.6     
01/10/2021 Drug status updated: rituximab SC is TGA registered but no longer PBS listed.
24/01/2022 Pulmonary toxicity added to side effects.

Version 5

Date Summary of changes
09/03/2020 Biosimilar rituximab added to clinical information. Version number changed to v.5    
27/03/2020

Protocol presented and reviewed at the Haematology Reference Committee meeting. 

  • Updated CNS prophylaxis note.
  • Evidence section updated.

Version 4

Date Summary of changes
11/10/2013 New protocol taken to Haematology Reference Committee meeting.
14/11/2013 Approved and published on eviQ review in 2 years.
29/05/2014 References added to the notes section regarding the compatibility and stability of compounding vincristine + doxorubicin + etoposide/phosphate.
13/08/2014 Added link to ALLG, ANZCTR and Lymphoma Australia website with statement 'Patients with NHL should be considered for inclusion into clinical trials'.
11/09/2015

Reviewed at Haematology Reference Committee meeting with changes as below:

  • Indications section: removed elderly patients and added Burkitt lymphoma.
  • Notes re: outpatient administration being feasible and the need for a separate protocol for CNS prophylaxis added.
  • Added update from phase 3 study.
  • Added section in the evidence on treatment of Burkitt lymphoma.
31/05/2017 Transferred to new eviQ website. Version number change to v.3.Other changes include:
  • diluent volume of vincristine changed from ‘50 to 100 mL’ to ‘50 mL’ as per Australian Injectable Handbook Sixth Edition.
12/03/2018

Added:

  • Link to subcutaneous​ rituximab document underneath the treatment schedule.
  • Clinical information block on subcutaneous rituximab.
  • Link to the subcutaneous rituximab document into administration section.
  • Injection-site reaction side effect.
  • Note about subcutaneous rituximab to the patient information.
  • Version number changed to v.4.
09/07/2018

Protocol presented and reviewed at the May Haematology Reference Committee meeting. Discussion continued over email and protocol approved for publication with the following changes: 

  • Removal of limited evidence flag due to inclusion of phase III trial. 
  • Updated indications to include double- and triple-hit lymphomas 
  • Evidence section updated.
13/09/2019

Protocol presented and reviewed at the Haematology reference committee meeting. 

  • Evidence section updated.
10/10/2019 Clinical information updated with PBS expanded indications for G-CSF. 

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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https://www.eviq.org.au/p/783

31 Mar 2023