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Non-Hodgkin lymphoma ESHAP (etoposide methylprednisolone cytarabine ciSplatin)

This protocol was published over 10 years ago and has been assessed by the reference committee as suitable to be reviewed as required. The review due date has been removed. If something in this protocol requires reference committee consideration, please click on the feedback button at the bottom of the page.

Read more about the as required review process in this factsheet.

Patients with lymphoma should be considered for inclusion into clinical trials. Link to ALLG website opens in a new tab or window, ANZCTR website opens in a new tab or window and Lymphoma Australia website. opens in a new tab or window

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Cycle 1 to 3

Drug Dose Route Day
Methylprednisolone sodium succinate 500 mg IV infusion 1 to 5
ciSplatin 25 mg/m2 IV infusion 1 to 4
Etoposide 40 mg/m2 IV infusion 1 to 4
Cytarabine (Ara-C) 2,000 mg/m2 IV infusion 5
Pegfilgrastim 6 mg Subcut 6

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

Frequency:
21 days to 28 days depending on myelosuppression
Cycles:
3 to 6
Notes:
  • For patients unable to tolerate full dose methylprednisolone, consider 250 mg (dose range in the trial was 250 mg to 500 mg daily).
  • While rituximab has been given in combination with ESHAP, there is no evidence indicating R-ESHAP is superior to ESHAP alone (Aviles et al 2010).r
  • Rituximab would be included in second line therapy if there is relapse after a reasonable remission (greater than 6 months), however rituximab would often be omitted in patients with primary refractory disease.r
Drug status:

Pegfilgrastim: (PBS authority opens in a new tab or window)

All other drugs in this protocol are on the PBS general schedule opens in a new tab or window

Cost:
~ $860 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). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

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.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

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, growth factor support 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 3

Day 1 to 4
Methylprednisolone sodium succinate 500 mg (IV infusion) in 50 mL to 100 mL sodium chloride 0.9% over 30 minutes
ciSplatin 25 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 24 hours
Etoposide 40 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
Day 5
Methylprednisolone sodium succinate 500 mg (IV infusion) in 50 mL to 100 mL sodium chloride 0.9% over 30 minutes
Cytarabine (Ara-C) 2,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 2 to 3 hours
Day 6
Pegfilgrastim 6 mg (Subcut) inject subcutaneously 24 hours after chemotherapy

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

Frequency:
21 days to 28 days depending on myelosuppression
Cycles:
3 to 6

Cycle 1 to 3

Drug Dose Route Day
Methylprednisolone sodium succinate 500 mg IV infusion 1 to 5
ciSplatin 25 mg/m2 IV infusion 1 to 4
Etoposide 40 mg/m2 IV infusion 1 to 4
Cytarabine (Ara-C) 2,000 mg/m2 IV infusion 5
Pegfilgrastim 6 mg Subcut 6

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

Frequency:
21 days to 28 days depending on myelosuppression
Cycles:
3 to 6
Notes:
  • For patients unable to tolerate full dose methylprednisolone, consider 250 mg (dose range in the trial was 250 mg to 500 mg daily).
  • While rituximab has been given in combination with ESHAP, there is no evidence indicating R-ESHAP is superior to ESHAP alone (Aviles et al 2010).r
  • Rituximab would be included in second line therapy if there is relapse after a reasonable remission (greater than 6 months), however rituximab would often be omitted in patients with primary refractory disease.r
Drug status:

Pegfilgrastim: (PBS authority opens in a new tab or window)

All other drugs in this protocol are on the PBS general schedule opens in a new tab or window

Cost:
~ $860 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). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

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.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

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, growth factor support 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 3

Day 1 to 4
Methylprednisolone sodium succinate 500 mg (IV infusion) in 50 mL to 100 mL sodium chloride 0.9% over 30 minutes
ciSplatin 25 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 24 hours
Etoposide 40 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
Day 5
Methylprednisolone sodium succinate 500 mg (IV infusion) in 50 mL to 100 mL sodium chloride 0.9% over 30 minutes
Cytarabine (Ara-C) 2,000 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 2 to 3 hours
Day 6
Pegfilgrastim 6 mg (Subcut) inject subcutaneously 24 hours after chemotherapy

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

Frequency:
21 days to 28 days depending on myelosuppression
Cycles:
3 to 6
  • Relapsed/refractory non-Hodgkin lymphoma prior to transplant
  • Usually used in transplant eligible patients for both salvage and peripheral blood stem cell (PBSC) mobilisation. This is an intense chemotherapy regimen and patients with poor ECOG performance status and significant comorbidities may not be appropriate for this regimen
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.

Read more about Hypersensitivity reaction
Antiemetics for multi-day protocols

Patients being treated with multi-day anticancer protocols should receive antiemetics tailored to the emetogenic risk of the drugs administered each day during treatment and for two days after completion of the anticancer protocol.

No standard antiemetic regimen exists for multi-day anticancer protocols. 

As this protocol includes a steroid, additional antiemetic steroids may not be required, despite the PBS approved combination of an NK1 receptor antagonist, 5HT3, and a steroid for the prevention of nausea and vomiting associated with all moderate to highly emetogenic anti-cancer therapies.

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
Cytarabine-induced neurotoxicity

This may occur in patients treated with high-dose cytarabine. Assess cerebellar function prior to each cytarabine dose.

Note: an increased risk of cytarabine-induced neurotoxicity has been associated with kidney dysfunction.

Read more about neurotoxicity associated with high-dose cytarabine and access the cytarabine cerebellar neurotoxicity assessment chart  
Ocular toxicities

Administer corticosteroid eye drops to minimise corneal toxicity from high dose cytarabine. Commence on the day of first dose of cytarabine and continue for at least 72 hours after completion of final cytarabine dose.

Read more about ocular toxicities associated with high dose cytarabine
Cytarabine syndrome

Treatment with cytarabine may cause a "cytarabine syndrome" characterised by flu-like symptoms, skin rash and occasionally chest pain.
Ototoxicity

Ototoxicity may occur with platinum-based therapy; patients should be monitored for signs and symptoms. Platinum compounds should be used with caution in patients with pre-existing conditions or risk factors.

Ototoxicity may become more severe in patients being treated with other drugs with nephrotoxic potential e.g. aminoglycosides.

An audiometry test should be performed if symptoms develop.

Read more about ototoxicity - tinnitus and hearing loss
Cisplatin dosing

Directly measured glomerular filtration rate (mGFR) is preferred for initial dosing when eGFR < 60 mL/min/1.73 m2, especially when cisplatin dose > 50 mg/m2 or when eGFR is unreliable (e.g., extremes of body composition, amputees, paraplegia).

Read more about prevention and management of cisplatin induced nephrotoxicity.
Hydration

Hydration helps to prevent cisplatin-induced nephrotoxicity.

The default regimen is appropriate for patients with normal electrolytes, kidney function, fluid status etc. and should be adjusted according to individual requirements.

Read more about cisplatin hydration regimens
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

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
Antifungal prophylaxis ­

Read more about antifungal prophylaxis drugs and doses.
Biosimilar drug

Read more about biosimilar drugs on the Biosimilar Awareness Initiative opens in a new tab or window page
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 opens in a new tab or window
Blood tests

FBC at baseline and repeat prior to each cycle.
EUCs, eGFR, LFTs, LDH and BSL at baseline and regularly throughout treatment as clinically indicated.
Hepatitis B screening and prophylaxis

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

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

Live vaccines are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease. Possible suboptimal response to inactivated vaccines.

For more information about vaccinations in people with cancer refer to the Australian Immunisation Handbook opens in a new tab or window.
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 fetal 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 impact of cancer treatment on fertility opens in a new tab or window
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) opens in a new tab or window unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

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

Haematological toxicity
ANC x 109/L (pre-treatment blood test), platelets x 109/L (pre-treatment blood test)
ANC less than 1.0 and/or platelets less than 100 Delay treatment until recovery
Kidney dosing recommendations 
  • Suggested dose modifications are based on the International Consensus Guideline on Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).
  • Where one or more drugs in a protocol is recommended to be avoided, consider using a clinically appropriate alternative treatment protocol instead.
  • Before dose adjusting or omitting a drug, consider treatment intent.
  • In kidney replacement therapy consult a multidisciplinary team consisting of oncology/haematology with nephrology and/or clinical pharmacology for the management of dosing. 
  • For complete information on individual drug recommendations please review the individual drug monograph in the ADDIKD guideline.
eGFR
(mL/min/1.73m2)		 Cisplatin Cytarabine* Etoposide Methylprednisolone**
≥ 60

Full dose

Full dose

Full dose

No dose reduction required in kidney dysfunction

 

 

 

 

 

 

 

 

 

 

 

 

 
45 - 59

Alternative protocol

OR

Reduce by 25 to 50%^

Potential for increased risk of adverse events

Reduce by 50%

Increased risk of adverse events 

Full dose

Increased risk of adverse events
30 - 44

Avoid

Not recommended - use alternative protocol

Alternative protocol

This drug may be given at this eGFR level (see ADDIKD guideline) however not recommended in this protocol

Alternative protocol

This drug may be given at this eGFR level (see ADDIKD guideline) however not recommended in this protocol
15 - 29

Avoid

Not recommended - use alternative protocol

Avoid

Not recommended - use alternative protocol

Alternative protocol

This drug may be given at this eGFR level (see ADDIKD guideline) however not recommended in this protocol
< 15
(without kidney replacement therapy)

Avoid

Not recommended - use alternative protocol

Avoid

Not recommended - use alternative protocol

Avoid

Not recommended - use alternative protocol

* Cytarabine dose modifications based on high dose cytarabine (≥ 1000 mg/m2) recommendations.

** This drug was not included in the ADDIKD guideline.

^ Extent of dose reduction should take into account intent of treatment, performance status, potential total cumulative cisplatin exposure.
Hepatic impairment
Consider dose reduction in mild and moderate hepatic impairment and omit in severe impairment

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:  

For more information see References & Disclaimer.

Cisplatin
  Interaction Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney function closely
Ototoxic drugs (e.g. aminoglycosides, frusemide, NSAIDs) Additive ototoxicity Avoid combination or perform regular audiometric testing
Neurotoxic drugs (e.g. vincristine, paclitaxel) Additive neurotoxicity Monitor closely for neuropathy if combination used
Paclitaxel Administration schedule may influence the development of myelosuppression Minimise toxicity by administering paclitaxel first in regimens using the combination
Carbamazepine, phenytoin, valproate Decreased antiepileptic plasma levels Monitor antiepileptic serum levels and seizure frequency for efficacy; adjust dosage as appropriate or select alternative antiepileptic (e.g. clonazepam, diazepam, lorazepam)
Cytarabine
  Interaction Clinical management
Cytidine deaminase (CDA) inhibitors (e.g. cedazuridine) Potential increased effect/toxicity of cytarabine due to reduced clearance Avoid combination or monitor for increased cytarabine effect/toxicity
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
Methylprednisolone
  Interaction Clinical management
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of methylprednisolone possible due to reduced clearance Avoid combination or monitor for methylprednisolone toxicity
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John's wort etc.) Reduced efficacy of methylprednisolone possible due to increased clearance Avoid combination or monitor for decreased clinical response to methylprednisolone
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 opens in a new tab or window and P‑gp opens in a new tab or window inhibitors. If treating VTE, avoid use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 opens in a new tab or window and P‑gp opens in a new tab or window  inhibitors.

Dabigatran: avoid combination with strong P‑gp opens in a new tab or window 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 opens in a new tab or window

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 or address chemical compatibilities related to IV drug preparation and administration. 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 opens in a new tab or window and Australian Injectable Drugs Handbook opens in a new tab or window websites for further information.

eviQ is currently updating the way information is presented in the administration section, if you notice any discrepancies please let us know, via feedback@eviq.org.au.

Days 1 to 4

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

Anti-cancer drug patient assessment tool prior to each day of treatment.

Anti-cancer drug induced neuropathy screening tool prior to each 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
  • strict fluid balance
  • dipstick urinalysis prior to treatment

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Commence corticosteroid eye drops before starting cytarabine. Continue for 72 hours after completion of the last dose of cytarabine.

Methylprednisolone

  • administer via IV infusion over at least 30 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%
  • there are reports of cardiac arrhythmias, circulatory collapse and/or cardiac arrest following rapid administration of large IV doses (greater than 500 mg over less than 10 minutes)

Cisplatin

Commence prehydration for cisplatin:
  • administer 10 mmol magnesium sulphate (MgSO4) in 1000 mL sodium chloride 0.9% over 60 minutes
  • ensure patient has passed urine prior to cisplatin administration as per institutional policy.
Administer cisplatin (irritant):
  • via IV infusion over 24 hours
  • flush with 100 mL of sodium chloride 0.9%
  • observe for hypersensitivity reactions which can increase with the number of cycles administered and when given with concomitant radiation therapy. 
Infusion-related reaction (IRR):

Stop infusion at first sign of anaphylaxis or severe IRR and manage as per emergency. 

Etoposide

Administer etoposide (irritant):
  • via IV infusion over 30 to 60 minutes
    • if using etoposide phosphate administer in ~ 50 mL sodium chloride 0.9% or glucose 5% over ~15 minutes
  • flush with ~ 100 mL sodium chloride 0.9%.
Infusion-related reaction:

Stop infusion at first sign of anaphylaxis or severe IRR and manage as per emergency. 

  • 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.
Potential adverse events:
  • rapid infusion may cause hypotension.

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

Day 5

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

Anti-cancer drug patient assessment tool prior to each treatment.

  • daily weight 
  • strict fluid balance  

Hydration if prescribed

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Continue corticosteroid eye drops until 72 hours after completion of the last dose of cytarabine.

Methylprednisolone

  • administer via IV infusion over at least 30 minutes
  • flush with ~ 50 mL of sodium chloride 0.9%
  • there are reports of cardiac arrhythmias, circulatory collapse and/or cardiac arrest following rapid administration of large IV doses (greater than 500 mg over less than 10 minutes)

Cytarabine 

Prior to administration:

Ensure corticosteroid eye drops have been administered before starting cytarabine.

Verify that cytarabine neurological assessment has been performed prior to administration of cytarabine:

  • if the patient scores 0 then administer cytarabine as charted
  • if the patient scores 1 or above, do not administer the cytarabine and immediately notify medical officer.
Administer cytarabine:
  • via IV infusion over 2 to 3 hours:
  • flush with ~50 mL of sodium chloride 0.9%.

Deaccess TIVAD or CVAD.

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

Day 6

Subcutaneous injection

Anti-cancer drug patient assessment tool prior to each day of treatment.

Continue corticosteroid eye drops until 72 hours after completion of the last dose of cytarabine.

Pegfilgrastim

  • administer subcutaneously on day 6; or ensure arrangements have been made for administration

Discharge information

Antiemetics - as/if prescribed.

Corticosteroid eye drops - for at least 72 hours after completion of final cytarabine dose.

Growth factor support - as/if prescribed, and arrangements for administration.

Prophylaxis medications - as/if prescribed, i.e. antifungals, antivirals, PJP prophylaxis, tumour lysis prophylaxis.

Patient information

Ensure patient receives protocol 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.
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Bone pain

Bone pain, usually in the lower back or pelvis, associated with G-CSF.
Cytarabine (Ara-C) syndrome

Flu-like symptoms including fever, myalgia and malaise can occur 6 to 12 hours after cytarabine administration. Symptoms generally resolve within 24 hours of completing therapy.
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
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Neurotoxicity

High dose cytarabine has been associated with acute cerebellar syndrome and diffuse cerebral dysfunction.

Read more about neurotoxicity associated with high dose cytarabine
Ocular toxicities

Reversible corneal toxicity (keratitis), haemorrhagic conjunctivitis, vision loss and other ocular side effects can occur with high dose cytarabine.  Corticosteroid eye drops must be administered concurrently with treatment. 

Read more about ocular toxicities associated with cytarabine
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
Oral mucositis

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following anti-cancer treatment, 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 and stomatitis
Fatigue

Read more about fatigue
Diarrhoea

Read more about treatment induced diarrhoea
Nephrotoxicity

Kidney dysfunction resulting from damage to the glomeruli, tubules or renal vasculature.
Hypomagnesaemia, hypokalaemia, hypocalcaemia

Abnormally low levels of magnesium, potassium and calcium in the blood.
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.
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
Ototoxicity

Tinnitus and hearing loss may occur due to damage in the inner ear. Tinnitus is usually reversible, while hearing loss is generally irreversible. Hearing loss is dose-related, cumulative and may be worse in those with pre-existing hearing problems.

Read more about ototoxicity - tinnitus and hearing loss

Late (onset weeks to months)
Cognitive changes (chemo fog)

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

Read more about cognitive changes (chemo fog) 
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 and scalp cooling

The evidence supporting this protocol is provided by a randomised study by Velasquez and colleagues comparing ESHA (etoposide, methylprednisolone, cytarabine) with ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin).r

The first 63 patients were randomised however markedly different response rates between ESHA (33%) and ESHAP (75%) lead to deletion of the ESHA arm of the study. A total of 122 patients receiving ESHAP were studied and the regimen was found to be active and tolerable in relapsed and refractory lymphoma. ESHAP is most often used as a salvage regimen prior to autologous stem cell transplantation,r however it is also tolerated by those not fit for transplantation.r

Efficacy

The responses seen to ESHAP in the original study are summarized in the table.r Further case series in other populations show similar overall response rates (53-63%).rr There is also evidence that ESHAP is a good regimen for mobilisation of stem cells for autologous harvest prior to transplantation.rrr

ESHAP response tabler

Lymphoma classification Number of patients Complete response (%) Partial response (%)
Low-grade 34 35 41
Intermediate-grade 85 38 20

De novo

 46 26 22
Transformed 18 50 17
Others 21 52 18
High-grade 3 33 0
Total 122 37 27

As with other second line lymphoma regimens, ESHAP has been given in combination with rituximab and proven safe and effective.rr It should be noted that there is not any evidence that R-ESHAP is superior to ESHAP, with the only randomised comparison of the two regimens showing no difference in response rate or survival.r

When R-ESHAP was studied in relapsed diffuse large B cell lymphoma, rituximab-naïve patients responded significantly better than those previously exposed to the drug.r Adding rituximab to ESHAP is unlikely to be beneficial if the patient is refractory to a first line therapy that included rituximab.

Toxicity

In the original study, nausea, vomiting and diarrhoea occurred in 67 % of patients and were mostly grade 1 to 2. Serum creatinine elevation to twice or more of baseline value due to cisplatin administration occurred in 22% of patients. Other toxic effects related to chronic cisplatin administration such as generalised weakness, peripheral neuropathy, hypomagnesemia, hypokalemia and anaemia.r

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Version 6

Date Summary of changes
11/03/2024
  • Protocol updated with ADDIKD guideline recommendations. New kidney dosing recommendation table added to dose modification section. PDF of previous protocol.
  • Protocol assessed by eviQ Haematology Reference Committee and deemed suitable to be reviewed as required. Flag added, review date removed and version number increased to V.6. Read more about as required review protocol status in this factsheet.
02/04/2024 Extravasation, tissue or vein injury added to side effects per updates to extravasation document.

Version 5

Date Summary of changes
22/09/2020 Biosimilar drug added to clinical information. Version number changed to V.5

Version 4

Date Summary of changes
09/10/2007 Minor editing and reformatting.
10/11/2008 Addition of links to hepatitis B and PCP information. Review and reformatting of patient information sheet.
08/09/2009 Reviewed and transferred to eviQ.
04/05/2011 New format to allow for export of protocol information.
Protocol version number changed to V.2.
Additional Clinical Information, Key Prescribing table and Key Administration table combined into new section titled Clinical Considerations.
Drug specific information placed behind the drug name link.
19/08/2011 Full protocol review at Haematology Reference Committee meeting:
- addition of information regarding addition of rituximab
- number of cycles changed to 3 to 6 (previously 1 to 2)
- cisplatin administration changed to 24 hours daily for 4 days (previously 22 hours) to be consistent with original trial
- antifungal prophylaxis preclinical information added
- evidence section rewritten
13/12/2011 PHC Role permission added.
11/08/2013 Discussed at review categorisation meeting, no changes, review in 2 years. PHC view removed.
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 RCM, no changes, review in 2 years, updated drug costs.

31/05/2017

 Transferred to new eviQ website. Version number change to V.4.
25/05/2018 Reviewed by Haematology Reference Committee with no significant changes, review in 2 years
13/09/2019 Reviewed by Haematology Reference Committee, no changes made. Review in 5 years.
10/10/2019 Clinical information updated with PBS expanded indications for G-CSF. 
27/03/2020 Reviewed by Haematology Reference Committee with no significant changes, review in 4 years.

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/124

29 Apr 2025