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Non-Hodgkin lymphoma R-MiniCHOP (rituximab CYCLOPHOSPHamide DOXOrubicin vinCRISTine prednisolone)

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

This protocol is based on limited evidence; refer to the evidence section of this protocol for more information.

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Cycle 1 to 6

Drug Dose Route Day
Prednisolone 40 mg/m2 ONCE a day PO 1 to 5
Rituximab 375 mg/m2 IV infusion 1
DOXOrubicin 25 mg/m2 IV 1
vinCRISTine 1 mg IV infusion 1
CYCLOPHOSPHamide 400 mg/m2 IV infusion 1
Pegfilgrastim 6 mg Subcut 6
Frequency:
21 days 
Cycles:
6 
Notes:
  • Consideration should be given to administering the first dose of rituximab on the day prior to CHOP in patients who have very bulky disease and likely to react.
  • A prephase treatment of prednisolone 100 mg PO daily for five to seven days prior to cycle 1 was administered in the NHL-B2 trialr to improve the performance status of their patients and reduce the side effects of the first cycle of chemotherapy. This may be considered at clinician's discretion prior to R-miniCHOP as this was not part of the study protocol.
  • G-CSF support was used at the clinician's discretion in the R-miniCHOP trial where the rate of neutropenia was 64%, with 40% of these patients experiencing grade 3 toxicity.r In view of these results and the vulnerability of this elderly population to infection, G-CSF support is recommended.
Drug status:

Pegfilgrastim: (PBS authority)

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

Cost:
~ $520 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, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

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

Cycle 1 to 6

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Prednisolone 40 mg/m2 (PO) ONCE a day on days 1 to 5.* Take in the morning 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 25 mg/m2 (IV) over 5 to 15 minutes
vinCRISTine 1 mg (IV infusion) in 50 mL sodium chloride 0.9% over 5 to 10 minutes

via minibag
CYCLOPHOSPHamide 400 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
Day 2 to 5
Prednisolone 40 mg/m2 (PO) ONCE a day on days 1 to 5.* Take in the morning with food.
Day 6
Pegfilgrastim 6 mg (Subcut) inject subcutaneously on day 6

* Dose for day 1 should be taken 60 minutes before rituximab infusion.

Frequency:
21 days 
Cycles:
6 

Cycle 1 to 6

Drug Dose Route Day
Prednisolone 40 mg/m2 ONCE a day PO 1 to 5
Rituximab 375 mg/m2 IV infusion 1
DOXOrubicin 25 mg/m2 IV 1
vinCRISTine 1 mg IV infusion 1
CYCLOPHOSPHamide 400 mg/m2 IV infusion 1
Pegfilgrastim 6 mg Subcut 6
Frequency:
21 days 
Cycles:
6 
Notes:
  • Consideration should be given to administering the first dose of rituximab on the day prior to CHOP in patients who have very bulky disease and likely to react.
  • A prephase treatment of prednisolone 100 mg PO daily for five to seven days prior to cycle 1 was administered in the NHL-B2 trialr to improve the performance status of their patients and reduce the side effects of the first cycle of chemotherapy. This may be considered at clinician's discretion prior to R-miniCHOP as this was not part of the study protocol.
  • G-CSF support was used at the clinician's discretion in the R-miniCHOP trial where the rate of neutropenia was 64%, with 40% of these patients experiencing grade 3 toxicity.r In view of these results and the vulnerability of this elderly population to infection, G-CSF support is recommended.
Drug status:

Pegfilgrastim: (PBS authority)

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

Cost:
~ $520 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, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

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

Cycle 1 to 6

Day 1
Paracetamol 1,000 mg (PO) 60 minutes before treatment
Loratadine 10 mg (PO) 60 minutes before treatment
Prednisolone 40 mg/m2 (PO) ONCE a day on days 1 to 5.* Take in the morning 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 25 mg/m2 (IV) over 5 to 15 minutes
vinCRISTine 1 mg (IV infusion) in 50 mL sodium chloride 0.9% over 5 to 10 minutes

via minibag
CYCLOPHOSPHamide 400 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 30 to 60 minutes
Day 2 to 5
Prednisolone 40 mg/m2 (PO) ONCE a day on days 1 to 5.* Take in the morning with food.
Day 6
Pegfilgrastim 6 mg (Subcut) inject subcutaneously on day 6

* Dose for day 1 should be taken 60 minutes before rituximab infusion.

Frequency:
21 days 
Cycles:
6 
  • Diffuse large B-cell non-Hodgkin lymphoma (NHL) in elderly patients not suitable for full dose R-CHOP
Safety alert vincristine administration

For safe administration of vincristine refer to the safety alert issued by the Australian Commission on Safety and Quality in Health Care
Venous access required

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

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

High risk with rituximab.

Hypotension may occur during rituximab infusion. Evaluate individual patient benefits and risks and consider withholding antihypertensive treatments for 12 hours prior to and during, and for one hour after each infusion.

Read more about Hypersensitivity reaction
Premedication

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

Note: a corticosteroid is included as part of this treatment and therefore additional corticosteroid may not be required as premedication.

Please refer to the treatment schedule for the 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.

Even though a combination of an NK1 receptor antagonist, 5HT3, and a steroid is available on the on the PBS for the prevention of nausea and vomiting associated with all moderate to highly emetogenic anti-cancer therapies, we have opted not to include the NK1 in the treatment schedule.  

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

Ensure that patients also have sufficient antiemetics for breakthrough emesis:

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

Prochlorperazine 10 mg PO every 6 hours when necessary.

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

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

Criteria for reducing the total anthracycline cumulative lifetime dose include:

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

Baseline clinical assessments include echocardiogram (ECHO) or gated heart pool scan (GHPS) and electrocardiogram (ECG) evaluation.

Patients with normal baseline cardiac function (left ventricular ejection fraction (LVEF) > 50%) and low risk patients require LVEF monitoring when greater than 70% of the anthracycline threshold is reached or if the patient displays symptoms of cardiac impairment. Post-treatment cardiac monitoring is recommended for patients who have received high levels of total cumulative doses of anthracyclines at the clinician's discretion.

Read more about cardiac toxicity associated with anthracyclines
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
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.
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

­

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.
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, eGFR, LFTs, LDH and BSL at baseline, prior to each treatment, and 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.

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 impact 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.

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 75 Dose modification is not generally indicated. Consider treatment delay and/or add G-CSF
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)		 Cyclophosphamide Doxorubicin Rituximab Vincristine Prednisolone*
≥ 60

Full dose

Full dose

Full dose

 Full dose

No dose reduction required in kidney dysfunction.

 

 

 

 

 

 

 

 

 

 

 
45 - 59

Full dose

Full dose 

Full dose 

Full dose
30 - 44

Full dose

Full dose

Full dose

Full dose
15 - 29

Full dose

Potential for increased risk of adverse events

Full dose

Full dose

Full dose
< 15
(without kidney replacement therapy)

Consult a multidisciplinary
team consisting of
oncology/haematology with
nephrology and/or clinical
pharmacology for the
management of dosing.

Full dose

Full dose

Full dose

* This drug was not included in the ADDIKD guideline.
Hepatic impairmentr
Bilirubin (micromol/L)*
20 to 50  Reduce doxorubicin by 50% 
51 to 85  Reduce doxorubicin by 75% and reduce vincristine by 50% 
Greater than 85  Not recommended, consider alternative protocol 
*Note: elevated bilirubin can occur in disorders where dose reduction may not be indicated (e.g. Gilbert's syndrome, haemolysis etc). If dose reduction is considered, reassess liver function prior to each cycle and increase doses if tolerated.
Peripheral neuropathy
Grade 2 Consider omitting vincristine

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.

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
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor kidney function closely
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 etc.) 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
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, contrast dye, frusemide, NSAIDs etc.) Additive nephrotoxicity Avoid combination or monitor kidney function closely
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, ritonavir etc.) 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
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
Immunosuppressants (eg. abatacept and baricitinib etc.) Increased risk of infection Concurrent use not recommended. If an immunosuppressant must be used, monitor closely for signs of infection
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 and Australian Injectable Drugs Handbook websites for further information.

Day 1

Approximate treatment time: 8 hours (initial); 4 to 6 hours (subsequent)

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).

Insert IV cannula or access TIVAD or CVAD.

  • weigh patient each visit
  • dipstick urinalysis each visit

Hydration if prescribed.

Prednisolone

Administer prednisolone:
  • orally ONCE a day on days 1 to 5
  • to be taken in the morning with or immediately after food.

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 40 mg/m2 orally (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 ~ 50 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

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 ~ 50 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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Doxorubicin

Extravasation of a vesicant is a medical emergency. Monitor for signs of extravasation throughout administration.

Administer doxorubicin (vesicant):
  • over 5 to 15 minutes
    • via a minibag OR
    • by IV bolus via a side port of a freely flowing IV infusion
  • flush with ~150 mL of sodium chloride 0.9%.
Potential adverse events:
  • potential for flare reaction during administration of doxorubicin (facial flushing and red streaking along the vein), stop infusion and exclude extravasation before continuing at a slower rate of infusion
  • although rare, cardiac arrhythmias may occur during or immediately after doxorubicin administration, if sudden onset of dyspnoea, palpitations or irregular pulse occurs, stop administration and obtain urgent medical officer review.

Vincristine

Extravasation of a vesicant is a medical emergency. Monitor for signs of extravasation throughout administration.

Administer vincristine (vesicant):
  • via a minibag over 5 to 10 minutes
  • flush with ~150 mL of sodium chloride 0.9%.

Cyclophosphamide

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

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

Day 6

Pegfilgrastim

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

Discharge information

Prednisolone tablets - with written instructions on how to take them.

Antiemetics - as/if prescribed.

Laxatives - ensure patient has prophylactic laxatives.

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.

Immediate (onset hours to days)
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
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Red-orange discolouration of urine

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

Read more about taste and smell changes

Early (onset days to weeks)
Neutropenia

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

Read more about immediate management of neutropenic fever
Thrombocytopenia

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

Read more about thrombocytopenia
Constipation
Fatigue

Read more about fatigue
Haemorrhagic cystitis

An inflammatory process, characterised by diffuse bladder mucosal inflammation resulting in haemorrhage. Patients are at risk following blood and marrow transplant (BMT) or treatment with cyclophosphamide, ifosfamide and/or radiation therapy.

Read more about haemorrhagic cystitis
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
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)
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
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
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

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy worldwide and its incidence increases with age with approximately 40% of cases occurring in patients over 70 years of age.r r r Retrospective analyses have shown that the outcome of elderly patients is worse than that of younger patients but that some elderly patients do have a complete response to treatment and long-term survival.rrrrrr It is unclear if DLBCL in the elderly is intrinsically different from that in younger patients. There are concerns about the tolerability and efficacy of chemotherapy in the elderly due to the paucity of data in this patient population and the evidence that dose reductions in the treatment of DLBCL affects overall survival.rr There is also greater variability in drug pharmacokinetics in the elderly for example older women have reduced rituximab clearance, resulting in higher serum levels and prolonged exposure times.r The addition of rituximab to chemotherapy in the elderly may offset the potential negative effect of chemotherapy dose reduction, leading to acceptable efficacy and reduced toxicity.rrrr

The evidence supporting this protocol is provided by the only prospective trial in this patient cohort. This study was a multicenter, single-arm, phase 2 study of 150 patients aged over 80 years who had DLBCL between Jan 9, 2006, and Jan 23, 2009. 149 patients were included in the intention-to treat analyses.r

Inclusion criteria

  • Patients greater than 80 years with untreated histological proven CD20+ diffuse large B cell lymphoma according to WHO classification
  • Ann Arbor stage I bulky to stage IV disease
  • Age-adjusted international prognostic index score of 1,2 or 3
  • Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less Minimum life expectancy of 3 months
  • Negative HIV, hepatitis B virus, and hepatitis C virus

Exclusion Criteria

  • Any other lymphoma subtype
  • History of treated or non-treated indolent lymphoma
  • CNS or meningeal involvement
  • Contraindication to any drug in the chemotherapy regimen
  • Serious active disease according to the investigator's decision
  • Organ dysfunction: Creatinine greater than 150 umol/L, bilirubin concentration greater than 30 umol/L or transaminases over 2.5 times the maximum normal concentration, unless related to lymphoma
  • Neutrophil count less than 1.5x109/L or platelet count less than 100x109/L, unless caused by bone marrow infiltration
  • History of cancer during the past 5 years, except non-melanoma skin tumours or stage 0 (insitu) cervical carcinoma
  • Treatment with any investigational drug within 30 days before the planned first cycle of chemotherapy
  • Under the care of a guardian

All patients received six cycles of rituximab combined with low-dose CHOP (R-miniCHOP) at 3-week intervals. Patients received 375 mg/m2 rituximab, 400 mg/m2 cyclophosphamide, 25 mg/m2 doxorubicin, and 1 mg vincristine on day 1 of each cycle, and 40 mg/m2 prednisone was given on days 1–5 with no pre-phase prednisone which can be used to improve the performance status reduce toxicity of the first cycle in older patients.r Prevention of tumour lysis syndrome by alkalinisation or hypouricaemic drugs was done if necessary. Antiemetic therapy with 5HT3 antagonists was given at each cycle. Prophylactic granulocyte colony-stimulating factor (G-CSF) or erythropoietin support was left to the discretion of the treating physician. However, in the event of severe neutropenia or neutropenic fever, subcutaneous G-CSF was recommended from day 6 to 13 of the subsequent cycle or until neutrophils were 1.0 x109/L or more. There was no dose adjustment in the event of haematological toxicity. However, the next R-miniCHOP cycle was postponed until the neutrophil count reached 1.0 x 109/L and the platelet count 100 x 109/L, with a maximum of 28 days between two consecutive cycles. If these counts were not reached within 28 days, treatment was stopped. In the event of grade 2 neurological vincristine-related toxicity (sensory or motor polyneuritis, constipation, or visual or auditory changes) vincristine was discontinued.r

The primary endpoint was overall survival, both unadjusted and adjusted for treatment and baseline prognostic factors. The secondary endpoints were response to treatment; event-free survival, disease-free survival, progression free survival and safety.r

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase II trials Peyarde et al Yes Yes  
N/A N/A N/A  
Case series N/A N/A N/A  
Observational studies N/A N/A N/A  
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN Version 4.2023 Yes Yes  
BCCA N/A N/A N/A  
CCO N/A N/A N/A  

Efficacy

The median age was 83 years (range 80–95). After a median follow-up of 20 months (range 0–45), the median overall survival was 29 months (95% CI 21 to upper limit not reached); 2-year overall survival was 59% (49–67%). In multivariate analyses, overall survival was only affected by a serum albumin concentration of 35 g/L or less (hazard ratio 3.2, 95% CI 1.4–7.1; p=0.0053). Median progression-free survival was 21 months (95% CI 13 to upper limit not reached), with a 2-year progression free survival of 47% (38–56).r Quality of life assessment was not planned in the protocol. Instrumental activities of daily living were used to assess patient ability to tolerate immunochemotherapy but not comprehensive geriatric assessment. In univariate analyses, an impaired IADL score was associated with poor survival, independent from ECOG. Despite the absence of a control arm, this study suggests that in selected patients older than 80 years who have DLBCL and a good performance status, immunochemotherapy with R-miniCHOP offers a good compromise between efficacy and safety.

Figure 1: Univariate analysis of prognostic factors for overall survival.r

© The Lancet 2011

Figure 2: Multivariate analyses of prognostic factors for overall survival. r

© The Lancet 2011

Figure 3: Progression free survial, response at end of treatment and disease-free survial. r

© The Lancet 2011

Toxicity

58 deaths were reported, 33 of which were secondary to lymphoma progression. 12 deaths were attributed to toxicity of the treatment. The most frequent side-effect was haematological toxicity (grade =3 neutropenia in 59 patients; febrile neutropenia in 11 patients).r

Table 1: Association of deaths with treatment during the treatment phase.r

© The Lancet 2011

Table 2: Incidence of non-haematological toxicity by grade and serious adverse events.r

© The Lancet 2011

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Version 6

Date Summary of changes
20/03/2024

Protocol updated with ADDIKD guideline recommendations. New kidney dosing recommendation table added to dose modification section. PDF of previous protocol.

Hepatic impairment dose modification recommendations updated as per the eviQ Haematology Reference Committee consensus.

Version number changed to V.6.

Version 5

Date Summary of changes
28/04/2023 Protocol reviewed electronically by the Haematology Reference Committee. Updates include:
  • subcutaneous rituximab information removed from the following sections - treatment schedule, clinical information, administration, patient information
  • Minor formatting changes

Increased to version 5. Review in 4 years.
07/09/2023

The following changes were made:

  • Fertility, pregnancy and lactation added to clinical information
  • Central venous access devices added to "Other information about your treatment" in the patient information

Version 4

Date Summary of changes
09/03/2020 Biosimilar rituximab added to clinical information. Version number changed to V.4     
27/03/2020 Reviewed by Haematology Reference Committee with no significant changes, review in 4 years.
01/10/2021 Drug status updated: rituximab SC is TGA registered but no longer PBS listed.
21/01/2022 Note added to dose modifications.
24/01/2022 Pulmonary toxicity added to side effects.

Version 3

Date Summary of changes
11/09/2015 New protocol discussed at RCM.
07/01/2016 Approved and Published on eviQ.
31/05/2017

Transferred to new eviQ website. Version number change to V.2. 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.3.
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. 

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/1882

11 Oct 2024