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Non-Hodgkin lymphoma R-GemOX (rituximab gemcitabine oxaliplatin)

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.

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
Rituximab 375 mg/m2 IV infusion * 1
Oxaliplatin 100 mg/m2 IV infusion 1
Gemcitabine 1,000 mg/m2 IV infusion 1

* 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.

Frequency:
14 days 
Cycles:
8 
Notes:
  • rituximab was given the day prior to gemcitabine and oxaliplatin in the El Gnaoui et al.r and Mounier et al.r trials.
  • order of drug administration for this protocol has been selected to minimise risk of extravasation. Some centres may choose to administer gemcitabine before oxaliplatin based on potential synergistic effects observed in vitro.rr
Drug status:

Rituximab SC: TGA registered but not PBS listed.

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

Cost:
~ $710 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
Dexamethasone 8 mg (PO) 60 minutes before treatment
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate *
Netupitant 300 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with palonosetron) 
Palonosetron 0.5 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with netupitant)
Oxaliplatin 100 mg/m2 (IV infusion) in 250 mL to 500 mL glucose 5% over 2 hours
Gemcitabine 1,000 mg/m2 (IV infusion) in 100 mL to 500 mL sodium chloride 0.9% over 30 minutes
Day 2 and 3
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 2 to 3 may not be required and may be reduced or omitted at the clinician's discretion. **

* 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.

** Link to ID 7 Prevention of chemotherapy induced nausea and vomiting

Note: order of drug administration for this protocol has been selected to minimise risk of extravasation. Some centres may choose to administer gemcitabine before oxaliplatin based on potential synergistic effects observed in vitro.rr

Frequency:
14 days 
Cycles:
8 

Cycle 1 to 8

Drug Dose Route Day
Rituximab 375 mg/m2 IV infusion * 1
Oxaliplatin 100 mg/m2 IV infusion 1
Gemcitabine 1,000 mg/m2 IV infusion 1

* 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.

Frequency:
14 days 
Cycles:
8 
Notes:
  • rituximab was given the day prior to gemcitabine and oxaliplatin in the El Gnaoui et al.r and Mounier et al.r trials.
  • order of drug administration for this protocol has been selected to minimise risk of extravasation. Some centres may choose to administer gemcitabine before oxaliplatin based on potential synergistic effects observed in vitro.rr
Drug status:

Rituximab SC: TGA registered but not PBS listed.

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

Cost:
~ $710 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
Dexamethasone 8 mg (PO) 60 minutes before treatment
Rituximab 375 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% as per graded administration rate *
Netupitant 300 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with palonosetron) 
Palonosetron 0.5 mg (PO)

60 minutes before chemotherapy (fixed dose preparation with netupitant)
Oxaliplatin 100 mg/m2 (IV infusion) in 250 mL to 500 mL glucose 5% over 2 hours
Gemcitabine 1,000 mg/m2 (IV infusion) in 100 mL to 500 mL sodium chloride 0.9% over 30 minutes
Day 2 and 3
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone doses on day 2 to 3 may not be required and may be reduced or omitted at the clinician's discretion. **

* 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.

** Link to ID 7 Prevention of chemotherapy induced nausea and vomiting

Note: order of drug administration for this protocol has been selected to minimise risk of extravasation. Some centres may choose to administer gemcitabine before oxaliplatin based on potential synergistic effects observed in vitro.rr

Frequency:
14 days 
Cycles:
8 
  • Relapsed/refractory CD20 positive non-Hodgkin lymphoma in patients either ineligible for high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT), or who have relapsed from a prior ASCT
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 oxaliplatin 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.

A NK1 receptor antagonist and a 5HT3 receptor antagonist in combination with dexamethasone are available on the PBS for primary prophylaxis of oxaliplatin induced nausea and vomiting.

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
Pulmonary toxicity

Dyspnoea developing within hours of the infusion has been reported in about 10% of patients treated with gemcitabine.

Read more about pulmonary toxicity associated with anti-cancer drugs.
Laryngopharyngeal dysaesthesia associated with oxaliplatin

Sensation of loss of breathing related to oxaliplatin without objective evidence of respiratory distress. Symptoms are often precipitated by exposure to cold.

Read more about laryngopharyngeal dysaesthesia associated with oxaliplatin
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 
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 and dose reduce if appropriate.

Read more about peripheral neuropathy

Link to chemotherapy-induced peripheral neuropathy screening tool
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

Assess patient for risk of developing tumour lysis syndrome.

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

­

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

­

Read more about antiviral prophylaxis drugs and doses
Growth factor support

G-CSF (short or long-acting) is available on the PBS for chemotherapy induced neutropenia depending on 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 and LDH at baseline, and prior to each cycle 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 effect of cancer treatment on fertility
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.
The dose recommendations in kidney dysfunction (i.e.renal impairment) displayed may not reflect those in the ADDIKD guideline and have been included for historical reference only. Recommendations will be updated once the individual protocol has been evaluated by the reference committee, with this version of the protocol then being archived. Clinicians are expected to refer to the ADDIKD guideline prior to prescribing in kidney dysfunction.
International Consensus Guideline for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD).

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

Haematological toxicity
ANC x 109/L (pre-treatment blood test)
less than 1.0 or febrile neutropenia Delay treatment until recovery and consider adding G-CSF for subsequent cycles
Platelets x 109/L (pre-treatment blood test)
less than 100 Delay treatment until recovery
Peripheral neuropathy
Grade 2 which is present at the start of the next cycle Reduce oxaliplatin by 25%,
if persists, omit oxaliplatin until recovery
Grade 3 or Grade 4 Omit oxaliplatin
Acute laryngo-pharyngeal dysaesthesia Increase oxaliplatin infusion time to 6 hours
Cease gemcitabine either of the following develop:r
  • pulmonary toxicity
  • thrombotic microangiopathy (TMA)/haemolytic uraemic syndrome (HUS)

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:  

Gemcitabine
  Interaction Clinical management

Warfarin		 Increased anticoagulant effect/increased bleeding risk due to decreased hepatic metabolism of warfarin and decreased synthesis of clotting factors Monitor INR regularly and adjust warfarin dosage as appropriate
Oxaliplatin    
  Interaction Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor renal function closely
Neurotoxic drugs (e.g. vincristine, paclitaxel) Additive neurotoxicity Monitor closely for neuropathy if combination used
Rituximab
  Interaction Clinical management
Antihypertensives Additive hypotensive effect Consider withholding antihypertensive medications 12 hours prior to the rituximab infusion
NK-1 antagonist e.g. aprepitant, fosaprepitant, netupitant
  Interaction Clinical management
Dexamethasone Increased effects/toxicity of dexamethasone due to inhibition of its metabolism via CYP3A4

Reduce dose of antiemetic dexamethasone by approximately 50% when adding a NK-1 antagonist. For protocols that already recommend a NK-1 antagonist, the dose reduction of antiemetic dexamethasone has already been taken into account.

If dexamethasone is part of the chemotherapy protocol, dose reduction as per the product information is not routinely recommended in clinical practice and no additional dexamethasone is required for antiemetic cover. 
Warfarin

Reduced anticoagulant efficacy of warfarin due to increased clearance (aprepitant induces CYP2C9). *Note interaction only applicable to aprepitant/ fosaprepitant

INR should be monitored in the 2 week period, particularly at 7 to 10 days following the administration of aprepitant/ fosaprepitant
Combined oral contraceptive Reduced contraceptive efficacy due to increased clearance. *Note interaction only applicable to aprepitant/ fosaprepitant Alternative non-hormonal methods should be used during and for 1 month after stopping aprepitant/ fosaprepitant
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of NK-1 antagonist possible due to increased clearance Avoid combination or monitor for decreased antiemetic effect. Consider using an alternative antiemetic regimen
CYP3A4 inhibitors (e.g. azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of NK-1 antagonist possible due to reduced clearance Avoid combination or monitor for increased adverse effects of NK-1 antagonist (e.g. headache, hiccups, constipation)
Drugs metabolised by CYP3A4 (e.g. etoposide, imatinib, irinotecan, midazolam, paclitaxel, vinblastine, vincristine etc.) Increased effects/toxicity of these drugs possible due to inhibition of CYP3A4 by NK-1 antagonist Avoid combination or monitor for increased toxicity especially with orally administered drugs
General
  Interaction Clinical management
Warfarin Anti-cancer drugs may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

Interaction with both CYP3A4 and P-gp inhibitors /inducers.

DOAC and anti-cancer drug levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).

Apixaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. If treating VTE, avoid use with strong CYP3A4 and P‑gp inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 and P‑gp  inhibitors.

Dabigatran: avoid combination with strong P‑gp inducers and inhibitors.

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin Anti-cancer drugs can damage the lining of the intestine; affecting the absorption of digoxin. Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics Both altered antiepileptic and anti-cancer drug levels may occur, possibly leading to loss of efficacy or toxicity. Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the anti-cancer therapy.
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia. Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update
Vaccines Diminished response to vaccines and increased risk of infection with live vaccines. Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

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

Day 1

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

General patient assessment prior to each day of treatment.

Peripheral neuropathy assessment tool

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

Prime IV line(s).

Insert IV cannula or access TIVAD or CVAD.

  • weigh patient on each visit
  • urinalysis each visit

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
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

  • 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.

Oxaliplatin

  • Oxaliplatin is only compatible with glucose 5%, ensure IV lines are flushed with glucose 5% pre and post administration.
Administer oxaliplatin (irritant with vesicant properties):
  • via IV infusion over 2 hours
  • risk of laryngopharyngeal dysaesthesia
    • patients should not drink cold fluids
  • monitor for signs of hypersensitivity
  • flush with ~ 100 mL glucose 5%
  • if patient has laryngopharyngeal dysaesthesia or a hypersensitivity reaction - stop infusion and obtain medical officer review. If rechallenge indicated, premedicate patient and administer oxaliplatin at a slower rate (up to 6 hours).

Gemcitabine 

Administer gemcitabine (irritant):
  • via IV infusion over 30 minutes
    • if pain develops along the vein, verify the drug has not extravasated
    • further dilution (using a second saline line), warmth or temporarily slowing the infusion may help
  • flush with ~ 100 mL of sodium chloride 0.9% 
  • prolonged infusion times have been shown to increase toxicity.

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

Discharge information

Antiemetics
  • Antiemetics as prescribed.
Growth factor support
  • Arrangements for administration if prescribed.
Prophylaxis medications
  • Prophylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antivirals.
Patient information
  • Ensure patient receives patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Flu-like symptoms
Headache
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Laryngopharyngeal dysaesthesia

The sensation of difficulty breathing or an inability to swallow. This is associated with oxaliplatin and can occur during, and for up to 48 hours after treatment.

Read more about laryngopharyngeal dysaesthesia
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Taste and smell alteration

Read more about taste and smell changes

Early (onset days to weeks)
Abdominal pain

Dull ache, cramping or sharp pains are common with some anti-cancer drugs. These are caused by either increased or decreased gastrointestinal motility and can be associated with diarrhoea or constipation.
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Fatigue

Read more about fatigue
Fluid retention and oedema

An excess amount of fluid around the cells, tissues or serous cavities of the body, leading to swelling.
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
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
Palmar-plantar erythrodysaesthesia (PPE) - hand-foot syndrome (HFS)

Bilateral erythema, tenderness, pain, swelling, tingling, numbness, pruritus, dry rash, or moist desquamation and ulceration of the palms and soles. It is also known as hand-foot syndrome (HFS). Symptoms appear to be dose dependent and palms are affected more than soles.

Read more about hand-foot syndrome associated with chemotherapy
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
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
Thrombocytopenia

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

Read more about thrombocytopenia
Injection-site reaction

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

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
Haemolytic uraemic syndrome (HUS)

A rare but serious acute syndrome characterised by haemolysis of red blood cells and renal failure.

Read more about haemolytic uraemic syndrome (HUS)
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)
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

For patients with relapsed or refractory lymphoma such as  diffuse large B-cell lymphoma (DLBCL) or hodgkin lymphoma (HL), high dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) has been established as the standard. However, in those patients in whom HDCT/ASCT is precluded because of advanced age, other co-morbidities, and/or poor performance status, long-term survival rates following salvage therapy have been generally poor.

Conventional standard salvage regimens including R-ICE, R-DHAP, R-ESHAP, and R-GDP are potentially more toxic in older patients with relapsed/refractory lymphoma. While some patients may derive benefit from salvage therapy alone (without proceeding to HDCT/ASCT), it is necessary to balance the toxicity of further combination chemotherapy with the usually modest gain in progression-free survival (PFS) and overall survival (OS). Accordingly, there is a need to identify chemotherapy regimens which are both effective and tolerable in this cohort of patients who would not be considered eligible for HDCT and ASCT. There is a distinct paucity of such regimens.

GemOx (+/- rituximab) has been shown in a number of studies to be an active regimen, which is well-tolerated, particularly for patients greater than 65/70 years with relapsed DLBCL, HL, mantle and follicular lymphoma who are not suitable for HDCT/ASCT. Gemcitabine offers advantages over its parent compound, cytarabine, in terms of delivery of highly effective intracellular concentrations. Gemcitabine has demonstrated single-agent efficacy in relapsed or refractory aggressive lymphoma, including mantle cell lymphoma (MCL).r In addition, the platinum derivative oxaliplatin has similar efficacy to cisplatin, with improved renal safety and reduced induction of chemo-resistance.

The favourable safety profile of oxaliplatin makes this agent potentially suitable for elderly patients with co-morbidities. The mechanistic synergy and non-overlapping toxicity profiles of rituximab, gemcitabine and oxaliplatin (R-GemOx) indicate that combination regimens containing these three agents may offer advantages over conventional regimens in terms of efficacy, safety and tolerability.

Each component of the (R-)GemOx regimen may contribute to its efficacy; indeed, the results of this study support a synergistic or supra-additive action for rituximab when combined with gemcitabine and oxaliplatin. This observation is consistent with results from previous studies in lymphoma and other cancers. Response rates of 20% to 25% have been reported for single-agent gemcitabine in relapsed or refractory aggressive lymphoma (including MCL).r

Gemcitabine and oxaliplatin display supra-additive effects in human colon cancer cell lines, and the feasibility and safety of this combination has been shown in various solid tumours and in patients with lymphoma.

The schedule of GemOx is usually every 2 weeks. However, in the study by Lopez et alr, after the first cycles, most patients suffered treatment delays to the degree that in most cases they were administered every 3 weeks. Since this study reported 33% grade IV neutropenia, it was felt that in order to administer R-GemOX every 2 weeks, it will require the administration of growth factors.

In multiple prospective and retrospective studies rrrrrrr (R-)GemOx has been shown to be effective, and safe among older patients with relapsed/refractory lymphomas and who are not generally considered sufficiently fit for HDCT and ASCT. There are limited published retrospective data in the use of GemOx as salvage pre-ASCT. 

A search of the literature found moderate evidence to support the use of R-GemOX in the treatment of Non-Hodgkin Lymphoma. The expert reference panel supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the study by El Gnaoui et al.

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol? Comments
Phase II trials El Gnaoui et al. 2007r Yes No Gemcitabine and Oxaliplatin administered on day 2
  Lopez et al. 2008r Yes Yes -
  Mounier et al. 2013r Yes No Rituximab was given on day 1 and Gemcitabine and Oxaliplatin administered on day 2
Case series N/A N/A N/A -

Observational studies

 Dhanapal et al. 2017r Yes Yes -
Franch-Sarto et al. 2018r Yes Yes  -
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol? Comments
NCCN V 5.2019 Yes N/A -
BCCA N/A N/A N/A -
CCO N/A N/A N/A -

Efficacy

A brief summary of the three key trials of R-GemOx in relapsed/refractory aggressive NHL are shown in the table below.

  Lopez et alr El Gnaoui et alr Mounier et alr
Number 32 46 49
Age (years) 69 64 (43-78) 69 (41-77)
ORR 43% 83% 61%
PFS (med) 6 months 43% (at 2 years) 6 months
OS (med) 9.1 months 66% (at 2 years) 12 months

Among a total of more than 120 patients in the above 3 studies results are reasonably consistent and demonstrate favourable response rates, as well as median PFS and OS.

Retrospective studiesrr demonstrate less favourable response rates than the original studies (ORR 44%; CR 30%), likely reflecting relapse after primary therapy with rituximab-based chemotherapy and poorer outcomes in patients not enrolled in clinical trials, however toxicities remain comparable.

Toxicity

The GemOx (+/- R) regimen has a favourable toxicity profile.

No nephrotoxicity has been seen, and haematological toxicity has been manageable with the help of growth factor support, primarily in order to maintain a 14-day rather than a 21-day schedule.

Oxaliplatin-associated neurotoxicity occurred in only 9% of cycles in the study by El Gnaouir with no grade 3 or 4 events, but was grade 3 or 4 in 7% of patients (all reversible) in the study by Lopez et al.r In retrospective studies rates of febrile neutropenia are 14-22%.rr

In conclusion, the GemOx (+/- Rituximab) regimen shows promising activity with an acceptable toxicity profile, and may be a favourable treatment option for patients with relapsed/refractory lymphoma who are not eligible for HDCT and ASCT.

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Version 4

Date Summary of changes
09/03/2020 Biosimilar rituximab added to clinical information. Version number changed to V.4     
02/09/2021 Note added under treatment schedule about order of drug administration.
01/10/2021 Drug status updated: rituximab SC is TGA registered but no longer PBS listed.

Version 3

Date Summary of changes
10/04/2015 New protocol published on eviQ.

31/05/2017

Transferred to new eviQ website. Version number changed to V.2.

Antiemetic change: A NK1 receptor antagonist and a 5HT3 receptor antagonist in combination with dexamethasone has been added as available on the PBS for primary prophylaxis of oxaliplatin induced nausea and vomiting.

Order of administration updated: oxaliplatin then gemcitabine based on extravasation risk.
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.
25/05/2018 Reviewed by Haematology Reference Committee with no significant changes, review in 2 years
25/06/2018 Antiemetics updated to be in line with international guidelines. Note to dexamethasone added.
13/09/2019

Reviewed at the Haematology reference committee meeting with the following changes: 

  • Evidence updated
  • Reference list updated 

 Nil other significant changes. Protocol to be reviewed in 5 years. 
10/10/2019 Clinical information updated with PBS expanded indications for GCSF. 

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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31 Mar 2023