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NK T-Cell lymphoma DDGP (dexamethasone ciSplatin gemcitabine pegaspargase)

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 6

Drug Dose Route Day
Dexamethasone 15 mg/m2 ONCE a day IV/PO 1 to 5
Pegaspargase 2,500 Units/m2 * IM ** 1
Gemcitabine 800 mg/m2 IV infusion 1 and 8
ciSplatin 20 mg/m2 IV infusion 1 to 4
Pegfilgrastim *** 6 mg Subcut 9

* Pegaspargase dose 2500 units/m2 based on studies by Li et al.r and Zhang et al.r
** Intramuscular (IM) injection is the preferred route of administration due to the lower incidence of hepatotoxicity, coagulopathy, and gastrointestinal and kidney disorders, compared to the intravenous route.rr Pegaspargase can be administered intravenously over 1 - 2 hours.
*** Pegfilgrastim or equivalent G-CSF can be used. If bone pain develops consider switching to a daily G-CSF alternative for next cycle. 

Frequency:
21 days 
Cycles:
3 or 4 for early stage; 6 cycles for advanced stage or relapsed/refractory disease (unless disease progression or unacceptable toxicity).
Notes:

For newly diagnosed early stage disease, radiation therapy was administered following completion of DDGP treatment.rrr

Drug status:

Cisplatin, gemcitabine, dexamethasone are on the PBS general schedule

Filgrastim: (PBS authority)

Pegaspargase: Not TGA approved or PBS reimbursed for this indication 

Dexamethasone is available as 0.5 mg and 4 mg tablets

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
Dexamethasone 15 mg/m2 (IV/PO) ONCE a day orally in the morning with food OR by IV infusion on days 1 to 5.
Granisetron 2 mg (PO) 60 minutes before chemotherapy
Pegaspargase 2,500 Units/m2 (IM) inject intramuscularly. Rotate site of administration.*
Gemcitabine 800 mg/m2 (IV infusion) in 100 mL to 500 mL sodium chloride 0.9% over 30 minutes
ciSplatin 20 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 60 minutes
Day 2 to 4
Dexamethasone 15 mg/m2 (IV/PO) ONCE a day orally in the morning with food OR by IV infusion on days 1 to 5.
Granisetron 2 mg (PO) 60 minutes before chemotherapy
ciSplatin 20 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 60 minutes
Day 5
Dexamethasone 15 mg/m2 (IV/PO) ONCE a day orally in the morning with food OR by IV infusion on days 1 to 5.
Day 8
Gemcitabine 800 mg/m2 (IV infusion) in 100 mL to 500 mL sodium chloride 0.9% over 30 minutes
Day 9
Pegfilgrastim 6 mg (Subcut) inject subcutaneously on day 9 at least 24 hours after chemotherapy**

*Intramuscular (IM) injection is the preferred route of administration due to the lower incidence of hepatotoxicity, coagulopathy, and gastrointestinal and kidney disorders, compared to the intravenous route.rr Pegaspargase can be administered intravenously over 1 - 2 hours. Pegaspargase dose 2500 units/m2 based on studies by Li et al.r and Zhang et al.r

**Pegfilgrastim or equivalent G-CSF (filgrastim or lipegfilgrastim) can be used. If bone pain develops consider switching to a daily G-CSF alternative for next cycle. 

Frequency:
21 days 
Cycles:
3 or 4 for early stage; 6 cycles for advanced stage or relapsed/refractory disease (unless disease progression or unacceptable toxicity).

Cycle 1 to 6

Drug Dose Route Day
Dexamethasone 15 mg/m2 ONCE a day IV/PO 1 to 5
Pegaspargase 2,500 Units/m2 * IM ** 1
Gemcitabine 800 mg/m2 IV infusion 1 and 8
ciSplatin 20 mg/m2 IV infusion 1 to 4
Pegfilgrastim *** 6 mg Subcut 9

* Pegaspargase dose 2500 units/m2 based on studies by Li et al.r and Zhang et al.r
** Intramuscular (IM) injection is the preferred route of administration due to the lower incidence of hepatotoxicity, coagulopathy, and gastrointestinal and kidney disorders, compared to the intravenous route.rr Pegaspargase can be administered intravenously over 1 - 2 hours.
*** Pegfilgrastim or equivalent G-CSF can be used. If bone pain develops consider switching to a daily G-CSF alternative for next cycle. 

Frequency:
21 days 
Cycles:
3 or 4 for early stage; 6 cycles for advanced stage or relapsed/refractory disease (unless disease progression or unacceptable toxicity).
Notes:

For newly diagnosed early stage disease, radiation therapy was administered following completion of DDGP treatment.rrr

Drug status:

Cisplatin, gemcitabine, dexamethasone are on the PBS general schedule

Filgrastim: (PBS authority)

Pegaspargase: Not TGA approved or PBS reimbursed for this indication 

Dexamethasone is available as 0.5 mg and 4 mg tablets

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
Dexamethasone 15 mg/m2 (IV/PO) ONCE a day orally in the morning with food OR by IV infusion on days 1 to 5.
Granisetron 2 mg (PO) 60 minutes before chemotherapy
Pegaspargase 2,500 Units/m2 (IM) inject intramuscularly. Rotate site of administration.*
Gemcitabine 800 mg/m2 (IV infusion) in 100 mL to 500 mL sodium chloride 0.9% over 30 minutes
ciSplatin 20 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 60 minutes
Day 2 to 4
Dexamethasone 15 mg/m2 (IV/PO) ONCE a day orally in the morning with food OR by IV infusion on days 1 to 5.
Granisetron 2 mg (PO) 60 minutes before chemotherapy
ciSplatin 20 mg/m2 (IV infusion) in 500 mL sodium chloride 0.9% over 60 minutes
Day 5
Dexamethasone 15 mg/m2 (IV/PO) ONCE a day orally in the morning with food OR by IV infusion on days 1 to 5.
Day 8
Gemcitabine 800 mg/m2 (IV infusion) in 100 mL to 500 mL sodium chloride 0.9% over 30 minutes
Day 9
Pegfilgrastim 6 mg (Subcut) inject subcutaneously on day 9 at least 24 hours after chemotherapy**

*Intramuscular (IM) injection is the preferred route of administration due to the lower incidence of hepatotoxicity, coagulopathy, and gastrointestinal and kidney disorders, compared to the intravenous route.rr Pegaspargase can be administered intravenously over 1 - 2 hours. Pegaspargase dose 2500 units/m2 based on studies by Li et al.r and Zhang et al.r

**Pegfilgrastim or equivalent G-CSF (filgrastim or lipegfilgrastim) can be used. If bone pain develops consider switching to a daily G-CSF alternative for next cycle. 

Frequency:
21 days 
Cycles:
3 or 4 for early stage; 6 cycles for advanced stage or relapsed/refractory disease (unless disease progression or unacceptable toxicity).

Indications:

  • Newly diagnosed early- or advanced-stage, or relapsed/refractory extranodal NK/T-cell lymphoma 

Contraindications

Pegaspargase should not be used in patients who have:

  • previous anaphylaxis or severe hypersensitivity to asparaginase formulations
  • severe hepatic impairment
  • existing or a history of pancreatitis
  • previous haemorrhagic or severe thrombotic events

Cautions/exclusions:

  • CNS involvement
  • Pegaspargase should be used with caution in patients over 40 years of age and those with a body mass index (BMI) greater than 30 due to an increased risk of side effects.  
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 pegaspargase. 

Hypersensitivity reactions may occur, e.g. life-threatening anaphylaxis, particularly in patients with known hypersensitivity to the other forms of asparaginase. Adequate medical treatment and provisions should be available for immediate use in the event of an anaphylactic reaction. Patients that develop hypersensitivity to the E. coli derived formulation may be able to switch to Erwinia asparaginase.

Read more about Management of asparaginase therapy
Antiemetics for multi-day protocols

Antiemetic therapy should be administered throughout the duration of the chemotherapy protocol and to cover delayed nausea. The acute and delayed emetic risk of multi-day chemotherapy protocols will overlap depending on the individual drugs and their sequence of administration. More or less antiemetic cover may be 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
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.
Hydration

Hydration helps to prevent cisplatin-induced nephrotoxicity.

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

Read more about cisplatin hydration regimens
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
Pegaspargase

Pegaspargase is associated with numerous toxicities including hypersensitivity, hepatotoxicity, coagulation abnormalities, pancreatitis, hyperlipidaemia, hyperglycaemia and CNS effects. Therefore routine monitoring and assessment of several parameters are required throughout treatment.

For comprehensive information on formulations, dosing, interactions, adverse reactions and specific monitoring parameters for asparaginase, see Management of asparaginase therapy document.
Pancreatitis

Pancreatitis (both haemorrhagic or necrotising) has been reported in patients receiving pegaspargase with fatal outcomes. If pancreatitis is suspected pegaspargase should be discontinued and not restarted if confirmed.  Serum amylase and/or lipase measurements should be performed frequently to identify early signs of pancreatic inflammation. If treatment is discontinued due to pancreatitis, appropriate investigations (e.g. ultrasound) should be performed at least four months following termination of therapy.
Peripheral neuropathy

Assess prior to each treatment. If a patient experiences grade 2 or greater peripheral neuropathy, a dose reduction, delay, or omission of treatment may be required; review by medical officer before commencing treatment.

Read more about peripheral neuropathy

Link to chemotherapy-induced peripheral neuropathy screening tool
Thrombotic events

Serious thrombotic events may occur in patients receiving pegaspargase and should be discontinued if they occur. Increased prothrombin time (PT), increased activated partial thromboplastin time (APTT), and hypofibrinogenaemia may occur in patients receiving pegaspargase. A baseline coagulation profile (including antithrombin III) should be established and periodically monitored during and after treatment. 

Patients should be on thromboprophylaxis with enoxaparin to prevent thrombotic events unless contraindicated.

Read more about Management of asparaginase therapy
Hepatotoxicity

Caution is required when pegaspargase is given in combination with other hepatotoxic substances. If pegaspargase is given in combination with hepatotoxic substances, the patient should be closely monitored for liver impairment, especially if there is pre-existing hepatic impairment.
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

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

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

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

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

­

Read more about antiviral prophylaxis drugs and doses
Antifungal prophylaxis

Antifungal prophylaxis is recommended.

Read more about antifungal prophylaxis drugs and doses.
Biosimilar drug

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

FBC, EUC, BSL, LDH, uric acid, albumin, triglycerides and total cholesterol levels at baseline and prior to each cycle. LFTs, bilirubin, lipase, amylase, APTT, PT, INR, fibrinogen, antithrombin III levels at baseline and at least once or twice a week 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

Delay treatment for 1 week*

If after 1 week:

  • ANC < 1.0 but ≥ 0.5, consider proceeding with treatment 
  • ANC < 0.5, delay treatment until ANC ≥ 0.5
Platelets x 109/L  (pre-treatment blood test)
Less than 75

Delay treatment for 1 week.*

If after 1 week:

  • platelets < 75 but ≥ 50, consider proceeding treatment with platelet transfusions as necessary
  • platelets <50, delay treatment until platelets ≥ 50
Day 8: Platelets x 109/L  (pre-treatment blood test)
Less than 75 and greater or equal to 50 Reduce gemcitabine by 25% from this cycle’s day 1 dose
Less than 50 Omit gemcitabine and pegaspargase

*If counts presume to be low due to marrow involvement, treat after 1 week delay (i.e. at 4 weeks or day 28) despite counts

Non-haematological toxicity
Grade 2† No dose reduction required
Grade 3†† Reduce gemcitabine and cisplatin by 25%
Grade 4 Delay treatment until recovery and consider resuming at a reduced dose at the clinician’s discretion.

† Except grade 2 pneumonitis thought to be secondary to gemcitabine, discontinue gemcitabine permanently.

†† In the event of grade 3 tinnitus, reduce cisplatin dose only

Renal impairment
Creatinine clearance (mL/min)
30 to 50 Consider reducing cisplatin by 25%
less than 30

Omit cisplatin and consider gemcitabine dose reduction.
Hepatic impairment
Hepatic dysfunction
Moderate

Consider gemcitabine dose reduction if bilirubin>27 micromol/L
Severe Pegaspargase contraindicated if bilirubin > 3 x ULN or transaminases > 10 x ULN 
Cease treatment if any one of the following develops:
  • Pulmonary toxicity
  • Severe hypersensitivity reaction or anaphylaxis
  • Thrombotic microangiopathy (TMA)/haemolytic uraemic syndrome (HUS)
  • Grade 4 non-haematologic toxicities
  • Elevations of serum creatinine levels greater than 200 mmol/L
Pegaspargase-related reactions
Grade 1 local allergic reactions not requiring intervention Continue pegaspargase
Grade 2 or greater systemic reactions Consider discontinuation of pegaspargase and substitute with erwinia asparaginase if available 
Grade 3 or 4 allergic reaction/hypersensitivity (such as anaphylaxis), pancreatitis or thrombotic events Discontinue pegaspargase, if discontinued due to allergy/hypersensitivity only, consider changing to erwinia asparaginase. 
Pegaspargase should not be withheld for asymptomatic coagulation laboratory abnormalities. Cryoprecipitate and anti-thrombin III infusions may be required.

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:  

Cisplatin
  Interaction Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor renal 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)
Dexamethasone
  Interaction Clinical management
CYP3A4 interactions Dexamethasone is a substrate of CYP3A4 and a weak to moderate inducer of CYP3A4. The clinical relevance of CYP3A4 induction by dexamethasone is unknown as the mechanism has yet to be established The effects of the concomitant use of dexamethasone with other CYP3A4 inducers, inhibitors or substrates is variable. If used concomitantly, monitor patients closely for adverse drug reactions
Warfarin Concurrent use may result in increased risk of bleeding or diminished effects of warfarin Monitor prothrombin time / INR (especially during initiation or discontinuation) and for signs of drug toxicity during concomitant use; adjust warfarin dose as required
Oral hypoglycaemics Corticosteroids may cause hyperglycaemia and worsen diabetes control Monitor blood glucose levels and adjust oral hypoglycaemic dose as required
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
Pegaspargase
There are no documented interactions for pegaspargase. However, a range of clinical effects can occur due to the mechanism of action of pegaspargase.
Clinical effect Action Clinical management
Effect on use with other chemotherapy agents

Pegaspargase may affect the action of other cytotoxic drugs requiring cell division for their effect (i.e. methotrexate, cytarabine). This effect can be either synergistic or antagonistic, depending on the timing of administration of the agents.

Adherence to the treatment schedule is recommended to minimise these potential interactions.
Immediately preceding or concomitant treatment with vincristine can increase the toxicity of pegaspargase and increases the risk of anaphylactic reactions. Administer vincristine 12 hours prior to pegaspargase to minimise toxicity.
Effects on protein-bound drugs Due to its effects on protein synthesis and hepatic function, pegaspargase can potentially interfere with metabolism and clearance of other drugs including chemotherapy drugs known to interact with CYP enzymes. Monitor for hepatotoxicity if used concomitantly.
Coagulation effects

Use of pegaspargase can lead to fluctuating levels of coagulation factors. This may increase the risk of bleeding and/or thrombosis.

Caution is needed when anticoagulants are given concomitantly.
Alterations in coagulation parameters can be more pronounced when glucocorticoids (e.g. prednisolone) and pegaspargase are given concomitantly. Monitor levels of coagulation parameters such as fibrinogen and ATIII
Oral contraceptive effects Pegaspargase hepatotoxicity may impair the hepatic clearance of oral contraceptives. Concomitant use of pegaspargase and oral contraceptives is not recommended. A method other than oral contraception should be used in women of childbearing potential
 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
General
  Interaction Clinical management
Warfarin Anti-cancer drugs may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

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

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

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

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

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

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

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

Day 1

General patient assessment prior to each day of treatment.

Peripheral neuropathy assessment tool

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

Prime IV line(s) with sodium chloride 0.9%.

Insert IV cannula or access TIVAD or CVAD.

  • baseline weight

Dexamethasone

  • administer orally ONCE a day in the morning with food OR
  • via IV infusion over 15 minutes on days 1 to 5
  • flush with ~ 50mL sodium chloride 0.9%

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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Pegaspargase

  • administer via intramuscular (IM) injection (alternatively may be administered intravenously over 1 to 2 hours)
  • when administered IM, the volume at the injection site should be less than or equal to 2 mL; if volume to administer is larger than 2 mL, use multiple injection sites and ensure site rotation

Note: monitor patient during and for one hour after drug administration, as anaphylaxis may occur. Ensure immediate access to emergency / adverse-reaction kit is available. 

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.

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 60 minutes
  • flush with 100 mL of sodium chloride 0.9%.

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

Days 2 to 4

General patient assessment prior to each day of treatment.

Peripheral neuropathy assessment tool

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

Prime IV line(s) with sodium chloride 0.9%.

Insert IV cannula or access TIVAD or CVAD.

Dexamethasone

  • administer orally ONCE a day in the morning with food OR
  • via IV infusion over 15 minutes on days 1 to 5
  • flush with ~ 50mL sodium chloride 0.9%

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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

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 60 minutes
  • flush with 100 mL of sodium chloride 0.9%.

Remove IV cannula and/or deaccess TIVAD or CVAD. 

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

Day 8

General patient assessment prior to each day of treatment.

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

Prime IV line(s) with sodium chloride 0.9%.

Insert IV cannula or access TIVAD or CVAD.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

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)

Day 9

Pegfilgrastim

  •  administer subcutaneously at least 24 hours post chemotherapy.

Discharge information

Dexamethasone tablets
  • Dexamethasone tablets with written instructions on how to take them.
Antiemetics
  • Antiemetics as prescribed.
Antidiarrhoeals
  • Antidiarrhoeals as prescribed.
Growth factor support
  • Arrangements for administration if prescribed.
Patient information
  • Ensure patient receives patient information sheet.
Prophylaxis medications
  • Prophylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antifungals, antivirals.

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

Immediate (onset hours to days)
Hypersensitivity reaction

Anaphylaxis and infusion related reactions can occur with this treatment.

Read more about hypersensitivity reaction 
Flu-like symptoms
Injection-site reactions

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

Read more about treatment induced diarrhoea
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.
Hepatotoxicity

Anti-cancer drugs administered either alone or in combination with other drugs and/or radiation may cause direct or indirect hepatotoxicity. Hepatic dysfunction can alter the metabolism of some drugs resulting in systemic toxicity.
Hyperbilirubinaemia

An abnormal increase in the amount of bilirubin circulating in the blood which may result in jaundice.
Hyperglycaemia

High blood sugar, an excess of glucose in the blood stream.
Hyperlipidaemia and hypercholesterolaemia

Abnormally elevated levels of lipids and cholesterol in the blood.
Hypomagnesaemia, hypokalaemia, hypocalcaemia

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

Renal dysfunction resulting from damage to the glomeruli, tubules or renal vasculature.
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
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
Pancreatitis

Inflammation of the pancreas with impairment of function is associated with asparaginase formulations. 
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
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
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
Thromboembolism

Serious thromboembolic events can occur in patients receiving pegaspargase. The majority of thromboses occur in the CNS. Patients should be carefully assessed for risk factors with baseline and regular monitoring of coagulation profile (including PT, APTT, fibrinogen, antithrombin III) during and after treatment. Antithrombotic prophylaxis is recommended.

Read more about Management of asparaginase therapy

Late (onset weeks to months)
Anaemia

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

Read more about anaemia
Alopecia - partial

Hair thinning and/or patchy hair loss. 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

Treatment results for extranodal natural killer/T-cell lymphoma (ENKTL) have historically been poor. With CHOP and CHOP-like chemotherapy, median survival is only 2-7.8 months with 5-year overall survival (OS) of ~30%.r The poor outcome is partly due to NK-cell expression of high levels of multi-drug resistant (MDR) P-glycoprotein, so that anthracycline-containing regimens are ineffective. Standard of care for advanced stage ENKTL has been SMILE (dexamethasone, methotrexate, ifosfamide, asparaginase and etoposide), based on a phase II study of 38 patientsr and a phase II multicentre study in a non-trial setting of 87 patients.r These studies have shown an overall response rate (ORR) of 79-81% and complete response (CR) of 50-56% after 2-3 cycles. 5-year OS was 50%, and 4-year disease-free survival (DFS) was 64%. SMILE has significant toxicity, with grade III/IV neutropenia in 72.7% and a treatment-related mortality (TRM) of 7%.

The DDGP protocol was developed due to toxicity issues related to SMILE, as well as the high rates of hypersensitivity reactions to L-asparaginase. 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 randomised controlled, open-label, multicentre study published in 2016 by Li et al. comparing DDGP and SMILE in 42 advanced stage, newly diagnosed patients.r An abstract of the follow-up to this study was presented at ASH 2019.r A total of 80 patients with newly diagnosed advanced stage ENKTL with an ECOG of 0-2 and aged between 14 and 70 years old were recruited between 2011 and 2019. Patients were randomised 1:1 to SMILE or DDGP, and given up to 6 cycles unless disease progression, unacceptable toxicity or patient choice.

Zhang et al. published a retrospective study of 80 patients in 2016, with 60% of patients being newly diagnosed, 11% in first relapse, and 29% in a primary refractory disease.r Of the newly diagnosed, 42% were stage I-II and the remainder were stage III-IV. More recently, DDGP has also been trialled in early-stage disease. A randomised, controlled, open-label, multicentre study compared DDGP combined with radiation therapy (RT) vs RT alone in newly diagnosed stage I-II NKTL.r Published in 2021, the study reported on 65 patients, with 35 patients receiving RT alone, and 30 treated with DDGP and RT. Another prospective cohort study from 2011 to 2016 examined effects of DDGP followed by RT (DDGP+RT) versus VIPD followed by RT (VIPD+RT) in 40 newly diagnosed stage I-II ENKTL patients.r

A real-world retrospective analysis of 376 patients on asparaginase-based vs non-asparaginase-based chemotherapy combined with RT in the treatment of early-stage ENKTCL demonstrated a significantly improved 5-year OS (84.5% vs 73.2%) and distant metastasis-free survival (84.4% vs 74.5%) with the asparaginase-based regimen in intermediate- to high-risk patients.r Out of the asparaginase-based group, 13 patients had DDGP overall, and 8 were in the intermediate- to high-risk group. Other asparaginase-based regimens included were GELOX, P-GEMOX and GDP-L.

Source Study & Year Published Supports Use Is the dose and regimen consistent with the protocol?  Comments
Phase II trials Li et al. 2016r Yes Yes Newly diagnosed, advanced stage. 
Wang et al. 2019r (Abstract) Yes Yes Newly diagnosed, advanced stage. 
Zhang et al. 2021r Yes Yes Newly diagnosed, early stage
Observational studies Zhang et al. 2016r Yes Yes Newly diagnosed, relapsed and primary refractory. 25% stage I-II. 
Wang et al. 2021r Yes Yes Relapsed/refractory
Zhang et al. 2022r Yes Yes Newly diagnosed, early stage
Zheng et al. 2021r Yes N/A Newly diagnosed, early stage
Guidelines Date published/revised Supports Use Is the dose and regimen consistent with the protocol?  Comments
NCCN V 1.2022 Yes  N/A  Consider clinical trial, DDGP, modified SMILE or P-GEMOX for induction in advanced disease
BCCA N/A N/A N/A N/A 
CCO Jan 2022 Yes  Yes  N/A 

Efficacy

For advanced stage, newly diagnosed ENKTL, Li et al. reported an overall response rate (ORR) of 95% vs 67% for SMILE; and a complete response (CR) of 71% vs 29% for SMILE. 1-year (overall survival) OS was 90% vs 57% for DDGP vs SMILE and progression-free survival (PFS) 86% for DDGP vs 38% for SMILE. 2-year OS was 74% vs 45% for DDGP and SMILE, respectively. The response rates for SMILE were significantly lower than those reported in previous clinical trials.r In the follow-up study, the ORR was significantly higher in DDGP vs SMILE (90% vs 60%), but there was no significant difference in CR (67.5% for DDGP vs 47.5% for SMILE). The 3-year PFS was 56.6% for DDGP and 41.8% for SMILE; 5-year OS 74.3% for DDGP and 51.7% for SMILE.r

Figure 1.Overall survival (A) and progression-free survival (B) curvesr

© AACR 2016

The 2016 retrospective study by Zhang et al. reported an ORR of 91.3% and CR of 60%. The 1-year OS and PFS were 88.6% and 86.1%, and 2-year OS and PFS were 87% and 81%.r Another retrospective study of 54 patients with relapsed/refractory disease treated with either DDGP or SMILE in 2021 demonstrated that the 31 patients who received DDGP had a higher CR rate (61.3% vs 30.4%) and 5-year PFS (45.4% vs 27.6%) and 5-year OS (50.1% vs 32.5%) compared to the SMILE group.r There was no significant difference in the ORR (83.9% vs 60.9%) between the two groups.

The 2021 study by Zhang et al. comparing DDGP+RT versus RT alone reported the combined modality group having superior CR (73.3% vs 48.6%) and ORR (83.3% vs 60%). 5-year PFS (82.9% vs 56.5%) and OS (85.7% vs 60.4%) were also significantly better in the combined modality group.r Another prospective cohort study comparing DDGP+RT and VIPD+RT reported better CR rate (85% vs 50%) and OR rate (95% vs 65%) in the DDGP+RT arm .r Whilst 5-year PFS was better in the DDGP+RT group (83.3% vs 44.4%), there was no significant difference in the 5-year OS between the two groups (83.0% vs 72.1%).

Toxicity

Li et al. reported significantly fewer adverse events in the DDGP arm; particularly lower rates of leukopenia, neutropenia, hypersensitivity reactions and gastrointestinal side effects.r DDGP had higher rates of anaemia and coagulation abnormalities. Grade 3 or 4 leukopenia occurred in 13 patients (54%) with DDGP, compared to 19 (90%) with SMILE. Grade 3 or 4 anaemia occurred in 11 (52%) and thrombocytopenia in 13 (62%). There were no documented cases of allergic reactions with DDGP, but they occurred in 7 patients (33%) in the SMILE group. There were no reported deaths.

Adverse effects between DDGP and SMILE groupsr

© AACR 2016

In the expanded cohort, grade 3 or 4 haematologic toxicity occurred in 25 patients (62.5%) compared to 34 (85%) in the SMILE group.r Grade 3 or 4 neutropenia occurred in 26 patients (65%). Non-haematologic toxicity including elevated transaminases, mucositis or allergic reactions did not occur with DDGP in this study. A ~10% treatment-related mortality was reported for DDGP, compared to 17.5% with SMILE, both significantly higher compared to previous studies. These were mainly due to infection and haemorrhage in the SMILE group.

Wang et al. reported no episodes of allergic reaction or pancreatitis. 49% had prolonged APTT and 41% hypofibrinogenaemia.r Grade 3 - 4 neutropenia occurred in 65% of patients, grade 4 thrombocytopenia in 35% and grade 4 anaemia in 5%. There were no treatment-related deaths. If there was a grade 4 toxicity, doses were reduced not more than 20% for subsequent cycles.

For early stage disease, reported adverse events of the DDGP+RT were as follows: grade 3 or 4 myelosuppression in 20-25%, grade 3 or 4 liver dysfunction in 3.3%, grade 3 or 4 gastrointestinal reactions in 16.7%, grade 3 or 4 alopecia in 16.7%.r There were no grade 3 or 4 coagulation abnormalities. It is noted that the RT only group was biased towards having more patient with a lower ECOG. Another study examining combined modality treatment noted the DDGP+RT group were more prone to grade I-II clotting dysfunction compared to the VIPD+RT group.r

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Version 3

Date Summary of changes
11/11/2022

Reviewed by Haematology Reference Committee. Updates include:

  • Treatment schedule - notes about radiation therapy and pegaspargase dosing added, number of cycles updated
  • Indications - early-stage disease added
  • Clinical information - blood tests amended
  • Evidence - studies supporting early-stage disease added
  • Patient information - number of cycles

For review in 4 years.

Version 2

Date Summary of changes
22/09/2020 Biosimilar drug added to clinical information. Version number changed to v.2
22/10/2021 Electronically reviewed by Haematology Reference Committee; nil changes. Review in 2 years.
22/01/2022 Interactions updated.

Version 1

Date Summary of changes
27/03/2020 New protocol presented at the Haematology Reference Committee meeting. Discussion continued over email and protocol approved for publication. For review in 1 year.  

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