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Lymphoma GDP (gemcitabine dexamethasone ciSplatin)

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

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Cycle 1 and 2

Drug Dose Route Day
Dexamethasone 40 mg ONCE a day PO 1 to 4
Gemcitabine 1,000 mg/m2 IV infusion 1 and 8
ciSplatin 75 mg/m2 IV infusion 1
Frequency:
21 days 
Cycles:
2 to 3, responding patients may be considered for high dose chemotherapy and autologous stem cell transplant otherwise, continue up to a total of 6 cycles, unless disease progression or unacceptable toxicity.
Notes:
  • It is the consensus of the eviQ Reference committee that cisplatin may be substituted with carboplatin (5 AUC) in patients with renal impairment (See Dose modifications section). If estimated GFR is greater than 125 mL/min (i.e. 5 AUC dose greater than 750 mg), obtaining direct measurement rather than an estimated renal function and/or dose capping is strongly recommended.
  • Rituximab may be added to this protocol for patients with CD20+ non-Hodgkin lymphoma.
Drug status:

All drugs in this protocol are on the PBS general schedule

Dexamethasone is available as 0.5 mg and 4 mg tablets

Cost:
~ $280 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 antineoplastic drugs only (not antiemetics or other supportive medications), 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 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 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 antineoplastic 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 and 2

Day 1
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)
Dexamethasone 40 mg (PO) ONCE a day orally in the morning with food
Gemcitabine 1,000 mg/m2 (IV infusion) in 100 mL to 500 mL sodium chloride 0.9% over 30 minutes
ciSplatin 75 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
Day 2 to 4
Dexamethasone 40 mg (PO) ONCE a day orally in the morning with food
Day 8
Metoclopramide 10 mg (PO)

one tablet when necessary (maximum of 30 mg/24 hours, up to 5 days)
Gemcitabine 1,000 mg/m2 (IV infusion) in 100 mL to 500 mL sodium chloride 0.9% over 30 minutes
Frequency:
21 days 
Cycles:
2 to 3, responding patients may be considered for high dose chemotherapy and autologous stem cell transplant otherwise, continue up to a total of 6 cycles, unless disease progression or unacceptable toxicity.

Cycle 1 and 2

Drug Dose Route Day
Dexamethasone 40 mg ONCE a day PO 1 to 4
Gemcitabine 1,000 mg/m2 IV infusion 1 and 8
ciSplatin 75 mg/m2 IV infusion 1
Frequency:
21 days 
Cycles:
2 to 3, responding patients may be considered for high dose chemotherapy and autologous stem cell transplant otherwise, continue up to a total of 6 cycles, unless disease progression or unacceptable toxicity.
Notes:
  • It is the consensus of the eviQ Reference committee that cisplatin may be substituted with carboplatin (5 AUC) in patients with renal impairment (See Dose modifications section). If estimated GFR is greater than 125 mL/min (i.e. 5 AUC dose greater than 750 mg), obtaining direct measurement rather than an estimated renal function and/or dose capping is strongly recommended.
  • Rituximab may be added to this protocol for patients with CD20+ non-Hodgkin lymphoma.
Drug status:

All drugs in this protocol are on the PBS general schedule

Dexamethasone is available as 0.5 mg and 4 mg tablets

Cost:
~ $280 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 antineoplastic drugs only (not antiemetics or other supportive medications), 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 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 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 antineoplastic 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 and 2

Day 1
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)
Dexamethasone 40 mg (PO) ONCE a day orally in the morning with food
Gemcitabine 1,000 mg/m2 (IV infusion) in 100 mL to 500 mL sodium chloride 0.9% over 30 minutes
ciSplatin 75 mg/m2 (IV infusion) in 1000 mL sodium chloride 0.9% over 60 minutes
Day 2 to 4
Dexamethasone 40 mg (PO) ONCE a day orally in the morning with food
Day 8
Metoclopramide 10 mg (PO)

one tablet when necessary (maximum of 30 mg/24 hours, up to 5 days)
Gemcitabine 1,000 mg/m2 (IV infusion) in 100 mL to 500 mL sodium chloride 0.9% over 30 minutes
Frequency:
21 days 
Cycles:
2 to 3, responding patients may be considered for high dose chemotherapy and autologous stem cell transplant otherwise, continue up to a total of 6 cycles, unless disease progression or unacceptable toxicity.

Indications:

  • Relapsed or refractory Hodgkin and non-Hodgkin lymphoma
  • Second line salvage chemotherapy followed by high dose chemotherapy and autologous stem cell transplant

Cautions/exclusions:

  • Pre existing neuropathies greater than Grade 2
  • Moderate/severe renal impairment (creatinine clearance less than 60 mL/min)
  • Significant hearing impairment/tinnitus
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
Emetogenicity HIGH

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

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

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 or 12.5 mg IV every 6 hours when necessary.

Read more about preventing chemotherapy 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 antineoplastic 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
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
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 jiroveci 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.
Growth factor support

Consider the use of G-CSF (filgrastim, lenograstim, lipegfilgrastim or pegfilgrastim)

Access the PBS website
Blood tests

FBC, EUC, LFTs, calcium and magnesium at baseline and prior to each cycle.
Repeat FBC prior to treatment on day 8 of each cycle.
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, including BCG, MMR, zoster and varicella 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.
Effects of cancer treatment on fertility

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive age prior to commencing treatment.

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 antineoplastic 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 and reference committee consensus. 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.
  • Dose modification recommendations in this protocol are based on the trial by Crump et al, 2014r
Haematological toxicity
DAY 1: 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 treatment and initiate G-CSF**
  • ANC < 0.5, delay treatment until ANC ≥ 0.5
DAY 8: ANC x 109/L (pre-treatment blood test)
Less than 1.0 and greater or equal to 0.5 Consider proceeding treatment and initiate G-CSF** OR reduce gemcitabine by 25%
Less than 0.5 Omit gemcitabine this cycle and initiate G-CSF**
Day 1: Platelets  x 109  (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  (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

*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

** G-CSF (filgrastim, lenograstim, lipegfilgrastim or pegfilgrastim) should be given prophylactically for all future cycles

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
Serum Creatinine
Greater than 1.5 to 3.0 x ULN Reduce cisplatin by 25%
Greater than 3.0 x ULN Delay treatment by 1 week until recovery

Note: It is the consensus of the eviQ reference committee that cisplatin may be substituted with carboplatin (5 AUC) in patients with renal impairment. If estimated GFR is greater than 125 mL/min (i.e. 5 AUC dose greater than 750 mg), obtaining direct measurement rather than an estimated renal function and/or dose capping is strongly recommended. 

Hepatic impairment
Bilirubin
Greater than 1.5 to 3.0 x ULN Reduce gemcitabine by 25%
Greater than 3.0 x ULN

Day 1: Delay treatment by 1 week until recovery
Day 8: Omit gemcitabine until recovery, and resume at a reduced dose for subsequent cycles 
Cease treatment if any one of the following develops:
  • Pulmonary toxicity
  • Haemolytic uraemic syndrome (HUS)
  • Grade 4 non-haematologic toxicities
  • Elevations of serum creatinine levels greater than 200 mmol/L

References & Disclaimer

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)
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
Dexamethasone
  Interaction Clinical management
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of dexamethasone possible due to increased clearance Avoid combination or monitor for decreased clinical response to dexamethasone
CYP3A4 and P-gp inhibitors (e.g. amiodarone, aprepitant, azole-antifungals, ritonavir, lapatinib, nilotinib, sorafenib, macrolides, ciclosporin, grapefruit juice etc.) Increased effect/toxicity of dexamethasone possible due to reduced clearance Monitor for dexamethasone toxicity; consider dose reduction if the protocol being used does not already take the interaction into account
Drugs metabolised by CYP3A4 (e.g. atorvastatin, benzodiazepines, calcineurin inhibitors, clarithromycin, dihydroergotamine, simvastatin, etc.) Reduced efficacy of these drugs possible due to induction of CYP3A4 by dexamethasone resulting in increased clearance Avoid combination or monitor for decreased clinical response to the interacting drugs (esp. anticoagulants, antimicrobials, antineoplastics, antivirals, antiparasitics)
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 netupitant. For protocols that already recommend netupitant, 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. 
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of netupitant 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 netupitant possible due to reduced clearance Avoid combination or monitor for increased adverse effects of netupitant (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 netupitant Avoid combination or monitor for increased toxicity especially with orally administered drugs.
General
  Interaction Clinical management
Warfarin Antineoplastic agents may alter the anticoagulant effect of warfarin Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant (e.g. LMWH or unfractionated heparin)
Digoxin Antineoplastic agents 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 antineoplastic 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 antineoplastic 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
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Day 1

Approximate treatment time: 5 hours

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 port or CVC.

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Dexamethasone

  • administer orally ONCE a day in the morning, on days 1 to 4
  • to be taken with or immediately after food.

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

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
  • followed by 200 mL of mannitol 20% over 15 minutes
    • mannitol should be administered via a controlled infusion
  • mannitol 10% may be used as per institutional policy; there is much variation in the use of mannitol and although there is no conclusive evidence that mannitol should be used, many sites have used it routinely without renal toxicity. The routine use of frusemide to increase urine flow is not recommended. Refer to your institutional guidelines and medical orders.
  • 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%.
Post hydration:
  • 1000 mL sodium chloride 0.9% over 60 minutes.

Remove IV cannula and/or deaccess port or CVC.

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

Day 8

Approximate treatment time: 60 minutes

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 port or CVC.

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 port or CVC.

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

Discharge information

Dexamethasone tablets
  • Dexamethasone tablets with written instructions on how to take them.
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, antifungals, antivirals.
Patient information
  • Ensure patient receives patient information sheet.

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

Immediate (onset hours to days)
Nausea and vomiting

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

Read more about taste and smell changes
Flu-like symptoms

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 neutropenia
Thrombocytopenia

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

Read more about thrombocytopenia
Fatigue

Read more about fatigue
Diarrhoea

Read more about treatment induced diarrhoea
Oral mucositis

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following chemotherapy, radiotherapy to the head, neck or oesophagus, and high dose chemotherapy followed by a blood and marrow transplant (BMT).

Read more about oral mucositis
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

Antineoplastic agents 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
Fluid retention and oedema

An excess amount of fluid around the cells, tissues or serous cavities of the body, leading to swelling.
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 antineoplastic agents. These include taxanes, platinum-based compounds, vinca alkaloids and some drugs used to treat multiple myeloma.

Read more about peripheral neuropathy
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.
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
Pulmonary toxicity

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

Read more about pulmonary toxicity associated with antineoplastic drugs

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
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)

Gemcitabine is a cytarabine analogue which has synergistic activity with cisplatin in vitro. These two agents, along with the dexamethasone dose used in DHAP were combined with intent to develop an efficacious outpatient regimen that does not adversely impact stem cell mobilisation capacity.r

Hodgkin lymphoma (HL)

In a Canadian study of relapsed/refractory Hodgkin Lymphoma,r 131 patients were treated with GDP (27% relapse less than 12 months after upfront therapy; 33% relapse greater than 12 months after upfront therapy; 40% primary refractory disease). After 2 cycles, 15% achieved CR and 61% achieved PR (overall response rate 76%). These patients were each able to mobilise adequate stem cells to proceed to BEAM ASCT, the standard ultimate goal in relapsed/refractory HL.r In a smaller preceding analysis of 34 patients receiving GDP,r there were response rates of 3/34 in CR (9%), 18/34 in PR (53%) and 9/34 (26%) with stable disease (30/34 in total with non-progressive disease). These patients were all able to proceed to BEAM ASCT, with OS (at 1.5 years) and PFS (at 1.2 years) of 90% and 76% respectively. Baetz and colleaguesr reported comparable findings in 23 patients with relapsed/refractory HL.

Ramzi et alr published a small, randomized study comparing GDP and ESHAP as salvage chemotherapy for relapsed/refractory Hodgkin lymphoma. Twenty-two patients were recruited to each arm. Overall response rates were 54.1% in the GDP group and 50.0% in the ESHAP group, with complete responses identical in the two groups (38.1%).

Non-Hodgkin lymphoma (NHL)

In a Canadian phase 2 study, 51 patients with aggressive non-Hodgkin lymphoma (40 DLBCL) were treated with 2 cycles of GDP.r Response rates were 8/51 in CR (16%) and 17/51 in PR (33%), with an overall response rate of 49%. 22 of the 23 patients who were eligible to proceed to ASCT were able to mobilise a target CD34 dose of 2 x 106/kg, indicating that capacity for stem cell mobilisation was not substantially impaired by this regimen. 

The NCIC-CTG LY.12. study randomized patients with relapsed and refractory aggressive lymphomas to receive either GDP or DHAP, followed by autologous stem cell transplantation. In this studyr, Crump and colleagues studied 619 patients, with several aggressive histological entities included - DLBCL (n=419), transformed indolent (n=87), PTCL (n=27), ALCL (n=23), and primary mediastinal B-cell lymphoma (n=18). An amendment in 2005 allowed patients with CD20+ diseases to receive rituximab in addition to the chemotherapy backbone. The patients were poor-risk with approximately 70% in each arm experiencing relapse within 1 year of primary therapy or having no response to primary therapy. At least 2 cycles of therapy were administered to 90% of the GDP group and 87% of the DHAP group. The rates of response were similar in the two groups (45.1% v 44.1%), meeting the prespecified criteria for non-inferiority. 52.1% of the GDP arm and 49.3% of the DHAP group proceeded to subsequent stem cell transplantation. 6 patients in the GDP arm and 7 patients in the DHAP arm failed to collect stem cells sufficient for subsequent transplantation. After a median follow-up of 53 months, the 4 year progression-free survival and overall survival were similar.

 

Progression free survival  and overall survival in the NCIC-CTG LY.12 study

© Journal of Clinical Oncology 2014

Aggressive lymphoma

The British Columbia group recently published a retrospective analysis of patients treated with GDP between Sep 2002 and Jun 2010. In the paper by Moccia and colleagues,r 152 patients with DLBCL and 83 patients with Hodgkin lymphoma were identified. Overall response rates in these two groups were 49% and 71% respectively, with 52% and 96% of patients respectively proceeding to transplant (in those patients eligible for transplantation). The 2 year progression-free and overall survivals were 21% and 28% in the DLBCL group respectively, and 58% and 85% in the HL group respectively.

Peripheral T-cell lymphoma (PTCL)

Several small studies have evaluated GDP specifically in the setting of PTCL. Jia et alr evaluated the role of 3 different front-line protocols. In this retrospective study, 93 patients were treated with CHOP (n=40), CHOPE (n=42), and GDP (n=11). GDP appeared to have similar complete response rates to CHOPE, and overall response rate of 90.9%. Median PFS was 9.7 months in the GDP arm, with a 100% OS at 1 year which was significantly higher than the CHOP-treated group (p=0.024).

In the relapsed setting, Park et alr demonstrated a 72% overall response rate after a median of 4 cycles, with 12 of 25 patients studied achieving a complete response to GDP. In this study, cisplatin was administered at a lower dose of 70mg/m2.  At a median follow-up of 27.1 months, median PFS was 9.3 months. Qi et alr published the Chinese experience of GDP in 25 patients treated with a median on 4 cycles. An overall response rate of 64.0% was demonstrated, with 5 patients achieving a complete response. After a median follow-up of 9 months, median overall survival and progression free survival were 9.3 and 5.4 months respectively.

Rituximab

Note that rituximab is routinely incorporated into salvage regimens for B-cell lymphomas. This is based on randomised evidence in follicular lymphomar and more limited evidence in diffuse large B-cell lymphoma.r As mentioned, rituximab was included as a protocol amendment in the Crump 2012 abstract in each arm, but a detailed analysis of its potential benefit is not yet available.

Source Study & Year Published Is the dose and regimen consistent with the protocol?
Phase III trials Crump et al. 2014 Yes
Phase II trials

Baetz et al. 2003
Villa et al. 2012
Kuruvilla et al. 2006

 Yes
Park et al. 2015 cisplatin 70 mg/m2
Case series

Moccia et al. 2017
Qi et al. 2017
Jia et al. 2016

 Yes

Toxicity

The paper by Crump et alr demonstrated that Grade 3 or 4 adverse events were observed significantly less frequently during the first two cycles of chemotherapy among patients receiving GDP (47% v 61%; P < .001), including fewer episodes of febrile neutropenia (9% v 23%; P < .001). Furthermore, hospitalisations were less frequent in the GDP group (47% v 99%, P<0.001).

© Journal of Clinical Oncology 2014

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18 Nov 2018