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Anaplastic glioma temozolomide following radiation

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Cycle 1

Drug Dose Route Day
Temozolomide 150 mg/m2 ONCE a day * PO 1 to 5

Cycle 2 to 12

Drug Dose Route Day
Temozolomide 200 mg/m2 ONCE a day * PO 1 to 5

*If temozolomide was well tolerated in cycle 1, the dose should be increased to 200 mg/m2 once a day, days 1 to 5, from cycle 2.

Frequency:
28 days 
Cycles:
12 
Notes:

If patients are concurrently receiving dexamethasone, the dose of dexamethasone should not be changed the same week that the patient is receiving temozolomide as this makes it difficult to know if any problems that arise are a side effect of the drug or a result of the reduced steroid dose. 

Drug status:

Temozolomide is on the PBS general schedule

Temozolomide is available as 5 mg, 20 mg, 100 mg, 140 mg, 180 mg and 250 mg capsules (try to round the dose to simplify the number of different capsules taken to aid compliance)

Cost:
~ $520 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes 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

Day 1 to 5
Granisetron 2 mg (PO) 60 minutes before temozolomide
Temozolomide 150 mg/m2 (PO) ONCE a day on days 1 to 5. Take on an empty stomach, at least one hour before or two hours after food. (Note: dose increased to 200 mg/m2 from cycle 2 onwards if temozolomide was well tolerated in cycle 1)

Cycle 2 to 12

Day 1 to 5
Granisetron 2 mg (PO) 60 minutes before temozolomide
Temozolomide 200 mg/m2 (PO) ONCE a day on days 1 to 5. Take on an empty stomach, at least one hour before or two hours after food. (Note: dose increased to 200 mg/m2 from cycle 2 onwards if temozolomide was well tolerated in cycle 1)
Frequency:
28 days 
Cycles:
12 

Cycle 1

Drug Dose Route Day
Temozolomide 150 mg/m2 ONCE a day * PO 1 to 5

Cycle 2 to 12

Drug Dose Route Day
Temozolomide 200 mg/m2 ONCE a day * PO 1 to 5

*If temozolomide was well tolerated in cycle 1, the dose should be increased to 200 mg/m2 once a day, days 1 to 5, from cycle 2.

Frequency:
28 days 
Cycles:
12 
Notes:

If patients are concurrently receiving dexamethasone, the dose of dexamethasone should not be changed the same week that the patient is receiving temozolomide as this makes it difficult to know if any problems that arise are a side effect of the drug or a result of the reduced steroid dose. 

Drug status:

Temozolomide is on the PBS general schedule

Temozolomide is available as 5 mg, 20 mg, 100 mg, 140 mg, 180 mg and 250 mg capsules (try to round the dose to simplify the number of different capsules taken to aid compliance)

Cost:
~ $520 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes 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

Day 1 to 5
Granisetron 2 mg (PO) 60 minutes before temozolomide
Temozolomide 150 mg/m2 (PO) ONCE a day on days 1 to 5. Take on an empty stomach, at least one hour before or two hours after food. (Note: dose increased to 200 mg/m2 from cycle 2 onwards if temozolomide was well tolerated in cycle 1)

Cycle 2 to 12

Day 1 to 5
Granisetron 2 mg (PO) 60 minutes before temozolomide
Temozolomide 200 mg/m2 (PO) ONCE a day on days 1 to 5. Take on an empty stomach, at least one hour before or two hours after food. (Note: dose increased to 200 mg/m2 from cycle 2 onwards if temozolomide was well tolerated in cycle 1)
Frequency:
28 days 
Cycles:
12 

Indication:

  • Newly diagnosed anaplastic glioma (WHO grade III) in 1p19q non-co-deleted patients, commencing approximately 4 weeks after the completion of radiotherapy. 

Caution:

  • Poor performance status
Caution with oral antineoplastic agents

Select link for information on the safe prescribing, dispensing and administration of orally administered antineoplastic agents (cytotoxic and non-cytotoxic chemotherapy).

Read more about oral anticancer therapy
Emetogenicity MODERATE

A suggested default antiemetic has been added to the treatment schedule and may be substituted to reflect institutional policy.

Temozolomide is classified as having MODERATE emetogenicity. In clinical practice, the administration of a 5HT3 antagonist taken ONE hour prior to each temozolomide dose may be sufficient to control nausea and vomiting. Patients may already be prescribed concurrent dexamethasone (for cerebral oedema).

Note: nausea and vomiting may be reduced by taking temozolomide at night.

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
Pneumocystis jiroveci pneumonia (PJP) prophylaxis

Temozolomide induces significant lymphopenia and has been associated with increased risk of PJP. Other risk factors include cranial irradiation and concurrent high dose steroids

Consideration for PJP prophylaxis should be at the discretion of the treating clinician

Prophylaxis drugs and doses 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
Severe and prolonged myelosuppression

Female patients may be at increased risk of developing severe and prolonged myelosuppression with temozolomide.r
Cerebral oedema

Some patients may require dexamethasone to reduce cerebral oedema.

For patients requiring high doses dexamethasone (greater than 4 mg) for protracted periods, check BSL as clinically indicated, consider H2 antagonists or proton pump inhibitors, watch for opportunistic infections and consider prophylaxis if necessary. If patient is on enzyme-inducing anticonvulsant drugs, check anticonvulsant levels ~ 5 days after each alteration in dexamethasone dose if appropriate.

Read more about reducing cerebral oedema with dexamethasone
Constipation

Prescribe prophylactic laxatives to prevent 5HT3 antagonist induced constipation.
Blood tests

FBC, EUC and LFTs at baseline and prior to each cycle.
Hepatitis B screening and prophylaxis

Routine screening for HBsAg and anti-HBc is NOT usually recommended for patients receiving this treatment.

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: the following dose modifications have been adapted from the CATNON clinical trialr

Temozolomide dose levels

Dose level Dose (day 1 to 5) Comment
-1 100 mg/m2/day Reduction if prior toxicity
0 150 mg/m2/day This is the starting dose in cycle 1
+1 200 mg/m2/day This is the escalated dose as of cycle 2
(in absence of toxicity)
Haematological toxicity
ANC x 109/L (pre-treatment blood test)
1.0 to less than 1.5 Delay treatment until recovery. Resume temozolomide at same dose
less than 1.0 Delay treatment until recovery. Reduce temozolomide by one dose level
Febrile neutropenia Delay treatment until recovery. Reduce temozolomide by one dose level
Platelets x 109/L (pre-treatment blood test)
50 to less than 100 Delay treatment until recovery. Resume temozolomide at same dose
less than 50 Delay treatment until recovery. Reduce temozolomide by one dose level
Renal impairment
No dose modifications necessary
Hepatic impairment 
Hepatic dysfunction (at baseline)
No dose modification necessary
Hepatotoxicity during treatment (pre-treatment blood test)
Grade 2 Delay treatment until recovery to grade 1 or less, then resume temozolomide at same dose 
Grade 3 Delay treatment until recovery to grade 1 or less, then reduce temozolomide by one dose level 
Grade 4 Cease temozolomide

References & Disclaimer

Temozolomide
No specific clinically significant drug-drug interactions
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)
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

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

DOAC and antineoplastic 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 Antineoplastic agents can damage the lining of the intestine; affecting the absorption of digoxin Monitor digoxin serum levels; adjust digoxin dosage as appropriate
Antiepleptics Both altered antiepileptic and antineoplastic levels may occur, possibly leading to loss of efficacy or toxicity. If patient has never had a seizure, consider weaning off antiepileptics.
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 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

Days 1 to 5

This is an oral treatment

General patient assessment prior to each treatment.

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

Pre treatment medication

Verify antiemetics taken or administer as prescribed.

Temozolomide

  • administer orally on scheduled days
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • to be taken on an empty stomach, one hour before or two hours after food

Note: missed doses should not be replaced; if a capsule is forgotten or vomited, normal dosing should be resumed at the next scheduled dose

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

Discharge information

Temozolomide capsules
  • Temozolomide capsules with written instructions on how to take them.
Antiemetics
  • Antiemetics as prescribed.
Laxatives
  • Ensure patient has prophylactic laxatives.
Prophylaxis medication
  • PJP prophylaxis if prescribed.
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 treatment induced nausea and vomiting

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
Constipation
Fatigue

Read more about fatigue
Skin rash

Temozolomide can cause skin reactions including pruritis, erythema, and generalised maculopapular rash, which may be delayed in onset. An oral desensitisation protocol may be considered to rechallenge a patient with a cutaneous reaction to temozolomide, where there are no suitable alternative agents. Consult a specialist neuro-oncology centre and/or an immunologist for expert advice regarding temozolomide desensitisation.

Read more about skin rash
Side effects of corticosteroids

Insomnia, oedema, increased risk of infection e.g. oral thrush, gastric irritation, worsening of peptic ulcer disease, increased blood sugar levels, loss of diabetic control, mood and behavioural changes - including anxiety, euphoria, depression, mood swings, increased appetite and weight gain, osteoporosis and fractures (long term use), bruising and skin fragility are associated with corticosteroid use.

Late (onset weeks to months)
Anaemia

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

Read more about anaemia
Alopecia - 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

The evidence supporting this protocol is provided by interim results from a phase III, open-label study with 2x2 factorial design, multicentre international randomised trial (CATNON trial).r Eligible patients were aged 18 years or older and had newly diagnosed 1p/19q non-co-deleted anaplastic glioma. This was decided because patients with 1p/19q non-codeleted tumours had worse outcomes than patients with 1p/19q co-deletion tumours in the trials of procarbazine, lomustine and vincristine to treat anaplastic oligodendroglioma and did not derive a survival benefit from PCV.rr

Between 4 December 2007 and 19 September 2015, 1407 patients were screened and 748 were randomly assigned to treatment groups. Patients were assigned in equal numbers (1:1:1:1), to receive radiotherapy (59.4 Gy in 33 fractions of 1.8 Gy) alone or with adjuvant temozolomide (12 x 4-week cycles of 150-200 mg/m2 temozolomide given on days 1 to 5); or to receive radiotherapy with concurrent temozolomide 75 mg/m2 per day, with or without adjuvant temozolomide.

The primary end point was overall survival adjusted for institution, performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. A planned interim analysis was performed after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p <0.0084).r

Efficacy

At the time of analysis and median follow up of 27 months, the hazard ratio for overall survival with use of adjuvant temozolomide was 0.65 (99.125% CI, 0.45 - 0.93). Overall survival at 5 years was 55.9% (95% CI, 47.2 - 63.8) with, and 44.1% (36.3 - 51.6) without adjuvant temozolomide.r

The data do not necessarily imply that concurrent temozolomide has no beneficial effect, but at the time of the interim analysis the survival values did not cross the predefined boundaries.

The survival curves for adjuvant versus no adjuvant temozolomide diverged further with increasing length of follow-up, which suggests that with time overall survival could improve further. The role for concurrent temozolomide therefore remains to be clarified.

The study protocol was amended in 2011 to incorporate analysis of mutations in IDH1 and IDH2 to investigate their predictive value for temozolomide efficacy, for which the analyses are pending. MGMT methylation analysis with respect to treatment efficacy is ongoing and the results are not currently available

© Lancet 2017

(A) Overall survival, and B) Progression-free survival, according to treatment group

© Lancet 2017

Toxicity

Grade 3-4 adverse events were seen in 8-12% in temozolomide assigned patients and were mainly haematological and reversible. Treatment was generally well tolerated. Most frequent toxicity was thrombocytopenia (7-9%). Apart from constitutional and gastrointestinal events, most adverse events were judged to be unrelated to treatment. Grade 3 or 4 increases in aminotransferases occurred in five (1%) of patients who received temozolomide. 

In 31 (12%) of 262 patients who completed or stopped taking adjuvant temozolomide before the interim analysis, relative dose intensity was less than 70%. 167 (64%) of these 262 patients had at least one cycle delayed, 74 (28%) due to haematological adverse events, 16 (6%) due to non-haematological adverse events, eight (3%) because of both haematological and non-haematological adverse events, and 123 (47%) for non-drug related reasons.r

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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. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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Review due:

The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/2046

16 Dec 2018