Download Breast Adjuvant TC (DOCEtaxel and CYCLOPHOSPHamide)

Breast Adjuvant TC (DOCEtaxel and CYCLOPHOSPHamide)
ID: 000024 (V.2)
Approved: 10 Nov 2007
Last Modified: 22 Jul 2014
Review Due: 30 Jun 2016
Treatment Schedule Summary Drug
Dose
Route
Day
DOCEtaxel
75 mg/m2
IV
1
CYCLOPHOSPHamide
600 mg/m2
IV
1
Frequency: 21 days
Cycles: 4
Full View Indications and Patient Population Indications: ■
■
stage I to III operable invasive breast cancer after complete surgical excision of the primary tumour may be considered for use in patients where an anthracycline is contraindicated Drug Status:
Docetaxel: (PBS authority) Adjuvant treatment of operable breast cancer in combination with cyclophosphamide Cost: ~$165 per cycle (chemotherapy only)
Clinical Information Tools/Links
Venous access required
IV cannula (IVC) or central venous access device (CVAD) is required to administer
this treatment.
Premedication
Dexamethasone 8 mg TWICE a day for 3 consecutive days, commencing one day
prior to docetaxel administration. Dexamethasone premedication helps to reduce the severity and frequency of fluid
retention.
Emetogenicity MODERATE
Dexamethasone as per premedication then 8 mg daily for up to 3 days post
chemotherapy AND Palonosetron IV 0.25 mg day 1. Ensure that patients have sufficient antiemetics for breakthrough emesis: Metoclopramide 10 mg to 20 mg every 4 to 6 hours when necessary OR Prochlorperazine 10 mg PO every 4 to 6 hours when necessary.
Hypersensitivity
High risk with docetaxel.
Growth factor support
G-CSF (filgrastim, lenograstim or pegfilgrastim) is available on the PBS for the
secondary prevention of neutropenia.
Peripheral neuropathy
Assess prior to each cycle. If a patient experiences > grade 2 peripheral neuropathy, a
dose reduction or delay of treatment may be required; review by medical officer before
commencing treatment.
Blood tests
Baseline and repeat prior to each treatment FBC, EUC, LFTs. Nadir FBC cycle 1.
Page 1 of 10
Breast Adjuvant TC (DOCEtaxel and CYCLOPHOSPHamide)
Hepatitis B screening and prophylaxis
Routine screening for HBsAg and anti-HBc is recommended prior to initiation of
chemotherapy or immunosuppressive therapy for: haematology patients AND all
patients with solid tumours receiving curative treatment. Screening is NOT routinely
recommended for patients who are not being treated with curative intent, except those
receiving immunosuppressive chemotherapy, high dose glucocorticoids or an
anthracycline containing regimen.
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 oncology patients, as outlined
in the 2013 Australian Immunisation Handbook 10th Edition.
Effects of cancer treatment on fertility
Information regarding the effects on fertility of cancer treatments.
The supportive therapies included in the treatment schedule (antiemetics, premedications etc) are listed as defaults. These may be substituted to reflect individual institutional policy. Additionally, infusion times, diluents, volumes and routes of administration (as applicable) may vary between institutions.
Treatment Schedule
Drug list
Cycle 1 to 4 Day 1
Palonosetron 0.25 mg (IV bolus)
30 minutes before chemotherapy
Dexamethasone 8 mg (PO )
TWICE a day with or after food (to start the day before chemotherapy) DOCEtaxel 75 mg/m2 (IV infusion)
in 250 mL to 500 mL sodium chloride 0.9% over 60 minutes
CYCLOPHOSPHamide 600 mg/m2 (IV infusion)
in 500 mL sodium chloride 0.9% over 30 to 60 minutes
8 mg (PO )
TWICE a day with or after food
8 mg (PO )
ONCE a day with or after food. May be continued up to Day 4 if required for the
management of nausea.
Day 2
Dexamethasone Day 3
Dexamethasone Frequency:
21 Days Cycles:
4 Dose Modifications There is limited evidence for dose modification and the recommendations made on eviQ are intended as a guide only. They are generally conservative, placing a greater weight on safety compared to efficacy.
Link to Dosing Considerations & Disclaimer Note: All dose reductions are calculated as a percentage of the starting dose Haematological toxicity
ANC x 109/L (on day of chemotherapy)
0.5 to less than 1.0
Delay treatment until recovery and consider adding G-CSF for subsequent cycles
less than 0.5
Delay treatment until recovery and consider adding G-CSF for subsequent cycles; If patient is already on G-CSF, consider reducing docetaxel and cyclophosphamide by 25% for
subsequent cycles
Febrile neutropenia
Delay treatment until recovery and consider adding G­CSF for subsequent cycles; If patient is already on G­CSF, consider reducing docetaxel and cyclophosphamide by Page 2 of 10
Breast Adjuvant TC (DOCEtaxel and CYCLOPHOSPHamide)
25% for subsequent cycles Platelets x109/L (at any stage of the cycle)
50 to less than 100
Delay treatment until recovery
less than 50
Delay treatment until recovery and consider reducing docetaxel and cyclophosphamide by 25% for
subsequent cycles
Renal impairment
Creatinine clearance (mL/min)
30 to 50
Reduce cyclophosphamide by 25%
less than 30
Reduce cyclophosphamide by 50%
Link to classification of renal dysfunction for dose modification Hepatic impairment
Hepatic dysfunction
Minimal
Reduce docetaxel by 25%
Mild
Reduce docetaxel by 50%
Moderate/Severe
Omit docetaxel
Link to classification of hepatic dysfunction for dose modification Peripheral neuropathy
CTC grading
Grade 2 which is present at the start of the next cycle
Reduce docetaxel by 25%, if persists, reduce docetaxel by 50%
Grade 3 or Grade 4
Omit docetaxel
Mucositis & stomatitis
CTC grading
Grade 2
Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose for subsequent
cycles as follow: 1st occurrence: No dose reduction 2nd occurrence: Reduce docetaxel and cyclophosphamide by 25% 3rd occurrence: Reduce docetaxel and cyclophosphamide by 50% 4th occurrence: Withhold chemotherapy
Grade 3 or Grade 4
Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose for subsequent
cycles as follow: 1st occurrence: Reduce docetaxel and cyclophosphamide by 50% 2nd occurrence: Withhold chemotherapy
Diarrhoea
CTC grading
Grade 2
Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose for subsequent
cycles as follow: 1st occurrence: No dose reduction 2nd occurrence: Reduce docetaxel and cyclophosphamide by 25% 3rd occurrence: Reduce docetaxel and cyclophosphamide by 50% Page 3 of 10
Breast Adjuvant TC (DOCEtaxel and CYCLOPHOSPHamide)
4th occurrence: Withhold chemotherapy
Grade 3 or Grade 4
Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose for subsequent
cycles as follow: 1st occurrence: Reduce docetaxel and cyclophosphamide by 50% 2nd occurrence: Withhold chemotherapy
Interactions References & Disclaimer Cyclophosphamide
Interaction Clinical management
CYP3A4 inducers (e.g. carbamazepine,
phenytoin, phenobarbitone, rifampicin, St
John’s wort etc.)
Increased toxicity of cyclophosphamide
possible due to increased conversion to
active (and inactive) metabolites
Avoid combination or monitor for
cyclophosphamide toxicity
CYP3A4 inhibitors (e.g. aprepitant, azole
antifungals, clarithromycin, erythromycin,
grapefruit juice, ritonavir etc.)
Reduced efficacy of cyclophosphamide
possible due to decreased conversion to
active (and inactive) metabolites
Avoid combination or monitor for decreased
clinical response to cyclophosphamide
Amiodarone
Possible additive pulmonary toxicity with
high-dose cyclophosphamide (i.e. doses
used prior to stem cell transplant; 60
mg/kg daily or 120 to 270 mg/kg over a
few days)
Avoid combination or monitor closely for
pulmonary toxicity
Allopurinol, hydrochlorothiazide, indapamide
Delayed effect. Increased risk of bone
marrow depression; probably due to
reduced clearance of active metabolites
of cyclophosphamide
Avoid combination, consider alternative
antihypertensive therapy or monitor for
myelosuppression
Cyclosporin
Reduced efficacy of cyclosporin due to
reduced serum concentration
Monitor cyclosporin levels; adjust dosage as
appropriate; monitor response to cyclosporin
Suxamethonium
Prolonged apnoea due to marked and
persistent inhibition of cholinesterase by
cyclophosphamide
Alert the anaesthetist if a patient has been
treated with cyclophosphamide within ten days of
planned general anaesthesia
Link to table of CYP inducers, inhibitors and substrates
Docetaxel
Interaction Clinical management
CYP3A4 and P-gp inhibitors (e.g. amiodarone,
aprepitant, azole-antifungals, ritonavir,
lapatinib, nilotinib, sorafenib, macrolides,
cyclosporin, grapefruit juice etc.)
Increased toxicity of docetaxel possible
due to reduced clearance
Avoid combination or monitor for docetaxel
toxicity
CYP3A4 inducers (e.g. carbamazepine,
phenytoin, phenobarbitone, rifampicin, St
John’s wort etc.)
Reduced efficacy of docetaxel possible
due to increased clearance
Avoid combination or monitor for decreased
clinical response to docetaxel
Link to table of CYP inducers, inhibitors and substrates
General Interactions
Interaction Warfarin
Antineoplastic agents may alter the
anticoagulant effect of warfarin
Page 4 of 10
Clinical management
Monitor INR regularly and adjust warfarin dosage
as appropriate; consider alternative
anticoagulant (e.g. LMWH, oral Factor Xa
inhibitor, unfractionated heparin)
Breast Adjuvant TC (DOCEtaxel and CYCLOPHOSPHamide)
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
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 oncology patients, as outlined in the 2013 Australian Immunisation Handbook 10th Edition.
Administration Details Treatment time (~ 2.5 hours) General patient assessment prior to each day of treatment NOTE: Any toxicity greater than grade 2 may require dose reduction or delay of treatment and review by medical officer before commencing treatment. Prime IV lines Insert IV cannula or access Port, PICC or CVC Pre treatment medications
Verify dexamethasone premedication has been taken Administer 5HT3 antagonist PO or by IV bolus over 3 to 5 minutes
Chemotherapy ­
Time out Docetaxel infusion Prior to administration
The medicines information reference publications stipulate the use of non­PVC containing bags and administration sets. However, this is not consistently recommended in the product information, therefore the decision should be at the discretion of the administering unit. ■
■
■
assess for peripheral neuropathy prior to administration. Any toxicity grade 2 or above refer to medical officer
assess patient for fluid retention or weight gain prior to each cycle ● notify medical officer of any signs of fluid retention or unexplained weight gain if using frozen gel gloves these need to be commenced ~ 15 minutes prior to administering the docetaxel Administer docetaxel (irritant with vesicant properties) over 60 minutes ■
■
■
via IV infusion observe for hypersensitivity reactions flush with ~ 100 mL of sodium chloride 0.9% NOTE: Continue with frozen gel gloves for ~ 15 minutes post completion of docetaxel Page 5 of 10
Breast Adjuvant TC (DOCEtaxel and CYCLOPHOSPHamide)
Cyclophosphamide infusion Administer cyclophosphamide over 30 to 60 minutes ■
■
via IV infusion flush with ~ 50 mL of sodium chloride 0.9% NOTE: Rapid infusion can cause dizziness, rhinitis, nausea and perioral numbness. If symptoms develop, slow infusion rate. Remove IV cannula and/or disconnect Port, PICC or CVC Continue safe handling precautions until 7 days after completion of drug(s)
Discharge Information Premedication ■
dexamethasone tablets for next cycle of chemotherapy. Take home antiemetics ■
antiemetics as prescribed Growth factor support ■
arrangements for administration if prescribed Patient information ■
Patient Information Sheet Monitoring Test/Assessments
Frequency
Tools/Links
Peripheral neuropathy
Assess prior to each cycle. If a patient experiences > grade 2 a dose reduction or
delay of treatment may be required; review by medical officer before commencing
treatment.
Blood tests
Baseline and repeat prior to each treatment FBC, EUC, LFT. Nadir FBC cycle 1.
Side Effects 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 reaction. Nausea and Vomiting Treatment induced nausea and vomiting. Taste and Smell Alteration Changes in taste and smell can affect appetite and are a common side effect in patients receiving chemotherapy. Early (onset days to weeks) Neutropenia Low numbers of circulating neutrophils reduce the body's ability to fight infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. Thrombocytopenia A reduction in the number of circulating platelets increases the risk of bruising and bleeding. Oral Mucositis This is defined as chemotherapy induced damage to the oral mucosa which causes pain (ranging from mild soreness to severe ulceration associated with inability to eat or drink) and may become a portal for infection. This side effect focuses on oral mucositis; however mucositis can affect any mucous membrane. Arthralgia and Myalgia Generalised body aches and pains may occur a few days following treatment and last for several days. This may require moderately strong analgesia. Diarrhoea An increase in the frequency, or fluid content of stool. Page 6 of 10
Breast Adjuvant TC (DOCEtaxel and CYCLOPHOSPHamide)
Fatigue Fatigue is a feeling of excessive tiredness or exhaustion for most or all of the time, typically not relieved by rest or sleep. Skin Rash ­ Macular and Papular A disorder characterised by the presence of macules (flat) and papules (elevated lesions) and can be associated with pruritus Peripheral Neuropathy This is typically a symmetrical sensory neuropathy affecting the fingers and toes, and sometimes as treatment progresses may affect much of the hands and feet. Dosage adjustment, delay or cessation may be required. Hyperlacrimation Ocular symptoms include watery eyes, blepharitis, tear duct stenosis, acute and chronic conjunctivitis, photophobia, excessive lacrimation and drug excretion in tears. Fluid Retention Syndrome ­ associated with Docetaxel 27% despite dexamethasone premedication (Jones et al 2006) Presents as peripheral oedema and weight gain and less frequently as pleural effusion and/or ascites. Incidence and severity appear to be related to cumulative dose and is caused by capillary leak. Palmar­Plantar Erythrodysesthesia (PPE) ­ Hand Foot Syndrome Palmar­Plantar Erythrodysesthesia (PPE) also known as Hand Foot Syndrome (HFS) is characterized by the gradual onset of bilaterally symmetric erythema, tenderness, pain, swelling, tingling, numbness, pruritus, dry rash, or moist desquamation and ulceration over the palms and soles. Late (onset weeks to months) Anaemia Antineoplastic drugs can interfere with the reproduction of haematopoietic cells which results in a decreased production of red blood cell (RBC) precursors and mature RBCs. Alopecia is common and may include hair loss from all parts of the body. Cognitive Changes (chemo fog) Changes in cognition characterised by memory loss, forgetfulness and feeling vague during and after chemotherapy. Also referred to as 'chemo brain' or 'chemo fog'. Nail Changes severe nail changes can occur in 2% of patients having docetaxel Changes in the fingernail and toenails may be seen during chemotherapy. Nail changes include hyperpigmentation and damage to the epithelium under nails causing a change in the tight adhesion between the nail plate and nail bed which can lead to separation of the nail plate from the nail bed, causing pain. Physical and psychological effects can be significant. Delayed (onset months to years) Menopausal Symptoms Irregularity or cessation of menstrual periods due to ovarian failure may occur. This may be associated with menopausal symptoms such as hot flushes, mood swings, sleep disturbance, dyspareunia, night sweats, and a decrease in libido. Page 7 of 10
Breast Adjuvant TC (DOCEtaxel and CYCLOPHOSPHamide)
Evidence The evidence supporting this treatment comes from a phase III randomised trial by Jones comparing the efficacy of doxorubicin and cyclophosphamide (AC) to docetaxel and cyclophosphamide (TC)1, 2 Between June 1997 and December 1999, 1016 patients were randomly assigned to receive 4 cycles of the above regimens every 3 weeks as adjuvant therapy. Both treatment groups were well balanced with respect to major prognostic factors for breast cancer outcome. The primary end point was disease­free survival (DFS) and secondary endpoints included overall survival (OS). Efficacy At a median of 7 yrs followup the the difference in DFS between TC and AC was significant (81% TC v 75% AC; P=.033; hazard ratio [HR], 0.74; 95% CI 0.56 to 0.98) as was OS (87% TC v 82% AC; P=.032; HR, 0.69; 95% CI, 0.50 to 0.97). Disease Free Survival2
Overall Survival2
© Journal of Clinical Oncology 2009 Toxicity The TC group experienced significantly more grade 1 and 2 oedema, myalgia and arthralgia (p< 0.01) whereas in the AC group, patients had more grade 1 to 4 nausea and vomiting (p<0.01). In the AC group, 1 patient died from congestive heart failure and 4 patients died from myocardial infarction. In the TC group, no case of congestive heart failure was observed but 2 patients died from myocardial infarction. There was more febrile neutropenia observed with TC compared with AC (5% vs 2.5%; p=0.07). 2 patients died while receiving TC (one unrelated cardiac death and one death with sepsis and neutropenia). No patients died during treatment with AC. Frequency of Reported Adverse Events all Grades at Median Followup of 5.5 yrs1
TC (n=506) %
AC (n=510) %
Grade 1 & 2
Grade 3 &4
Grade 1 & 2
Grade 3 &4
Anaemia
5
<1
7
1
Neutropenia
1
61
3
55
Thrombocytopenia
<1
<1
<1
1
Asthenia
75
4
73
5
Oedema
34
<1
20
<1
Fever
19
5
15
3
Page 8 of 10
Breast Adjuvant TC (DOCEtaxel and CYCLOPHOSPHamide)
Infection
12
7
12
8
Myalgia
32
1
16
<1
Nausea
51
2
75
7
Phlebitis
11
<1
2
0
Stomatitis
33
<1
44
2
Vomiting
14
<1
37
5
This paper has been used as the reference for the side effects of TC in the adjuvant setting as the key study trial 9735 did not capture all the well known side effects of docetaxel 3 Non Haematological Toxicity3
© Japanese Journal of Clinical Oncology 2009 References 1.
2.
3.
Jones, S. E., M. A. Savin, F. A. Holmes, et al. 2006. "Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer." J Clin Oncol. 24
(34):5381­5387. Jones, S., F. A. Holmes, J. O'Shaughnessy, et al. 2009. "Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7­Year Follow­Up of US Oncology Research Trial 9735." J Clin Oncol 27(8):1177­1183. Takabatake, D., N. Taira, F. Hara, et al. 2009. "Feasibility study of docetaxel with cyclophosphamide as adjuvant chemotherapy for Japanese breast cancer patients." Jpn J Clin Oncol 39(8):478­483. Support & Information Services For telephone support Page 9 of 10
Breast Adjuvant TC (DOCEtaxel and CYCLOPHOSPHamide)
■
Cancer Council Helpline Phone 13 11 20 For online support ■
Cancer Connections www.cancerconnections.com.au For further information ■
■
■
■
■
■
■
■
eviQ Cancer Treatments online www.eviQ.org.au Cancer Council Australia www.cancer.org.au Cancer Council NSW www.cancercouncil.com.au Food Standards Australia New Zealand ­ Listeria & Food Safety (at www.foodstandards.gov.au/consumer/safety/listeria/pages/listeriabrochuretext.aspx) Cancer Australia www.canceraustralia.gov.au/affected­cancer/cancer­types/breast­cancer Breast Cancer Network Australia www.bcna.org.au Westmead Breast Cancer Institute www.bci.org.au Australasian Menopause Society www.menopause.org.au For patient advocacy ■
Cancer Voices NSW www.cancervoices.org.au For support for young people living with cancer (12­24 years): ■
■
Canteen www.canteen.org.au NOWWHAT www.nowwhat.org.au For free workshops on caring for your hair and skin while on treatment ■
Look Good Feel Better www.lgfb.org.au The currency of this information is guaranteed only up until the date of printing, for any updates please check www.eviq.org.au ­ 31 Oct 2014 Page 10 of 10