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Breast Adjuvant TC (DOCEtaxel CYCLOPHOSphamide) ID: 000024 (V.2) Approved: 10 Nov 2007 Last Modified: 15 Dec 2010 Review Due:31 Dec 2011 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: (authority) Adjuvant treatment of operable breast cancer in combination with cyclophosphamide Cost: ~ $2342 per cycle (chemotherapy only) Clinical Considerations 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 5HT3 antagonist 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 or 12.5 mg IV every 4 to 6 hours when necessary OR Prochlorperazine 25 mg rectally every 12 hours when necessary Hypersensitivity High Docetaxel Growth factor support G-CSF (filgrastim of pegfilgrastim) is available on the PBS for the secondary prevention of neutropenia Peripheral neuropathy Assess prior to each cycle for peripheral neuropathy. Dose modifications may be required Page 1 of 10 Breast Adjuvant TC (DOCEtaxel CYCLOPHOSphamide) Blood tests Baseline and repeat prior to each treatment FBC, EUCs, LFTs Nadir FBC cycle 1 Docetaxel is significantly cleared by the liver and may require a DOSE REDUCTION should liver function deteriorate Hepatitis B screening and prophylaxis Screening is recommended in all patients who are to receive treatment with cytotoxic and/or immunosuppressive therapy. Effects of anti-tumour drugs on fertility Information regarding the effects on fertility of cancer treatments Treatment Schedule Drug list Cycle 1 to 4 Day 1 Granisetron 2 mg (PO ) ONCE a day 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 3 days after chemotherapy Day 2 Dexamethasone Day 3 Dexamethasone Frequency: 21 Days Cycles: 4 Dose Modifications 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 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 Page 2 of 10 Breast Adjuvant TC (DOCEtaxel CYCLOPHOSphamide) 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% 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 Page 3 of 10 Breast Adjuvant TC (DOCEtaxel CYCLOPHOSphamide) References & Disclaimer Cyclophosphamide Interaction Clinical management CYP 3A4 inducers (eg phenytoin, phenobarbitone, rifampicin, St John’s Wort etc.) These drugs increase the conversion of cyclophosphamide to both its active and inactive metabolites The clinical significance of this interaction is unknown. Observe for altered effect of cyclophosphamide CYP 3A4 inhibitors (eg azole antifungals, ritonavir, erythromycin, grapefruit juice etc.) These drugs decrease the conversion of cyclophosphamide to both its active and inactive metabolites The clinical significance of this interaction is unknown. Observe for altered effect of cyclophosphamide Suxamethonium Cyclophosphamide inhibits cholinesterase metabolism of suxamethonium, which may prolong its neuromuscular blocking effect If a patient has had cyclophosphamide within ten days of planned general anaesthesia, the anaesthetist should be notified Link to table of CYP enzymes inducers, inhibitors and substrates Docetaxel Interaction CYP 3A4 inducers (eg phenytoin, phenobarbitone, rifampicin, St John’s Wort etc.) These drugs may increase the clearance of docetaxel, thus decreasing its efficacy CYP 3A4 inhibitors (eg azole antifungals, ritonavir, erythromycin, grapefruit juice etc.) These drugs may decrease the clearance of docetaxel thus increasing its toxicity Clinical management Avoid concurrent use. If this is not possible, monitor for decreased effect of docetaxel Avoid concurrent use. If this is not possible, monitor for increased docetaxel toxicity Link to table of CYP enzymes inducers, inhibitors and substrates General Interactions Interaction Clinical management Warfarin Antineoplastic agents may alter the anticoagulant effect of warfarin Monitor INR regularly and adjust the dose of warfarin if necessary, or consider other alternatives (eg, LMWH or standard heparin) Digoxin Antineoplastic agents can damage the lining of the intestine thus causing a decrease in the absorption of digoxin Monitor digoxin levels and adjust the dose of digoxin if clinically indicated Antiepileptics Both altered antiepileptic and antineoplastic levels may occur, possibly leading to loss of efficacy or toxicity. Avoid concurrent use of enzyme-inducing antiepileptics and antineoplastics. If this is not possible, monitor antiepileptic levels and adjust the dose if clinically indicated. The efficacy of antineoplastics should also be closely monitored Antiplatelet agents & NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia Avoid or minimise combination. If combination has to be used (eg 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 should be avoided Administration Details Administration Details (~ 2.5 hours) Safe handling and waste management Safe administration Page 4 of 10 Breast Adjuvant TC (DOCEtaxel CYCLOPHOSphamide) General patient assessment prior to each day of treatment. NOTE: Any toxicity greater than grade two may require dose reduction or delay of treatment; review by medical officer before commencing treatment. Prime IV lines Insert IVC or access PORT, PICC or CVC Chemotherapy Time out Pre treatment medications Verify dexamethasone premedication has been taken Administer 5HT3 antagonist PO or by IV bolus over 3 to 5 minutes Docetaxel infusion Prior to administration ■ ■ ■ assess for peripheral neuropathy prior to administration a dose reduction may be required. 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 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 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) Link to Excretion Table Discharge Information Premedication ■ dexamethasone tablets for next cycle of chemotherapy Take home antiemetics ■ ■ dexamethasone 8 mg daily up to 3 days post chemotherapy breakthrough antiemetics eg. metoclopramide OR prochlorperazine when required Growth factor support ■ arrangements for administration 24 hours post treatment if required Patient information ■ Patient Information specific to this regimen Monitoring Page 5 of 10 Breast Adjuvant TC (DOCEtaxel CYCLOPHOSphamide) Test/Assessments Frequency Tools/Links Peripheral Neuropathy Baseline and repeat prior to each treatment, may require a dose reduction Blood tests Baseline and repeat prior to each treatment FBC, EUCs, LFTs 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 to Antineoplastic Agents Risk of hypersensitivity reaction (HSR). Nausea and Vomiting Antineoplastic 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. 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. Thrombocytopenia A reduction in the number of circulating platelets increasing the risk of bruising and bleeding. Mucositis Painful inflammation and ulceration of the mucous membranes lining the mouth, oropharynx and the digestive tract. It may also affect any mucous membranes in the body. Arthralgia and Myalgia Typical pain from arthralgias and myalgias develops in the large joints of the arms and legs. The onset and length of symptoms will depend on the drug. Diarrhoea An increase in the frequency, or fluid content of stool that is different from the usual pattern. 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 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. Peripheral Neuropathy associated with Taxanes Impairment of the peripheral nervous system due to loss of axons and /or deterioration in the myelin sheath of nerve fibres. PalmarPlantar Erythrodysesthesia (PPE) Hand and Foot Syndrome PalmarPlantar Erythrodysesthesia (PPE) also known as HandFoot 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) Alopecia This treatment will cause hair loss. In some cases this 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 are often 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) Page 6 of 10 Breast Adjuvant TC (DOCEtaxel CYCLOPHOSphamide) Menopausal Symptoms Irregular or cessation of menstrual periods due to ovarian failure and associated menopausal symptoms of hot flashes, mood swings, sleep disturbance, dyspareunia, night sweats, and a decrease in libido. Page 7 of 10 Breast Adjuvant TC (DOCEtaxel 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 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. Link to external article 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. Link to external article 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 CYCLOPHOSphamide) ■ Cancer Council Helpline Phone 131120 For further information: ■ ■ ■ ■ ■ ■ ■ eviQ Cancer Treatments online www.eviQ.org.au Cancer Council NSW www.cancercouncil.com.au The Cancer Council Australia www.cancer.org.au National Breast & Ovarian Cancer Centre www.nbocc.org.au NSW Breast Cancer Institute www.bcna.org.au Food Standards Australia Listeria & Food Brochure http://www.foodstandards.gov.au/newsroom/publications/index.cfm Australasian Menopause Society www.menopause.org.au For patient advocacy: ■ ■ Breast Cancer Action Group NSW www.bcagnsw.org.au Cancer Voices NSW www.cancervoices.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 15 Dec 2010 Page 10 of 10
