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Breast adjuvant letrozole

Check for clinical trials in this patient group. Link to Australian Clinical Trials website

The anticancer drug(s) in this protocol have been updated with the ADDIKD guideline recommendations (if applicable). Recommendations may differ from other protocols which have not been updated. For further information refer to the dedicated eviQ ADDIKD guideline webpage.

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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.

Continuous treatment
Letrozole 2.5 mg (PO) ONCE a day

Continuous daily to complete a total of 5 to 10 years of adjuvant endocrine therapy

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.

Continuous treatment
Letrozole 2.5 mg (PO) ONCE a day

Continuous daily to complete a total of 5 to 10 years of adjuvant endocrine therapy

  • Hormone receptor-positive invasive breast cancer in post-menopausal women, for a total of 5 to 10 years of adjuvant endocrine therapy.rrrr
Emetogenicity MINIMAL

No antiemetics should be routinely administered before treatment in patients without a history of nausea and vomiting. If patients experience nausea and/or vomiting, consider using the low antiemetic prophylaxis regimen.
Bone mineral density (BMD)

Baseline BMD and repeat as clinically indicated. Lifestyle modification including regular exercise, particularly weight bearing exercises should be encouraged.
Supplements

Consider daily oral supplements of at least calcium 500 mg and vitamin D 400 International Units for the duration of the therapy.
Oestrogen preparations

Oestrogen preparations should be avoided due to insufficient data on safety as systemic absorption of oestrogen may negate the effect of aromatase inhibitors. Minimal use of topical oestrogen therapies for vulvo-vaginal complaints may be considered.
Blood tests

LFTs, lipid studies, calcium and vitamin D at baseline and repeat as clinically indicated.
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Note: All dose reductions are calculated as a percentage of the starting dose.

Kidney dosing recommendations 
No dose reduction required in kidney dysfunction.
Hepatic impairment
Hepatic dysfunction
Severe In patients with cirrhosis or severe hepatic impairment reduce the dose by 50% (2.5 mg every other day)

Drug interactions in eviQ protocols are under review and being updated to align with current literature. Further site-wide updates and changes will occur in due course. References & Disclaimer

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources: 

Letrozole
  Interaction Clinical management
Tamoxifen Reduced letrozole plasma levels occur when coadministered with tamoxifen Avoid combination
Oestrogen containing therapies Negate the pharmacological action of letrozole Combination contraindicated (minimal use of topical oestrogen therapy for vulvo-vaginal complaints may be considered)
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of letrozole possible due to reduced clearance Caution advised if combination used - monitor for letrozole toxicity
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of letrozole possible due to increased clearance Caution advised if combination used - monitor for decreased clinical response to letrozole

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

Administration

This is a continuous oral treatment

Letrozole

  • administer orally ONCE a day
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with or without food 
  • if nausea develops advise patient to take at night.

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

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Discharge Information

Letrozole tablets
  • Letrozole tablets with written instructions on how to take them.
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
Headache

Early (onset days to weeks)
Hot flushes
Hyperlipidaemia and hypercholesterolaemia

Abnormally elevated levels of lipids and cholesterol in the blood.
Fluid retention and oedema

An excess amount of fluid around the cells, tissues or serous cavities of the body, leading to swelling.

Late (onset weeks to months)
Arthralgia and myalgia

Generalised joint pain or and/or stiffness and muscle aches, often worse upon waking or after long periods of inactivity. Can improve with movement. May be mild or severe, intermittent or constant and accompanied by inflammation. 

Read more about arthralgia and myalgia
Vaginal atrophy

Read more about vaginal dryness

Delayed (onset months to years)
Osteoporosis

The evidence supporting this protocol is provided by a phase III multicentre international randomised trial (BIG 1-98) involving 8010 patients comparing five years of treatment with letrozole, letrozole followed by tamoxifen, tamoxifen, and tamoxifen followed by letrozole in post-menopausal women with hormone-receptor-positive breast cancer.r

Between March 1998 and March 2000, 1835 women were randomised to monotherapy with either letrozole 2.5 mg daily or tamoxifen 20 mg daily. From April 1999 to May 2003, an additional 6193 women were randomly assigned to one of the four groups.r

The primary end point was disease-free survival (DFS) and secondary end points were overall survival (OS), the occurrence of a second non-breast cancer, or death from any cause, safety, time to recurrence and time to distant recurrence.r

Efficacy

After a median follow-up of 71 months after randomization, DFS was not significantly improved with either sequential treatment as compared with letrozole alone (HR for tamoxifen followed by letrozole=1.05; 99% CI 0.84-1.32; HR for letrozole followed by tamoxifen=0.96; 99% CI 0.76-1.21). There were more early relapses among women who were assigned to tamoxifen followed by letrozole than among those who were assigned to letrozole alone. The updated analysis of monotherapy (76 month follow-up) also showed that there was a non-significant difference in OS between women assigned to treatment with letrozole and those assigned to treatment with tamoxifen (HR for letrozole=0.87; 95% CI 0.75-1.02; p=0.08).r

Kaplan-Meier analysis of DFS from the time of randomisation for the two monotherapy treatment groups (includes 619 patients who crossed over to letrozole)r

© N Engl J Med 2009

Cumulative incidence of the recurrence of breast cancerr

© N Engl J Med 2009

Toxicity

Toxicities were primarily grade 1 or 2 with hot flushes, arthritis, arthralgia and myalgia more common in the letrozole group.

Adverse eventsr
(all grades) 		 Tamoxifen %
(n=1540) 		 Letrozole %
(n=1534)		 Tamoxifen -> Letrozole %
(n=1540)		 Letrozole -> Tamoxifen %
(n=1526)		 p-value
CVA or TIA 2 1  2 2 0.74 
Thromboembolic events 5 2 5 4 <0.001
Cardiac events* 6 7  7 6 0.45
Hypercholesterolaemia 30 53 41 44.5 <0.001
Vaginal bleeding 10 5 7.5 6 <0.001
Hot flushes 43 38 44 42 0.003
Fractures 7 10 9 7.5 0.02
Arthralgias and myalgias 30 35 32 33 0.05

CVA: cerebrovascular accident; TIA: transient ischaemic attack
* cardiac events included ischaemic heart disease, arrhythmia, cardiac failure, cardiopathy, valvular disease, changes in the electrocardiogram, sudden cardiac death, and cardiac event not otherwise specified

Cardiovascular, cerebrovascular and thromboembolic events for aromatase inhibitors compared to tamoxifenr

© Cancer Treat Rev 2008

The evidence supporting prolonged endocrine therapy is provided by a phase III multicentre, international, randomised trial (MA.17) involving 5187 patients comparing letrozole with placebo in post menopausal women with early stage breast cancer within 3 months of completion of 5 years of tamoxifen therapy.r

Between August 1998 and September 2002, 2593 patients were randomised to receive letrozole 2.5 mg daily and 2594 patients were randomised to receive placebo daily for 5 years.

The primary end point was disease-free survival (DFS) and secondary end points were overall survival (OS), quality of life, and long-term safety.r

The trial was unblinded in 2003 and crossover was allowed after the first interim analysis demonstrated a statistically significant effect on DFS and a trend toward a survival advantage in the letrozole group. 1579 women chose to switch to letrozole (PLAC-LET group) and 804 remained in the placebo group (PLAC-PLAC group). Patients in the PLAC-LET group were younger, had a better performance status, and were more likely to have had node-positive disease, axillary dissection, and adjuvant chemotherapy than those in the PLAC-PLAC group.r In the PLAC-LET group the median time from the end of tamoxifen to the start of letrozole was 2.8 years.

Efficacy

Original randomisation: letrozole or placebo within 3 months of completing tamoxifen

After a median follow-up of 30 months, women in the letrozole arm had significantly better DFS (HR=0.58, 95% CI 0.45-0.76, p<0.001) and distant DFS (HR=0.60, 95% CI 0.43-0.84, p=0.002) than women in the placebo arm.r

The 4-year DFS for patients receiving letrozole was 94.4% and for patients receiving placebo was 89.8%. OS was the same in both arms (HR=0.82, 95% CI 0.57-1.19, p=0.3), however in the node positive cohort, OS was significantly improved with letrozole (HR=0.61, 95% CI 0.38-0.98, p=0.04).r

Kaplan-Meier curves for (A) DFS and (B) OSr

(A)

(B)

© J Natl Cancer Inst 2005

Late switch to letrozole (median 2.8 years after completing tamoxifen)

At median follow-up of 5.3 years from initial randomisation on MA.17, DFS (adjusted HR=0.37; 95% CI 0.23-0.61; p<0.0001) and distant DFS (HR=0.39; 95% CI 0.20-0.74; p=0.004) were superior in the PLAC-LET group compared to the PLAC-PLAC group.r

(These results should be viewed in the context of an adjusted, retrospective multivariate analysis where the intervention was self-selected; and not as a prospective, randomised trial. As a consequence, the effect on OS cannot be addressed in these patients.)

Kaplan-Meier curves for (A) DFS and (B) distant DFSr

© J Clin Oncol 2008

Toxicity

Hot flushes, anorexia, arthralgia, myalgia, and alopecia were all statistically significantly more common in those receiving letrozole, and vaginal bleeding was statistically significantly more common in those receiving placebo. More patients receiving letrozole had a fracture, a new diagnosis of osteoporosis, or cardiovascular disease on study, but only the incidence of self-reported new osteoporosis was statistically significantly different between the two arms. Diagnoses of new osteoporosis were reported by 364 patients, 209 (8.1%) of those receiving letrozole and 155 (6.0%) of those receiving placebo (p=0.003), with median times to occurrence of 0.70 years for those receiving letrozole and 0.52 years for those receiving placebo.r

When toxicity was assessed by age there was no difference between letrozole- and placebo- treated patients aged ≥ 70 years.r

Toxicityr

© J Clin Oncol 2008

Cardiovascular, cerebrovascular and thromboembolic events for aromatase inhibitors compared to tamoxifenr

© Cancer Treat Rev 2008

The evidence regarding extended adjuvant therapy with letrozole 2.5 mg daily is provided by three trials- GIM 4, NSABP B-42, and SOLE.rrr

GIM 4r

This trial compared the addition of 2-3 vs 5 years of letrozole in 2056 postmenopausal women with hormone receptor positive breast cancer who had already received 5 years of initial adjuvant endocrine therapy with tamoxifen. The primary end point was invasive disease free survival (IDFS) and secondary end points were overall survival (OS) and safety.

NSABP B-42r

This trial compared the addition of 5 years of letrozole vs placebo in 3966 postmenopausal women with hormone receptor positive breast cancer who had already received 5 years of initial adjuvant endocrine therapy with an aromatase inhibitor, or tamoxifen followed by an aromatase inhibitor. The primary end point was disease free survival (DFS) and secondary end points included OS, breast cancer-free interval, distant recurrence, incidence of osteoporotic fractures, and incidence of arterial thrombotic events.

SOLEr

This trial compared the addition of 5 years of continuous letrozole vs intermittent letrozole (daily for 9 months followed by a 3 month break in years 1 to 4 then daily in year 5) in 4851 postmenopausal women with hormone receptor positive breast cancer who had already received 4 to 6 years of initial adjuvant endocrine therapy. The primary end point was DFS and secondary end points included breast cancer-free interval, distant recurrence-free interval, OS, and adverse events.

A review by van Hellemond et al suggests considering extended adjuvant endocrine therapy with aromatase inhibitors for a total of 5 to 10 years treatment only in women with high-risk early breast cancer who tolerate treatment well.r

Efficacy

GIM 4r

After a median follow up of 11.7 years, the 12 year DFS was 62% (95% CI, 57 to 66) in the 2 to 3 year extended treatment group vs 67% (95% CI, 62 to 71) in the 5 year extended group (HR = 0.78, 95% CI, 0.65 to 0.93; p=0.0064). The 12 year OS was 84% (95% CI, 82 to 87) vs 88% (95% CI, 86 to 90) respectively.

NSABP B-42r

After a median follow up of 6.9 years, the 7 year DFS was 81.3% (95% CI, 79.3 to 83.1) in the placebo group vs 84.7% (95% CI, 82.9 to 86.4) in the letrozole group (HR = 0.85, 95% CI, 0.73 to 0.999; p=0.048). The 7 year OS was 92.3% (95% CI, 90.9 to 93.5) vs 91.8% (95% CI, 90.4 to 93.0) respectively.

SOLEr

After a median follow up of 84 months, the 7 year DFS was 81.4% (95% CI, 79 to 83) in the intermittent treatment group vs 81.5% (95% CI, 79.8 to 83.1) in the continuous treatment group (HR = 1.03, 95% CI, 0.91 to 1.17). There was no statistically significant difference between either group for any of the secondary end points.

Toxicity

Adverse eventsr

© N Engl J Med 2021

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Flinders Filters has partnered with eviQ to build reliable, robust search filters to retrieve core high level evidence on topics of significance to eviQ. The project goal is the provision of a sustainable model for evidence retrieval to ensure ongoing currency of content.

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Version 6

Date Summary of changes
19/07/2023

Protocol updated with ADDIKD guideline recommendations.

PDF of previous protocol.

Version number changed to V.6.

Version 4

Date Summary of changes
12/10/2020 Protocol reviewed electronically by Medical Oncology Reference Committee. Treatment duration changed to a total of 5 to 10 years in treatment schedule, indications and patient information. Version number changed to V.4. Next review 5 years.

Version 3

Date Summary of changes
17/01/2008 Addition of long term toxicities from review article
11/01/2010 Reviewed, new dose modifications and transferred to eviQ
05/05/2010 Link to Patient Information - "Managing Oral Cancer Treatments at Home" removed as chemotherapy safe handling is inappropriate for this treatment.
17/01/2011 New format to allow for export of protocol information.
Protocol version number changed to V.2.
Antiemetics and premedications added to the treatment schedule.
Additional Clinical Information, Key Prescribing table and Key Administration table combined into new section titled Clinical Considerations.
Drug specific information placed behind the drug name link.
27/04/2012 Protocol reviewed at Medical Oncology Reference Committee meeting.
Removed link to safe handling (as for antineoplastics).
Next review in 1 year.
21/04/2013 PBS restrictions updated.
24/06/2013 Evidence updated.
30/06/2013 Protocol reviewed by committee via email survey. No changes and next review in 2 years.
22/06/2015 Protocol reviewed electronically by Medical Oncology Reference committee. No changes and next review in 2 years
18/02/2016 Discussion with Medical Oncology Reference Committee Chairs and protocol to be reviewed every 5 years. Next review due in 4 years.
31/05/2017 Transferred to new eviQ website. Version number change to V3.

As ID 30 Breast adjuvant letrozole replaces an existing approved protocol, the individual History section is included below for consistency in documentation. 

ID 31 Breast adjuvant letrozole (late switch) version 4
Date Summary of changes
17/01/2008 Addition of long term toxicities from review article
11/01/2010 Reviewed, new dose modifications and transferred to eviQ
05/05/2010 Link to Patient Information - "Managing Oral Cancer Treatments at Home" removed as chemotherapy safe handling is inappropriate for this treatment.
17/01/2011 New format to allow for export of protocol information.
Protocol version number changed to V.2.
Antiemetics and premedications added to the treatment schedule.
Additional Clinical Information, Key Prescribing table and Key Administration table combined into new section titled Clinical Considerations.
Drug specific information placed behind the drug name link.
27/04/2012 Protocol reviewed at Medical Oncology Reference Committee meeting.
Removed link to safe handling (as for antineoplastics.
Next review in 1 year.
24/06/2013 Evidence updated.
30/06/2013 Protocol reviewed by committee via email survey. No changes and next review in 2 years.
22/06/2015 Protocol reviewed electronically by Medical Oncology Reference committee. No changes and next review in 2 years.
18/02/2016 Discussion with Medical Oncology Reference Committee Chairs and protocol to be reviewed every 5 years. Next review due in 4 years.
31/05/2017 Transferred to new eviQ website. Version number change to V.3.
09/10/2019 Duration changed in treatment schedule, indications and patient information. Version number changed to V.4.
12/10/2020 Protocol reviewed electronically by Medical Oncology Reference Committee. Reference added in indications section. Next review in 5 years.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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04 Dec 2023