www.asco.org/guidelines/endocrinebreast. ©american society of clinical oncology 2010. all rights...

www.asco.org/guidelines/endocrinebreast. ©American Society of Clinical Oncology 2010. All rights reserved

American Society of Clinical Oncology Clinical Practice Guideline Update on

Adjuvant Endocrine Therapy for Women with Hormone-Receptor Positive Breast Cancer


INTRODUCTION

• ASCO initially published its first technology assessment for the use of aromatase inhibitors (AIs) in the adjuvant setting for women with hormone receptor-positive breast cancer in 2002

• ASCO guidelines are updated at intervals by an Update Committee of the original Expert Panel; the last update was in 2004

• For the 2010 update, the Update Committee reviewed literature published since May 2007


Guideline Methodology: Systematic Review• The Update Committee completed a systematic review and

analysis of the medical literature, using the Cancer Care Ontario systematic review of literature through May 2007, and ASCO’s searches of literature from May 2007 to February 2009

Medline Pre-Medline Cochrane Collaboration Library ASCO and San Antonio Breast Cancer Symposium

abstracts from 2007 - 2009


Limitations of the literature

• Timing of randomization – patient populations in sequential, extended, and primary therapy trials may all differ from one another

• Longest median follow-up data available is 8 years, most studies less

• Median time to event yet to be achieved• Modest # of events, including for subgroups• Different definitions of study endpoints


Clinical Questions

1a. What adjuvant endocrine treatments should be offered to postmenopausal women with hormone receptor-positive breast cancer?

1b. What is the appropriate duration of adjuvant endocrine therapy?

1c. If tamoxifen is administered first, how long should it be continued before the switch to an AI?

2. Are there specific patient populations that derive differing degrees of benefit from an aromatase inhibitor in comparison to tamoxifen?


Clinical Questions, cont’d

3. What are the toxicities and risks of adjuvant endocrine therapy?

4. Are aromatase inhibitors effective adjuvant therapy for women who are premenopausal at the time of diagnosis?

5. Can the third-generation aromatase inhibitors be used interchangeably?


RecommendationsRecommendation 1a. The Update Committee recommends, based on data from randomized controlled trials, that most postmenopausal women consider taking an aromatase inhibitor during the course of adjuvant treatment to lower recurrence risk, either as primary therapy or after two to three years of tamoxifen, strategies that yield equivalent outcomes in prospective studies. Duration of aromatase inhibitor therapy should not exceed five years.


RecommendationsRecommendation 1b. Therapy with an aromatase inhibitor should not extend beyond five years in either the primary or extended adjuvant settings, outside of the clinical trials setting. In the sequential setting, the Update Committee recommends, based on available evidence from randomized controlled trials, that patients receive an AI after two or three years of tamoxifen for a total of five years of adjuvant endocrine therapy. The Update Committee recommends that patients who are initially treated with an AI but discontinue treatment before five years of therapy consider taking tamoxifen for a total of five years of adjuvant endocrine therapy.


RecommendationsRecommendation 1c. The Update Committee recommends that, based on available evidence from randomized controlled trials, patients who initially receive tamoxifen as adjuvant therapy may be offered an AI after two to three years (sequential) or after five years (extended) of therapy. The time to switch from an AI to tamoxifen (or the converse) that maximally improves outcomes is not known from available direct evidence. The Update Committee recommends switching at two to three years based on data from sequential trials that employed this strategy. Switching at five years is also a strategy supported by the extended adjuvant randomized trials.


Clinical setting Options Recommended duration of tamoxifen

Recommended duration of AI

Recommended total duration of endocrine therapy

If patient is commencing adjuvant endocrine therapy; (patient may have just finished surgery or chemotherapy) (P/S)

AI monotherapy

N/A 5 years 5 years

Tamoxifen AI

2-3 years 2-3 years 5 years

If patient in middle of tamoxifen (S)

Tamoxifen AI

2-3 years 2-3 years 5 years

If patient in middle of AI (S)

AI tamoxifen

2-3 years (administer second)

2-3 years (administer first)

5 years

If patient finishing five years of tamoxifen (E)

Tamoxifen AI

5 years 3-5 years 8-10 years

If patient is pre- or peri-menopausal

Tamoxifen 5 years NR 5 years

Strategies: (P)-primary; (S)-sequential; (E)-extended


Recommendations• Recommendation 2. Direct evidence from randomized

trials does not identify a specific marker or clinical subset that predicted which adjuvant treatment strategy, tamoxifen or AI monotherapy or sequential therapy, would maximally improve outcomes for a given patient.

• Among men with breast cancer, tamoxifen remains the standard adjuvant endocrine treatment.

• The Update Committee recommends against using CYP2D6 genotype to select adjuvant endocrine therapy. The Committee encouraged caution with concurrent use of CYP2D6 inhibitors (such as bupropion, paroxetine, fluoxetine) and tamoxifen because of the known drug-drug interactions.


RecommendationsRecommendation 3. The Update Committee recommends that clinicians consider side effect profiles, patient preferences, and pre-existing conditions when recommending an adjuvant endocrine strategy for postmenopausal women. Clinicians should discuss side effect profiles when presenting available treatment options to patients. The Update Committee suggests that clinicians consider recommending that patients change treatment if side effects are intolerable or patients are persistently non-compliant with therapy.


Recommendations• Recommendation 4. The Update Committee recommends that women

who are pre- or perimenopausal at the time of breast cancer diagnosis be treated with five years of tamoxifen.

• Additional considerations. The Update Committee recommends that clinicians use caution in evaluating menopausal status of patients who were pre- or perimenopausal at diagnosis. Unequivocal determination of menopausal status may be challenging to prove. Even among women who have not experienced menses for over one year, laboratory testing is inadequate as patients may recover ovarian function. This particularly applies to those patients who experience chemotherapy- or tamoxifen-induced amenorrhea.


Recommendations

Recommendation 5. In the absence of direct comparisons, the Update Committee interprets available data as suggesting that benefits of AI therapy represent a “class effect.” Meaningful clinical differences between the commercially available third-generation aromatase inhibitors have not been demonstrated to date. In the clinical opinion of the Committee (rather than direct evidence from randomized trials), postmenopausal patients intolerant of one AI but who are still candidates for adjuvant endocrine therapy may be advised to consider tamoxifen or a different AI.


Side-effects ComparisonTamoxifen AI

CVD √ (<1% difference in serious CVD incidence)

Hypercholesterolemia √

Hypertension √ slight

VTE √

Loss of BMD* √

Bone fracture √

Osteoporosis √

Musculoskeletal/arthralgia √

Gynecologic AEs √ (uterine cancer, benign endometrial pathology, hysterectomy, vaginal discharge)

Hot flashes √

Please note: √ represents higher risk of side-effect in column of that particular agent..

*BMD-bone mineral density


Guideline Methodology: Panel Members

Panel Member Institution

Harold Burstein, MD, PHD, co-chair

Dana-Farber Cancer Institute

Jennifer Griggs, MD, MPH, co-chair

University of Michigan Comprehensive Cancer Center

Holly Anderson, RN, BSN patient representative

Breast Cancer Coalition of Rochester

Thomas Buchholz, MD MD Anderson Cancer Center

Nancy Davidson, MD University of Pittsburgh Cancer Institute and UPMC Cancer Centers

Karen Gelmon, MD British Columbia Cancer Agency

Sharon Giordano, MD University of Texas – MD Anderson Cancer Center

Clifford Hudis, MD Memorial Sloan-Kettering Cancer Center


Guideline Methodology: Panel Members, cont’dPanel Member Institution

Jennifer Malin, MD, PhD Greater Los Angeles Veterans Affairs Healthcare System

Eleftherios (Terry) Mamounas, MD Aultman Health Foundation

Diana Rowden, MS patient representative

Susan G. Komen for the Cure

Alexander Solky, MD Interlakes Oncology and Hematology PC

MaryFran Sowers, PhD University of Michigan

Vered Stearns, MD Johns Hopkins School of Medicine

Eric P. Winer, MD Dana-Farber Cancer Institute


Additional ASCO Resources• The full text of the guideline, an abridged

version of the guideline, a Journal of Oncology Practice Summary, this slide set, and additional clinical tools and resources can be found at: http://www.asco.org/guidelines/endocrinebreast

• A patient guide, “What to Know” about this guideline, is available at: http://www.cancer.net


ASCO GuidelinesIt is important to realize that many management questions have not been comprehensively addressed in randomized trials and guidelines cannot always account for individual variation among patients. A guideline is not intended to supplant physician judgment with respect to particular patients or special clinical situations and cannot be considered inclusive of all proper methods of care or exclusive of other treatments reasonably directed at obtaining the same results. Accordingly, ASCO considers adherence to this guideline to be voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient’s individual circumstances. In addition, the guideline describes administration of therapies in clinical practice; it cannot be assumed to apply to interventions performed in the context of clinical trials, given that clinical studies are designed to test innovative and novel therapies in a disease and setting for which better therapy is needed. Because guideline development involves a review and synthesis of the latest literature, a practice guideline also serves to identify important questions for further research and those settings in which investigational therapy should be considered.

www.asco.org/guidelines/endocrinebreast. ©american society of clinical oncology 2010. all rights...

Documents

clinical questions

update committee

rights reserved limitations

adjuvant endocrine treatments

medical literature

primary therapy trials

postmenopausal women

ascos searches of literature