Hormone therapy in Breast Hormone therapy in Breast Cancer patients Cancer patients with comorbidities with comorbidities Diana Crivellari Diana Crivellari Centro di Riferimento Oncologico Centro di Riferimento Oncologico Aviano Aviano - - ITALY ITALY Madrid November 9th, 2007
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Hormone therapy in Breast Cancer patients with comorbidities · • BMD screening in breast cancer – All women aged > 65 years – All women aged 60–64 years with risk factors
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Hormone therapy in Breast Hormone therapy in Breast Cancer patientsCancer patients
with comorbiditieswith comorbidities
Diana CrivellariDiana CrivellariCentro di Riferimento OncologicoCentro di Riferimento Oncologico
AvianoAviano-- ITALYITALY
Madrid November 9th, 2007
Main issuesMain issues
•• Comorbidities in elderly womenComorbidities in elderly women
•• Hormonal drugs in adjuvant settingHormonal drugs in adjuvant setting
•• Hormonal drugs in metastatic Hormonal drugs in metastatic settingsetting
COMORBIDITIES
CAN ENHANCE THE RISK OF TREATMENT-RELATED COMPLICATIONS
CAN HAVE A MAJOR INFLUENCE ON SURVIVAL
MINIMAL GERIATRIC ASSESSEMENT
Comorbidities (Charlson scale, CIRS-G)Functional status (ADL, IADL)ECOG performance statusEvaluation of mental statusPolypharmacySocial support networkNutrition
Estrogen reduction
LDL Cholesterol
HDL Cholesterol
Increased Cardiovascular risk
Total n°of pts European Journal of Cancer 2005
2313 4185 1668 800
European Journal of Cancer 2005
Relative 5-year survival rates:
87% without comorbidity
77% with previous cancer
78% with diabetes mellitus
59% with 2+ coexistent diseases
European Journal of Cancer 2005
Breast carcinoma in elderly Breast carcinoma in elderly women: EIO experiencewomen: EIO experienceApril 1997 to February April 1997 to February 20022002
Total 2999 Total 2999 postmenopausal postmenopausal patientspatients
Young Post (50Young Post (50--64 yrs)64 yrs) 2052 pts (68.4%)2052 pts (68.4%)
Older Post (65Older Post (65--74 yrs)74 yrs) 801 pts (26.7%)801 pts (26.7%)
Elderly post (> 75 yrs)Elderly post (> 75 yrs) 146 pts (4.9%)146 pts (4.9%)
Gennari R et al Cancer 2004
Breast carcinoma in elderly Breast carcinoma in elderly women: EIO experiencewomen: EIO experience
•Relative risk ratio for fatal MIs (tamoxifen vs control):0.62 (95% CI: 0.41–0.93)•Risk ratio (excluding Scottish trial): 0.81 (95% CI: 0.48–1.37)
Lipid lowering effect of Lipid lowering effect of SERMs?SERMs?•• YesYes–– Tamoxifen studiesTamoxifen studies
•• 10 trials, 6 vs placebo; 657 patients10 trials, 6 vs placebo; 657 patients
•• Decrease in cholesterol seen in all studiesDecrease in cholesterol seen in all studies
•• Median decrease: 12.5% (range 3Median decrease: 12.5% (range 3––17)17)•• Decrease due to LDL cholesterolDecrease due to LDL cholesterol
•• But no protection against coronary But no protection against coronary events despite favorable changes in events despite favorable changes in lipid levelslipid levels
Herrington & Klein Womens Health Issues 2001;11:95−102Barrett-Connor E et al New Engl J Med 2006;355:125-137
Aromatase inhibitors trialsStudy Modality N. of pts %
A/TamMedian age
yrsHR [ RFS]
ATAC Up Front 3215/3116 64 0.74
BIG1–98 Up Front 4003/4007 61 0.72
IES SwitchExemestane
2362/2372 64 0.70
ITA SwitchAnastrozole
208/218 63 0.42
ABCSG/ARNO SwitchAnastrozole
1618/1606 63 0.60
MA17 ExtendedLetrozole
2575/2582 62 0.57
ABCSG6a ExtendedAnastrozole
387/409 63 0.64
RFS [relapse Free Survival]
Howell A. Modified Lancet 2005
Adverse events in AI trialsAdverse events in AI trials
•• AI and tamoxifen associated with hot flushesAI and tamoxifen associated with hot flushes•• Compared with tamoxifen, AIs associated withCompared with tamoxifen, AIs associated with–– Higher incidence of arthralgia Higher incidence of arthralgia –– Lower incidence of gynecological symptoms Lower incidence of gynecological symptoms including lower rates of invasive endometrial including lower rates of invasive endometrial cancercancer–– Lower incidence of thromboembolic events Lower incidence of thromboembolic events (including grade 3(including grade 3––5 events, letrozole vs 5 events, letrozole vs tamoxifen)tamoxifen)
ATAC TOLERABILITY DATA
Adverse events (AEs) on A (%) T (%) p-valuetreatment or within n=3092 n=309414 days of discontinuationDrug-related Aes 60.9 68.4 <0.0001
Aes leading to withdrawal 11.1 14.3 0.0002
Drug-related Aes leading 6.5 8.9 0.0005to withdrawal
All serious Aes ( SAEs ) 33.3 36.0 0.03
Drug-related SAEs 4.7 9.0 0.0001
SAEs leading to death 3.3 3.6 0.6Mansel R et al, ESMO 2006
BIG 1BIG 1--98 TRIAL DESIGN98 TRIAL DESIGN•• Postmenopausal women with receptorPostmenopausal women with receptor--positive early breast positive early breast
cancercancer•• International, randomized, doubleInternational, randomized, double--blind Phase III trialblind Phase III trial
8028 pts Randomized between March 1998 and May 2003
7963 received therapy
Includes initial treatment Arms C & D
TamoxifenLetrozole
LetrozoleLetrozole Tamoxifen
RANDOMIZE
0 2 5YEARS
ABCD
Tamoxifen
Coates et al. ASCO 2007
Data CollectionData Collection——AEsAEs
Coates et al. ASCO 2007
OBJECTIVEOBJECTIVE
To compare tamoxifen and letrozole To compare tamoxifen and letrozole with regard to the incidence and with regard to the incidence and timing of cardiovascular AEs, timing of cardiovascular AEs, including baseline cardiac risk including baseline cardiac risk factors, prior cholesterol, and factors, prior cholesterol, and serial cholesterol measurements.serial cholesterol measurements.
Coates et al. ASCO 2007
Cardiovascular AEsCardiovascular AEs
Coates et al. ASCO 2007
CONCLUSIONSCONCLUSIONS•• Taken together, cardiovascular AEs were relatively rare.Taken together, cardiovascular AEs were relatively rare.•• Cholesterol values decreased over time on both treatments, Cholesterol values decreased over time on both treatments,
but the decrease was greater and earlier on tamoxifen.but the decrease was greater and earlier on tamoxifen.•• Prior hypercholesterolemia was associated with an increase in Prior hypercholesterolemia was associated with an increase in
grade 3grade 3--5 cardiac AEs.5 cardiac AEs.•• Overall incidence of cardiac AEs was similar on both Overall incidence of cardiac AEs was similar on both
treatments. An unplanned subset analysis suggested a possible treatments. An unplanned subset analysis suggested a possible excess of Gr 3excess of Gr 3--5 cardiac AEs on letrozole. These events 5 cardiac AEs on letrozole. These events were reported at low frequency on both arms. were reported at low frequency on both arms.
•• Any increased incidence of cardiac AEs on letrozole seems to Any increased incidence of cardiac AEs on letrozole seems to be outweighed by the superior control of locobe outweighed by the superior control of loco--regional and regional and distant recurrence afforded by letrozole compared with distant recurrence afforded by letrozole compared with tamoxifen.tamoxifen.
•• Different methods and rigor of AE collection make crossDifferent methods and rigor of AE collection make cross--study comparisons with other AI trials inappropriate.study comparisons with other AI trials inappropriate.
Coates et al. ASCO 2007
BIG 1BIG 1--98 TRIAL DESIGN98 TRIAL DESIGN•• Postmenopausal women with receptorPostmenopausal women with receptor--positive early breast positive early breast
cancercancer•• International, randomized, doubleInternational, randomized, double--blind Phase III trialblind Phase III trial
TamoxifenLetrozole
LetrozoleLetrozole Tamoxifen
RANDOMIZE
0 2 5YEARS
ABCD
Tamoxifen
8010 pts randomized between March 1998 and May 2003
4922 pts allocated to five years of letrozole or tamoxifen
BIG 1BIG 1--98 TRIAL98 TRIAL
4922 pts allocated to five years of letrozole or tamoxifen
1590 patients are “older” (65-74 yrs)294 patients are “elderly”(over 75 yrs)
Although these numbers seem small compared to the larger group of younger patients, they do represent an impressive data set for elderly women with breast cancer
Crivellari D et al. ASCO 2007
OBJECTIVE and METHODSOBJECTIVE and METHODSTo explore potential differences in To explore potential differences in efficacy, treatment completion, and efficacy, treatment completion, and adverse events in older women receiving adverse events in older women receiving adjuvant tamoxifen or letrozole for five adjuvant tamoxifen or letrozole for five years in the BIG 1years in the BIG 1--98 trial.98 trial.Subpopulation Treatment Effect Pattern Plots (STEPP) were used to examine the patterns of differences in disease-free survival and incidences of AEs according to age.
Baseline characteristics of patients in BIG 1 study
Age groupAge groupAge <=64Age <=64 Age 65Age 65--7474 Age Age ≥≥7575
Percentage with Percentage with history of receiving history of receiving bisphosphonatesbisphosphonates
0.10.1 0.30.3 0.50.5 0.10.1 0.70.7 00
Bone fracturesBone fractures 7.87.8 8.78.7 11.211.2 10.110.1 16.416.4 15.515.5
757 733 146 148N°of pts
RESULTSRESULTS
•• Median followMedian follow--up 40.4 months.up 40.4 months.•• Patients 75 years of age and older Patients 75 years of age and older were less likely to complete trial were less likely to complete trial treatment, but at rates that were treatment, but at rates that were similar in the two treatment groups: similar in the two treatment groups: 39.7% (58/146) did not complete 39.7% (58/146) did not complete letrozole and 37.2% (55/148) did not letrozole and 37.2% (55/148) did not complete tamoxifen (p = 0.72).complete tamoxifen (p = 0.72).
Types of AEsTypes of AEs
D Crivellari et al JCO in press
Subpopulation Treatment Effect Pattern Plots (STEPP) of 4-year DFS percents for L vs T according to age.
D Crivellari et al JCO in press
Adverse Events (AEs)Adverse Events (AEs)Bone FracturesBone FracturesSTEPP analysis shows that the incidence of bone fractures, obserSTEPP analysis shows that the incidence of bone fractures, observed ved more often in the letrozole group, did not differ by agemore often in the letrozole group, did not differ by age. .
Frequency Distribution of Osteoporosis at Spine,Hip, Femoral Neck by age:
Total 1346 Total 1346 menopausal womenmenopausal women Spine (%)Spine (%) Hip (%)Hip (%) Femoral Femoral
Neck (%)Neck (%)50 yrs or younger50 yrs or younger 5.65.6 5.25.2 5.95.9
51 51 –– 55 yrs55 yrs 9.39.3 6.46.4 9.09.0
56 56 –– 60 yrs60 yrs 10.610.6 6.86.8 1010
61 61 –– 65 yrs65 yrs 15.915.9 14.514.5 14.214.2
66 66 –– 70 yrs70 yrs 23.723.7 19.719.7 20.420.4
71 71 –– 75 yrs75 yrs 17.117.1 22.122.1 16.616.6
76 yrs and older76 yrs and older 17.817.8 25.325.3 23.923.9
Weinstein L Obstet Gynecol Vol 93,1999
ASCO bone health guidelinesASCO bone health guidelines
•• BMD screening in breast cancerBMD screening in breast cancer–– All women aged > 65 yearsAll women aged > 65 years–– All women aged 60All women aged 60––64 years with risk 64 years with risk factorsfactors–– Postmenopausal women of any age Postmenopausal women of any age receiving AIsreceiving AIs–– Premenopausal women with therapyPremenopausal women with therapy--associated premature menopauseassociated premature menopause
•• Repeat BMD annually after initial Repeat BMD annually after initial examexam
Hillner et al. J Clin Oncol 2003;21:4042–57
8
ASCO 2003 Guidelines for Osteoporosis ASCO 2003 Guidelines for Osteoporosis Screening for Breast Cancer PatientsScreening for Breast Cancer Patients
ASCO 2003 Recommendations• High risk: BMD screening recommended
• T-score <-2.5: begin calcium and vitamin D, and begin therapy with alendronate, risedronate, zoledronic acid, or raloxifene; repeat BMD annually
• T-score between -1 and -2.5: begin calcium and vitamin D; repeat BMD annually
• T-score >-1: reassure; begin calcium and vitamin D; repeat BMD annually
• Low risk: BMD screening not recommended• Begin calcium and vitamin D• Monitor annually for risk status by history
ASCO, American Society of Clinical Oncology.Hillner, et al. J Clin Oncol. 2003;21:4042-4057; Chlebowski, et al. Amer J Oncol Rev.2006;5(suppl 1):1-40.
Black D M et al
Lyles KW et al New Engl J Med 2007
35% risk reduction
Lyles KW et al New Engl J Med 2007
28% risk reduction
TAM vs AIs:
TAM AIs
Controlateral tumors
Osteoporosis
Arthralgias
Serum lipids
Contralateral tumors
DVT
Endometrial cancer
Hot Flashes
Neurocognitive function?
Physicians should begin to individualize treatment in elderly patients based on comorbidities and risk factors
Recurrence hazard rates are dependent Recurrence hazard rates are dependent on knownon known prognostic factorsprognostic factors
•• Prominent early peak of recurrences (~ 3 yrs) in absence Prominent early peak of recurrences (~ 3 yrs) in absence of adjuvant therapyof adjuvant therapy
Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;351:1451.Update of Houghton. J Clin Oncol. 2005;23(16S):24s. Abstract 582.Saphner et al., J Clin Oncol. 14: 2738-2746, 1996
Main issuesMain issues
•• Comorbidities in elderly womenComorbidities in elderly women
•• Hormonal drugs in adjuvant settingHormonal drugs in adjuvant setting
•• Hormonal drugs in metastatic Hormonal drugs in metastatic settingsetting
WHAT’S GOING ONADJUVANTADJUVANT 11°° LINELINE 22°° LINE LINE
FULVESTRANT FULVESTRANT or EXEMESTANEor EXEMESTANE ANASTROZOLEANASTROZOLE
or FULVESTRANT or FULVESTRANT
Randomized phase III studiesRandomized phase III studiesof antiof anti--Aromatase Agents vs TamoxifenAromatase Agents vs Tamoxifen
as Initial Therapy of Metastatic Breast Canceras Initial Therapy of Metastatic Breast Cancer
Survival With Aromatase Inhibitors and Inactivators Versus
Standard Hormonal Therapy in Advanced Breast Cancer: Meta-analysis
The meta-analysis included a total of 23 eligible trialsand 8504 patients, of whom 4559 had been randomly assigned to receive aromatase inhibitors or inactivators and 3945 had been assigned to receive standard hormonal treatments.
Mauri - J Natl Cancer Inst 2006; 98:1285-91
Survival With Aromatase Inhibitors and Inactivators Versus
Standard Hormonal Therapy in Advanced Breast Cancer:Meta-analysis
Mean Mean ±± SD changes in plasma lipidSD changes in plasma lipidparameters during fulvestrant treatment parameters during fulvestrant treatment (n=31)(n=31)