MULTIDISCIPLINARY MANAGEMENT OF MULTIDISCIPLINARY MANAGEMENT OF METASTATIC DISEASE METASTATIC DISEASE SYSTEMIC THERAPY SYSTEMIC THERAPY F. Cardoso, MD F. Cardoso, MD Jules Bordet Institute, Brussels, Belgium Jules Bordet Institute, Brussels, Belgium BELGIAN BREAST MEETING 2008 October 4-5, 2008
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MULTIDISCIPLINARY MANAGEMENT OF METASTATIC DISEASE SYSTEMIC THERAPY F. Cardoso, MD Jules Bordet Institute, Brussels, Belgium BELGIAN BREAST MEETING 2008.
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MULTIDISCIPLINARY MANAGEMENT OF MULTIDISCIPLINARY MANAGEMENT OF METASTATIC DISEASEMETASTATIC DISEASE
SYSTEMIC THERAPYSYSTEMIC THERAPY
F. Cardoso, MDF. Cardoso, MDJules Bordet Institute, Brussels, BelgiumJules Bordet Institute, Brussels, Belgium
BELGIAN BREAST MEETING 2008
October 4-5, 2008
Breast Cancer
Despite ↑ incidence - ↓ mortality
* Screening & early diagnosis
* Education & advocacy
but also
* Better treatment options
* Better treatment strategies
BUT
The evolution as been quite different between adjuvant and metastatic settings
WHY?
Different diseases?
Different biology?
Different aims
Different attitude of physicians?
Advances in EARLY BC are measured in YEARS (DECADES)
Cohort by year of dxTotal n=2152
1991-92
(1)
1994-55
(2)
1997-98
(3)
1999-01
(4)
Median
survival days
438 450 564 667
p value Cohort 1+2 vs 3 (0.002) Cohort 3 vs 4 (0.04)
Chia et al ASCO 2003 Population Based Study in British Columbia
Advances in METASTATIC BC are measured in DAYS – MONTHS(max: few years; median survival MBC= 2-3 yrs)
Are MBC guidelines needed? definitely YES
RISK OF RECURRENCE REMAINS PRESENT THROUGHOUT ALL PATIENTS’ LIFETIME
Saphner T et al. J Clin Oncol 1996; 14: 2738–2746.
Recurrence rate/year (%)
0 1 2 3 4 5 6 7 8 9 10
0
2
4
6
8
10
12
14
16
Time (years)
Node-negative
Node-positive
Are MBC guidelines needed? definitely YES
EBCC-ESO METASTATIC BREAST CANCER GUIDELINES
First step: 12 Recommendations Statements Published: The Breast 16, 9–10, 2007
1st Session: EBCC-4 (Nice, March 2006):
“Are MBC guidelines possible?” - YES
Preparatory work: Task Force created; meetings; some decisions:
1. MBC guidelines cannot be rigid 2. Should be built on principles and not on specific treatment
regimens3. Need to be in line with latest research findings (biology…)
The management of MBC is complex; therefore involvement of all appropriate specialities in a multi/interdisciplinary team (medical, radiation, surgical and imaging oncologists, palliative care, psycho-social, among others) is crucial.
1ST STATEMENT
12 RECOMMENDATIONS STATEMENTS
2nd STATEMENT
From first diagnosis of MBC, patients should be offered personalised appropriate psychosocial, supportive and symptom-related interventions as a routine part of their care.
MAIN ISSUES IN MBC MANAGEMENTMAIN ISSUES IN MBC MANAGEMENT
• Confirmation of diagnosis Confirmation of diagnosis
• Definition of main goal of treatmentDefinition of main goal of treatment
• Available therapiesAvailable therapies
• Factors determining the choice of treatmentFactors determining the choice of treatment
• Special subgroups (Endocrine-responsive, HER-2+, Special subgroups (Endocrine-responsive, HER-2+, basal-like)basal-like)
HER-2 seems to be quite consistent between P and M sites:In our series, only 6% discordance by IHC & 7% by FISH (most discordant cases showed greater HER-2 overexpression in M)
However: Conflicting results exist &Interlaboratory variability for both IHC and FISH is a big problem
For all other markers, including Hormonal receptors, the consistency levels are lower
CONFIRMATION OF DIAGNOSIS CONFIRMATION OF DIAGNOSIS
WHENEVER POSSIBLE A BIOPSY OF THE METASTATIC LESION SHOULD BE PERFORMED
DEFINITION OF MAIN GOALS OF TREATMENTDEFINITION OF MAIN GOALS OF TREATMENT
CRUCIAL: Identify the small but very important subset of MBC patients can achieve complete
remission and a long survival – ISOLATED MET
FOR ALL OTHERS
MBC is incurableThe main treatment goal is PALLIATION, transform it
into a chronic diseaseIncrease survival, if possible
Maintain/improve QoLSymptom control
Test new agents/approaches before adjuvant setting
3rd & 4th STATEMENTS
ANY STEM CELL CAN SEED MORE
• Primary cancer must be controlled
• Metastatic foci must be controlled
HOWEVER
We must continue to strive to do better … and keep cure a goal for the future…
Adapted from W Wood, EBCC-6, 2008
• There are few proven standards of care in MBC management
• Well-designed, independent, prospective randomised trials are a priority
• Every proposed option must have a sound scientific rationale, preferably evidence-based
MAIN MESSAGES
AVAILABLE SYSTEMIC THERAPIESAVAILABLE SYSTEMIC THERAPIES
CROSS-TALK BETWEEN THE ER CROSS-TALK BETWEEN THE ER AND THE GF PATHWAYS AND THE GF PATHWAYS
HER2 EGFr
EREREREREE22
ERERERERTamTam
PI3KPTENPTEN
Cell proliferation
AkTAkT
BADBAD FKHRFKHRGSK-3GSK-3 mTORmTOR
SURVIVALSURVIVAL
Cell proliferation
FasLFasL
N-CORN-COR
Failure of mTOR inhibition to improve the activity of Failure of mTOR inhibition to improve the activity of lezotrole in advanced breast cancer lezotrole in advanced breast cancer
Results of a phase III trial in 992 patientsResults of a phase III trial in 992 patients
TANDEM STUDY: Randomized trial of ANASTROZOLE TANDEM STUDY: Randomized trial of ANASTROZOLE ± ± TRASTUZUMAB in advanced HER2+, HR+ breast cancerTRASTUZUMAB in advanced HER2+, HR+ breast cancer
N=207Median age 55 yearsVisceral disease 1/3
Prior chemo 1/2
Anastrozole
Cross-over 70%
6,8% Response rate 20,3%2,4m Median P.F.S. 4,8m p 0.0016
23,9m Median O.S. 28,5m
32,1m Median O.S. 41,9mif no liver mets p 0.03
Mackey et al., SABC 06, abst. 03
Anastrozole+
Trastuzumab
Trastuzumab added to anastrozole RR, PFS (and possibly OS if no liver mets) IMPORTANCE OF STARTING BIOLOGICAL AGENT SOONAdapted from M. Piccart
ADVANCED BREAST CANCERADVANCED BREAST CANCER
Available therapiesAvailable therapies
• ENDOCRINE vs. CHEMOTHERAPY• WHICH DRUGS? WHICH SCHEDULES?• COMBINATION vs. SEQUENTIAL SINGLE AGENTS• MAINTENANCE THERAPY• WHEN TO STOP
MAIN QUESTIONS
12 RECOMMENDATIONS
The choice between sequential use of single cytotoxic drugs and combination chemotherapy should be taken after consideration of the factors mentioned in paragraph 6, with greatest emphasis on the need for a rapid and significant response and quality of life.
For the majority of patients, overall survival outcomes from sequential use of single cytotoxic drugs are equivalent to combination chemotherapy.
Duration of each regimen and number of regimens should be tailored to each individual patient.
9th STATEMENT
Docetaxel vs. Docetaxel vs. Docetaxel + CapecitabineDocetaxel + Capecitabine
PHASE III TRIAL DOCETAXEL VS DOCETAXEL + CAPECITABINE IN MBC PTS FAILING ANTHRACYCLINES
O’Shaughnessy J et al. J Clin Oncol 2002;20:2812–23
DocetaxelCapecitabine +
docetaxel
n 256 255
L1/L2 (%) 31/53 35/48
Anthracyclines (%) 100 100
ORR (%) 30 42
TTP (months) 4.2 6.1
OS (months) 11.5 14.5
Phase III Registration Trial Planned Interim Analysis
Endpoint GT T p-value
Ind ORR 45.5% 25.5% <0.00005(95% C.I.) (38.5, 52.4) (19.2, 31.8)
Median TTP 5.2 2.9 <0.0001(95% C.I.) (4.2, 8.6) (2.6, 3.7)
Median OS, mos 18.5 15.8(95% C.I.) (16.5, 21.2) (14.4, 17.4)
Paclitaxel vs. Paclitaxel vs. Paclitaxel + GemcitabinePaclitaxel + Gemcitabine
COMBINATION vs. SEQUENTIAL SINGLE AGENTSCOMBINATION vs. SEQUENTIAL SINGLE AGENTS
NO OR MINIMAL CROSSOVER
BUTSubsequent Chemotherapy
PG vs. PDocetaxel 10.5% 10.3%Gemcitabine 3.8% 14.1%
T vs. TCCapecitabine 17 % Docetaxel 20 %
BENEFIT OF COMBINATION IS ONLY LEVEL-2 EVIDENCE-BASEDBENEFIT OF COMBINATION IS ONLY LEVEL-2 EVIDENCE-BASED
• Discuss with patients; new treatment option…• Consider combination in « high risk » fit patients
PACLITAXEL VERSUS DOXORUBICIN VERSUS BOTHPACLITAXEL VERSUS DOXORUBICIN VERSUS BOTHCROSSOVER PART OF TRIAL DESIGNCROSSOVER PART OF TRIAL DESIGN
AA TT ATAT
3434
6.26.2
1414
20.120.1
3333
5.95.9
20 20
22.222.2
4646
8.08.0
--
22.422.4
p valuep value
SS
SS
SS
NSNS
RR%-1st lineRR%-1st line
MEDIAN TTF, mosMEDIAN TTF, mos
MEDIAN OS, mosMEDIAN OS, mos
RR% - 2nd lineRR% - 2nd line
QOLQOL Different toxicities, similar tolerabilityDifferent toxicities, similar tolerability
Sledge, ASCO ‘ 97Sledge, ASCO ‘ 97
739 MBC pts
>Toxicity>Impact on daily life
No or very small gain in survivalUses up “all weapons” faster
COMBINATIONCOMBINATION
>RRFaster symptom/disease control
SEQUENTIAL SINGLE AGENTSSEQUENTIAL SINGLE AGENTS
<ToxicitySimilar survival
Better overall QoLBetter management of resources
<RRSlower symptom/disease control
ESO-EBCC MBC RECOMMENDATIONS
Sequential use of single cytotoxic drugs should be the preferred choice except if:
rapidly progressing diseaselife threatening visceral metastasesneed for rapid disease/symptom control
9th STATEMENT –
2008 Proposal
Define the subgroup of pts who need first line combination because we will not be able to rescue the; with 2nd or 3rd line CT
ADVANCED BREAST CANCERADVANCED BREAST CANCER
MAIN ISSUESMAIN ISSUES
• Confirmation of diagnosis Confirmation of diagnosis
• Definition of main goal of treatmentDefinition of main goal of treatment
• Available therapiesAvailable therapies
• Factors determining the choice of treatmentFactors determining the choice of treatment
• SPECIAL SUBGROUPSSPECIAL SUBGROUPS (Endocrine-responsive, (Endocrine-responsive, HER-2+,HER-2+, basal-like) basal-like)
OPTIMAL DURATION OF TRASTUZUMAB TREATMENTOPTIMAL DURATION OF TRASTUZUMAB TREATMENT
– Response rate (48.0 vs. 27.0%; p=0.01)– Clinical benefit rate (75.3 vs 54%; p=0.007)– Time to progression (8.2 vs 5.6 mos; p=0.03)– Overall survival (25.5 vs 20.4 mos; non sign. trend)– No increase in toxicity
Study Design of GBG 26
X: X: Capecitabine 2500 mg/m² d 1 – 14 q 22
R
XH: Capecitabine 2500 mg/m² d 1 – 14 q 22
and continuation of Trastuzumab 6 mg/kg q22
156 pts (from 482 pts needed) recruited between 01/04
- 05/07 ; Recruitment stopped after FDA registration of
lapatinib on advice of IDMC
RESULTS OF THE BIG-GBG TBP
&
Bulk of retrospective data
PUTTING INTO PERSPECTIVE
• Adds to the bulk of existing retrospective data (eg Hermine study)
• The only randomised trial that reached reasonable accrual…
• No safety issues
BUT… LANDSCAPE IS CHANGING: New anti-HER2 drugs
• When to continue trastuzumab with another CT regimen vs. changing to another anti-HER-2 therapy (i.e. Lapatinib)?
• Which are the pts that benefit from continuing trastuzumab vs. shifting to another anti-HER-2 drug vs. shifting to a combination strategy
• MAIN MESSAGE: the HER-2 pathway should continue to be blocked in HER-2 + pts even after progression (for how long?)
THE FUTURE THE FUTURE • NEW AGENTS
• “NEW-OLD AGENTS” (i.e. Capecitabine, liposomal anthracyclines, new taxanes…)
• NEW BIOLOGICAL AGENTS (i.e. Lapatinib, Sunitinib, Bevacizumab…)
• COMBINATION OF “STANDARD” + BIOLOGICAL AGENTS
• COMBINATION OF BIOLOGICAL AGENTS
• BIOMARKERS (Treatment tailoring)
MBC – SYSTEMIC THERAPIESMBC – SYSTEMIC THERAPIES
ADVANCED BREAST CANCER TREATMENTADVANCED BREAST CANCER TREATMENTStill an art…but with GUIDENCEStill an art…but with GUIDENCE
STANDARDS STANDARDS OF CAREOF CARE
TREATMENT TREATMENT TAILORING TAILORING
(BIOLOGICAL (BIOLOGICAL MARKERS)MARKERS)
PATIENT’SPATIENT’SPREFERENCESPREFERENCES
MULTI-DISCIPLINARY TEAM (medical, radiation, surgical and imaging oncologists, palliative
care, psycho-social)
Appropriate PSYCHOSOCIAL, SUPPORTIVE and PALLIATIVE
interventions essential part of routine care
QUALITY OF LIFE ASSESSMENTS
PREVIOUS PREVIOUS THERAPIES, THERAPIES,
OTHER OTHER FACTORSFACTORS
NEW AGENTSNEW AGENTS
RATIONAL USE RATIONAL USE OF AVAILABLE OF AVAILABLE
AGENTS & AGENTS & RESOURCESRESOURCES
KNOWING WHEN KNOWING WHEN TO STOP!!TO STOP!!
CLINICAL CLINICAL TRIALSTRIALS
It matters not how long we live, but how.
“Festus”, Philip James Bailey
BACK-UP
TREATMENT OF WOMEN WITH ADVANCED BREAST CANCERTREATMENT OF WOMEN WITH ADVANCED BREAST CANCERTAKE-HOME MESSAGES - 1TAKE-HOME MESSAGES - 1
• Management of MBC is Management of MBC is complexcomplex; ; multi-disciplinary teammulti-disciplinary team essential essential
• From diagnosis, offer pts appropriate psychosocial, supportive From diagnosis, offer pts appropriate psychosocial, supportive and palliative interventions as a routine part of their careand palliative interventions as a routine part of their care
• PatientsPatients should be invited & encouraged to actively should be invited & encouraged to actively participateparticipate in in all decision-makingall decision-making
• Few Standards of care; ENTER PTS IN WELL-DESIGNED TRIALSFew Standards of care; ENTER PTS IN WELL-DESIGNED TRIALS
• Main therapy goal: PALLIATION (except Main therapy goal: PALLIATION (except small subsetsmall subset who can who can achieve achieve CR & long survivalCR & long survival; treat aggressively); treat aggressively)
• Treatment choiceTreatment choice must take into account several pt- & disease- must take into account several pt- & disease-associated associated factorsfactors (i.e. DFI, previous Rx, ps, HER, HER-2, etc…) (i.e. DFI, previous Rx, ps, HER, HER-2, etc…)
• Hormonal therapyHormonal therapy is the preferred option for HR + MBC, unless is the preferred option for HR + MBC, unless there is concern or prove of endocrine resistance there is concern or prove of endocrine resistance
• Maintenance hormonal treatmentMaintenance hormonal treatment after CT is not established but is after CT is not established but is reasonablereasonable
• HER-2 positive MBCHER-2 positive MBC is a separate disease and should be treated is a separate disease and should be treated accordingly; probably the same for accordingly; probably the same for basal-like BCbasal-like BC
• For the majority of patients, OS outcomes from sequential use of For the majority of patients, OS outcomes from sequential use of single agents are equivalent to combination CTsingle agents are equivalent to combination CT
NEED: New agents but also rational use of available agents (TREATMENT TAILORING – Biological markers)
TREATMENT OF WOMEN WITH ADVANCED BREAST CANCERTREATMENT OF WOMEN WITH ADVANCED BREAST CANCERTAKE-HOME MESSAGES - 2TAKE-HOME MESSAGES - 2
CONFIRMATION OF DIAGNOSIS CONFIRMATION OF DIAGNOSIS
• Is the metastatic lesion representative of the primary tumor?
• Does the biology of the cancer changes during the metastasis process?
• Are HR, HER-2 & other markers concordant between primary and metastatic sites?
SHOULD A BIOPSY OF THE METASTATIC LESION BE MANDATORY?
RISK EVALUATION IN MBCRISK EVALUATION IN MBC
YesYes Hormone receptorsHormone receptors NoNo
> 2 years> 2 years Disease-free intervalDisease-free interval < 2 years< 2 years
limitedlimited No. of metastasesNo. of metastases extensiveextensive
soft tissue, bonesoft tissue, bone Sites of metastasesSites of metastases visceraviscera
NoNo Vital organ involvementVital organ involvement YesYes