Transcript Metastatic Breast Cancer The role of surgery

Metastatic Breast Cancer:
A Surgical Challenge
M.R. CHRISTIAENS MD PHD
MULTIDISCIPLINAIR BORSTCENTRUM LEUVEN
Traditional and new concepts
 MBC has a bad prognosis: survival of 1-2 years
 Palliative treatment: optimal choice
 Aggressive approaches: useless patient distress
 New treatments: improve survival
Giordano et al; MD Anderson; Proc Am Soc Clin Oncol 2002
Median survival
Months
3 y OS
%
5 y OS
%
1974-1979
15
15
10
1995-2000
51
61
40
Principles (1)
 30% of patients with potential curable BC will eventually
develop metastasis
 MBC remains incurable
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Limited understanding of the molecular mechanisms of metastasis
Conventional model:
primary tumor is heterogeneous
 Subpopulations of cells acquire stepwise genetic alterations,
facilitating dissemination
 But:
 Evidence in human tumors is lacking!
 Clinical observations are challenging this model
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Principles (2)
 New concepts
 Microarray studies:
Metastatic potential is an inherent, genetically predetermined
property that is expressed very early
 TC are programmed to metastasize to a certain site in the presence
of a favorable microenvironment
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‘Escape cell’
Seed distant sites
 ‘Self-seed’ to the primary tumor or other ongoing tumor growths
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Self-seed theory would support complete excision of
the primary (Frank et al. Int. J. Radiation Oncology Biol. Phys. 2008)
Evolving insights in treatment of MBC
 Targeted therapy: tumor cells and microenvironment
 Today’s stage IV is very different from that 15-20 years
ago: progress in imaging!
 Limited distant disease can be rendered clinically free of
disease by local treatment : potential to achieve CR –
longer DFS
 Surgical treatments are improving: minimal invasive
techniques
 Median survival is improving
“chronic disease”
Challenge
 Metastasis restricted to one organ, resection combined
with systemic therapy and/or RT may prolong survival
 In selected patients, resection of the primary tumor may
improve progression free survival and mortality
Literature Review: selection bias, publication bias, small
series, retrospective nature
Urgent systemic recurrences
 May require regional RT or surgery or interventional
procedures prior to, or along with systemic therapy
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Brain metastasis
Cord compression
Choroid disease
Pleural effusion
Pericardial effusion
Pending/pathologic fracture
Obstruction of
Biliary tree
 Ureters
 Trachea
 Bowel
 Esophagus

Solitary lung metastasis
 3% develop a solitary pulmonary lesion
(2003)
 8 retrospective studies: surgery +/- systemic treatment
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Median survival times: 42 - 79 months
5 y actuarial survival: 35 - 89%
10 y actuarial survival: 8 - 60%
Medical treatment only: median survival shorter
Largest study (n=467)
Fridel et al. Eur J Cardiothoracic Surgery 2002
DFI > 36 months and complete excision with or without chemotherapy:
5 year survival rate: 50%
15 year survival rate: 25%
Conclusion: Pos. survival outcome after surgery (+/- chemo)
is associated with 1. longer DFI after complete excision of the
primary tumor and 2. receptor positive status
Liver metastasis (1)
 > 50% of MBC
(2003)
 Late finding – other metastasis
 5% confined to the liver
 Median survival:
 19 months ~ pre-taxane regimens
 22-26 months ~ taxane-containing regimens
 Isolated hepatic metastases treated with surgery
 6 small, retrospective studies
Median survival: 22 - 44 months
 5 y survival rates: 22 - 38%
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Liver metastasis
(2)
Conclusions:
 Improved median survival
 Agreement on selection of patients?
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Normal performance status
Normal liver function tests
Size and number do not influence survival
Complete excision (all M+ ; free margins)
DFI?????
 Role of radiofrequency ablation?
 Studies ongoing – promising
(2003)
Bone and Brain metastasis
Bone:
(2003)
 Majority receptor positive tumors – R/ endocrine treatment
 Symptoms: pain, fractures, spinal cord compression
 Indications for surgery:
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Reduce risk of fractures (Bifosfonates)
Treat spinal cord compression (RT)
Solitary sternum metastasis
Brain:
 In 1/3 the only site
 5 small studies
 WBRT + surgery: median survival: 15-37 months
 Recommendation may be:
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Surgical excision where possible
Stereotactic radio surgery for inaccessible sites
Recommendations - Surgery for metastasis
 Outcome related to
 Performance status
 Long DFI / response to systemic treatment
 Complete excision of the M+
 Solitary M+ or multiple M+ at a single site
E. Singletary et al. Oncologist 2003
Stage IV BC – Loco-regional treatment?
 Conventional :
 Systemic treatment
 Surgery of the primary site: ‘palliation’ or ‘symptom control’:
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Ulceration
Infection
Bleeding
Quality of life
 Randomised clinical trials focus on stage 0-III
 Challenge:
 Which patients could benefit from surgery of the primary tumor?
 Timing of the surgery?
 Intend of the surgery?
 Possible benefit to be expected?
 Khan et al.
Surgery 2002
 Surgery at primary site, with negative margins: survival advantage
 Rapiti et al.
JCO 2006
 1977-1996: 300 MBC patients
 Complete excision with negative margins: 40% reduced risk of death
 Multi adjusted HR: 0.6 (95% CI, 0,4-1.0)
 In bone metastasis only: HR: 0.2 (95% CI 0,1 to 0,4)
p= .001
 Ruiterkamp et al.
SABCS 2007
 Retrospective : 288 of 728 patients underwent surgery
 Median survival: 2,55 vs. 1,17 years (p<0,0001)
 Surgery : independent prognostic factor
 HR: 0.69 (after correction)
 Multiple metastasis and co-morbidity: reduced effect but still significant
 Conclusion: 40% risk reduction of mortality
 Shien et al.
ASCO-BCS 2008
 Retrospective: 160 LRT vs. 184 No-LRT
 OS improved with surgery
p= 0.049
(but also with young age, bone or soft
tissue metastasis)
 Barkley et al.
SABCS 2007
 Overall survival with adjustment for age, number of sites of metastasis,
chemotherapy, endocrine therapy, trastuzumab and ER status
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Therapeutic resection: 5.34 years
No therapeutic resection : 2.36 years (p=0.0004)
Barkley et al. SABCS 2007
 Conclusions:
 Therapeutic surgery
significantly improves
survival in patients with
Stage IV breast cancer
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Optimal timing to
integrate surgery remains
unclear
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Prospective trial is
warranted to confirm
these results
Loco-regional treatment
Randomized trial
Badwe et al.
ASCO BCS 2008 –poster-abstract
 Randomized controlled trial – OS
 Standard chemotherapy
 93 women randomized:
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Complete LRT (surgery + RT)
vs.
No LRT
 6 months post randomization : 33% PD
 Progression free survival:
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61% vs. 72% (No LRT vs. LRT): p= 0.194
Cox prop. Hazard : LRT and receptor status determinants for PFS
Loco-regional treatment at presentation
Timing of surgery
Rao et al.
Ann Surg Oncol 2008
 M.D. Anderson : 224 patients – 82 included
 Systemic treatment:
 Antracycline based regimen and/or HT (TAM/AI)
 HER2 positive: trastuzumab
 RECIST guidelines
(1997-2002)
 3 groups: date of diagnosis – day of surgery
 Group 1: 0- 2.9 months
 Group 2: 3-8.9 months
 Group 3: > 9 months
Study end points: death and metastatic progression
Median OS predicted to be 54 months
Univariate analysis
OS: p-value
(log-rank)
MFS: p-value
(log-rank)
62 (83)
13 (17)
0.013
0.002
39 (52)
36 (48)
0.34
0.006
23 (31)
44 (59)
8 (11)
0.033
0.009
41 (55)
34 (45)
0.051
0.025
No. (%)
No. of metastatic sites
1
2 or more
Type of surgery
Partial mastectomy
Mastectomy
Surgical margin status
Positive
Negative
Unknown
Type of axillary evaluation
ALND
SLNB or no surgery
Multivariate analysis of
metastatic progressionfree survival
Factor
p value
Hazard ratio (95%
confidence interval)
Ethnicity: other versus
Caucasian
0.004
2.7
(1.4–5.3)
No. of sites: >1 vs. 1
0.024
2.6
(1.1–5.8)
Margins : + vs. −
0.013
2.3
(1.2–4.4)
The effect of the timing on metastatic progression-free survival
Rao et al.
Ann Surg Oncol 2008
Conclusion:
Rao et al.
Ann Surg Oncol 2008
 Improved metastatic progression free survival:
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One site of metastasis
Resection of the intact primary tumor and lymph nodes
Negative margins
> 3 - <9 months after diagnosis of Stage IV
Expanding role of surgery in stage IV BC
Take Home Message (1)
 Evolving concepts of cancer biology and treatment
 Emerging evidence of a potential survival benefit of
loco-regional surgery
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> 3 and <9 months after diagnosis
Good response to systemic treatment
Single site M+
Young patients
Provided: complete LRT : negative margins + axilla +
radiotherapy
Expanding role of surgery in stage IV BC
Take Home Message (2)
 Select patients for surgery of metastasis
 Good response to systemic treatment
 Long disease free interval
 Single site or multiple confined to one organ
 Provided: Complete excision of all M+ can be obtained
Follow-up recommendations to be adapted
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Bone scintigraphy: symptomatic M+; most non-surgical
treatment
CT/MRI Brain: symptomatic M+
Chest X-ray and Liver US: cost effective analysis?
Expanding role of surgery in stage IV BC
Take Home Message (3)
 Multidisciplinary treatment and patient counseling
in all stages
 Guidelines to be developed?
 Prospective trial?
Thank you!
Good night!
“Blue Beauty” by Astronaut Sunita Williams