M.R. CHRISTIAENS MD PHD MULTIDISCIPLINAIR BORSTCENTRUM LEUVEN Metastatic Breast Cancer: A Surgical Challenge
Feb 22, 2016
M.R. CHRISTIAENS MD PHD
M U LT I D I S C I P L I N A I R B O R S T C E N T R U M L EU V EN
Metastatic Breast Cancer: A Surgical Challenge
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 survivalMonths
3 y OS%
5 y OS %
1974-1979 15 15 101995-2000 51 61 40
Principles (1)
30% of patients with potential curable BC will eventually develop metastasis
MBC remains incurable 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
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
‘Escape cell’ Seed distant sites ‘Self-seed’ to the primary tumor or other ongoing tumor
growths
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 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 Median survival times: 42 - 79 months 5 y actuarial survival: 35 - 89% 10 y actuarial survival: 8 - 60% Medical treatment only: median survival shorter
Conclusion: Pos. survival outcome after surgery (+/- chemo)is associated with 1. longer DFI after complete excision of theprimary tumor and 2. receptor positive status
Largest study (n=467) Fridel et al. Eur J Cardiothoracic Surgery 2002DFI > 36 months and complete excision with or without chemotherapy:
5 year survival rate: 50% 15 year survival rate: 25%
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%
Liver metastasis (2)
Conclusions: (2003)
Improved median survival Agreement on selection of patients?
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
Bone and Brain metastasis
Bone: (2003)Majority receptor positive tumors – R/ endocrine treatmentSymptoms: pain, fractures, spinal cord compressionIndications for surgery:
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 monthsRecommendation may be:
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’:
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 Therapeutic resection: 5.34 years No therapeutic resection : 2.36 years (p=0.0004)
Conclusions: Therapeutic surgery
significantly improves survival in patients with Stage IV breast cancer
Optimal timing to integrate surgery remains unclear
Prospective trial is warranted to confirm these results
Barkley et al. SABCS 2007
Loco-regional treatment Randomized trial
Badwe et al. ASCO BCS 2008 –poster-abstract
Randomized controlled trial – OS Standard chemotherapy 93 women randomized:
Complete LRT (surgery + RT) vs. No LRT
6 months post randomization : 33% PD
Progression free survival: 61% vs. 72% (No LRT vs. LRT): p= 0.194 Cox prop. Hazard : LRT and receptor status determinants for
PFS
Loco-regional treatment at presentationTiming of surgery
Rao et al. Ann Surg Oncol 2008
M.D. Anderson : 224 patients – 82 included (1997-2002) Systemic treatment:
Antracycline based regimen and/or HT (TAM/AI) HER2 positive: trastuzumab
RECIST guidelines
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 No. (%) OS: p-value (log-rank)
MFS: p-value
(log-rank) No. of metastatic sites 1 62 (83) 0.013 0.002 2 or more 13 (17) Type of surgery Partial mastectomy 39 (52) 0.34 0.006 Mastectomy 36 (48) Surgical margin status Positive 23 (31) 0.033 0.009 Negative 44 (59) Unknown 8 (11) Type of axillary evaluation ALND 41 (55) 0.051 0.025 SLNB or no surgery 34 (45)
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)
Multivariate analysis of metastatic progression-
free survival
Conclusion: Rao et al. Ann Surg Oncol 2008
Improved metastatic progression free survival:
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 > 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 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 BCTake Home Message (3)
Multidisciplinary treatment and patient counseling in all stages
Guidelines to be developed?
Prospective trial?