M.R. CHRISTIAENS MD PHD

MULTIDISCIPLINAIR BORSTCENTRUM LEUVEN

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 10

1995-2000 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

Multivariate analysis of metastatic progression-

free survival

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:

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?

Thank you!Good night!

“Blue Beauty” by Astronaut Sunita Williams