The optimal therapeutic approach toTHE OLIGOMETASTATIC DISEASE

Rita CeccheriniCentro Sociale Oncologico Trieste

METASTATIC BREAST CANCER: CURRENT MANAGEMENT AND FUTURE PERSPECTIVES

Rome, April 23, 2010

OLIGOMETASTASIS • …..“In some tumors the anatomy and physiology may

limit or concentrate these metastases to a single or a limited number of organs”……

……“An attractive consequence of

a “clinically significant “

OLIGOMETASTATIC STATE

is that some patients should be amenable to a curative therapeutic strategy……..

Hellman S, Weichselbaum RR: J Clin Oncol 1995;13:8-10, modified

Potentially curable Stage IV (1-10%)ESO-MBC Task-Force Consensus

• “A small but very important subset of MBC patients, for example those with a solitary metastatic lesion, can achieve complete remission and a long survival.

• A more aggressive and multidisciplinary approach schould be considered for these selected patients.

•

• A clinical trial addressing this specific situation is needed

Pagani et al: J Nat Cancer Inst 2010;102,:456-463

GOALS OF THERAPY IN MBC

• Prolungation of survival • Symptoms relief• Maintenance of a good quality of life• Delay of disease progression

Can MBC be cured ?

Biases• Definition of “cure”

• Influence of the new technologies to detect minimal residual disease

• Most MBC trials have relatively short follow-up

MBC Survival improved over time

MBC Survival improved over time

Chia et al:Cancer 2007;110:973-9

Survival in Metastatic Breast Cancer. A Population Based Analysis

438 450

564667

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100

200

300

400

500

600

700

1991-2 1994-5 1997-8 1999-01

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MORE TOOLS , MORE LIFE

Chia et al:Cancer 2007;110:973-9

Median days survival

P=.01P<. 001

Factors to consider in risk assessment and treatment decision making for MBC

DESEASE-RELATED FACTORS

• Disease-free interval

• Tumor burden (number and sites of metastases)

• Prior therapies and response

• Biological factors (Hormonal receptors, HER2)

• Need for rapid disease/symptom control

PATIENT-RELATED FACTORS

• Patient’s preferences

• Biological age

• Menopausal status

• Co-morbididities and performarce status

• Socio-economic and psychological

Available therapies in the patient’s country

Cardoso &Castiglione: Annals of Oncology 20 (Suppl 4), 2009

Characteristics of the Long-Term Disease-Free Survivors

• Limited metastatic disease (one organ site involved)

• Young age• Excellent performance status• No adjuvant chemotherapy• Normal organ function• Absence of significant co-morbidity

Oligometastatic state in breast cancer: hypothesis or reality?

• Are there patients whose survival improvement could translate into cure?

• How many are they?

• How can we select patients who are likely to benefit curative treatment?

SURVEY OF TREATMENT RESULTS

ROLE OF SYSTEMIC TREATMENT

• Conventional Chemotherapy

• High-dose Chemotherapy

• Adjuvant systemic after local treatment

ROLE OF LOCAL TREATMENT

• Surgery for Primary Tumor in the presence of limited metastatic disease

• Surgery for Lung and liver metastases

MBC chemotherapy trials showing survival benefits

TRIAL Survival (months)

P value N of patients (line)

First author (year)

CAF > CMxF 15.2 vs 10.9 0.003 249 (first) Stewart (1997)

Pac > CMFP 17.3 vs 13.9 0.025 209 (first) Bishop (1999)

Doc> Mito/VB 11.4 vs 8.7 0.0097 392 (second) Nabholtz (1999)

APac > FAC 23.3 vs 18.3 0.013 267 (first) Jassem (2001)

Cap/Doc > Doc 14.5 vs 11.5 0.013 511(second ) O’Shaughnessy (2002)

Chemo + T > Chemo 25.1 vs 20.3 0.046 469 (first) Slamon (2001)

Doc +T >Doc 31.2 vs 22.7 0.0325 186 (first) Marty (2005)

Paclit +Gem > Paclit 18.6 vs 15.8 0.02 529 (first) Albain (2008)

Modified from Smith: Annals of Oncology 19 (Supplement 7) 2008

Long-Term Follow-Up of Patients With Complete Remission Following Combination Chemotherapy for Metastatic Breast Cancer

Greenberg et al, J Clin Oncol 1996

Between 1973 to 19821581 patients 263 RC (16.6%)

•49 NED after 5 years (3.1%)•26 NED after 15 years (1.5%)•4 Died in CR after 118-234 months

Greemberg et al, JCO 1996

Disease patterns and Outcome

Results and Long Term Follow-up for 1581 patients with MBC Treated with

Standard dose Doxo-Containing Regimens

Rahman et al: Cancer 1999;85:104-11

Response and Survival

Response to chemotherapy is a mayor parameter-influencing long-term survival in metastatic breast cancer patients

Pierga et al: Annals of Oncology 12:231-237, 2001

•1430 patients from 1977 to 1992

•8 trials antracycline-based first-line chemotherapy

•Median follow up 155 months

MBC first –line doxorubicin-containing chemotherapy: Effect of adjuvant chemotherapy on outcome

Pierga et al: Cancer 2001; 91: 1079-1089

MBR first –line doxorubicin-containing chemotherapy: Effect of adjuvant chemotherapy on outcome

Pierga et al: Cancer 2001; 91: 1079-1089

Overall survival Survival according with CT type

Is there a role for HDC?

Farquhar et al: Cochrane Database Syst Rev 2005; (3) CD003142

6 randomized controlled trials

HDC438 patients

CC412 patients

OS: no difference More toxicity

NO HDC OUTSIDE OF CLINICAL TRIALS

Stage IV NED

Primary Breast Cancer

Surgery +/or Radiotherapy +/- Adjuvant Systemic Therapy

Solitary Metastasis

Surgical Resection +/- Radiotherapy

Stage IV NED (No Evident Disease)

DFS by treatment Overall Survival

Waeber et al: Annals of Oncology 14:1215, 2003

N.SP=0.053

Adjuvant Chemotherapy in Stage IV NED

Rivera et al: The Breast J: 8; 2-9, 2002

Adjuvant Therapy in Stage IV NED

Rivera et al: The Breast J: 8; 2-9, 2002

Disease-free survival of patients with stage IV-NED breast cancer according to study group

Months

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 24 48 72 96 120 144 168 192 216 240

Study 3 (45 Pts)

Study 2 (80 Pts)

Study 1 (134 Pts)

Control (62 Pts)

P < 0.001

Rivera et al: The Breast J: 8; 2-9, 2002

Overall survival of patients with stage IV-NED breast cancer according to study group

Rivera et al: The Breast J: 8; 2-9, 2002

IV NED Breast CancerOutcomes for the Three Doxorubicin-based Studies, Combined (n=259)

0.0

0.2

0.4

0.6

0.8

1.0

0 100 200 300 400

Months from Treatment

Dis

ease

-Fre

e S

urvi

val P

roba

bilit

y

Median DFS: 42 mos

3-yr DFS: 57%

5-yr DFS: 41%

10-yr DFS: 34%

20-yr DFS: 26%

Median 0S: 87 mos

3-yr DFS: 75%

5-yr DFS: 56%

10-yr DFS: 42%

20-yr DFS: 26%

Disease-free Survival Overall Survival

Hanrah et al : Cancer 104: 1158-1171, 2005

Docetaxel-based trial duration and probability of overall survival (26 patients prior adjuvant antracycline based chemotherapy)

Median follow-up 44 months

3-yr DFS: 58%

Hanrah et al : Cancer 104: 1158-1171, 2005

Combined-Modality Treatment for Isolated Recurrences of Breast Carcinoma Update on 30 Years of Experience M. D. Anderson Cancer Center

Assessment of Prognostic Factors

Hanrah et al : Cancer 104: 1158-1171, 2005

• 62 pts minimal disease

• Local therapy + HDC

Nieto et al : J. Clin Oncol 20:707, 2002

P= .000.4P= .03

P=.0008

Nieto et al : J. Clin Oncol 20:707, 2002

MBC : Surgery for primary tumor

• 3.5% -7% MBC at diagnosis

• 7.000 new patients /year

• 50% T1-T3 primary tumor

Surgery?

MBC : Surgery for the intact primary

Pagani et al: J Nat Cancer Inst 2010;102,:456-463

Surgical resection of lung metastasis

Pagani et al: J Nat Cancer Inst 2010;102,:456-463

Friedel et al Eur. J. of Cardioth. Surg. 22: 335-344, 2002

Lung resection: important diagnostic tool

From 7% to 66%

second primary lung cancer

and benign lesion

Pagani et al: J Nat Cancer Inst 2010;102,:456-463

Surgical resection of isolated liver metastases

Pagani et al: J Nat Cancer Inst 2010;102,:456-463

Hepatic resection in MBC: results and prognostic factors

Pocard et al Eur J Oncol 26:155, 2000

Hepatic resection in MBC: results and prognostic factors

Pocard et al Eur J Oncol 26:155, 2000

ESO-MBC Task-Force Consensus

• “A small but very important subset of MBC patients, for example those with a solitary metastatic lesion, can achieve complete remission and a long survival.

• A more aggressive and multidisciplinary approach schould be considered for these selected patients.

•

• A clinical trial addressing this specific situation is needed

Pagani et al: J Nat Cancer Inst 2010;102,:456-463

Characteristics of the Long-Term Disease-Free Survivors

• Limited metastatic disease (one organ site involved)

• Young age• Excellent performance status• No adjuvant chemotherapy• Normal organ function• Absence of significant co-morbidity

CONCLUSIONSOligometastatic state in breast cancer hypothesis or reality?

CLINICAL CONSEQUENCES

• selected subset of oligometastatic MBC patients should be approached with curative intent

• the current minimalistic postoperative follow-up schould be revised to allow early diagnosis of low-burden disease relapse ?