Treatment of Metastatic

Breast Cancer
Eric P. Winer, MD
Dana-Farber Cancer Institute
Brigham and Womens Hospital
September, 2009

Breast Cancer In Relation To Other Cancers

in U.S. Women

Breast
Lung
Colorectal
Endometrial
Lymphoma
Ovaria
Pancreas

New Cases
31%
12%
12%
6%
4%
4%
2%

Deaths
15%
25%
11%
2%
4%
5%
6%
CA Cancer J Clin 2002

Epidemiology of Metastatic Breast

Cancer
Approximately 40,000 deaths per year from breast
cancer (though almost certainly on the decline)
Median survival 2-3 years, but mean duration
duration of survival is longer
At any time, approximately 150,000-200,000
women living with MBC in the U.S.

Heterogeneity of Metastatic Breast Cancer

What accounts for the differences?
Performance status
and co-morbidity

Disease-free
interval

Other host factors

Sites and volume of

disease

Genetic differences
(somatic)

Prior treatment
extent of therapy
response to therapy

ER and PR
HER-2 status

Have We Improved Outcomes for Women with

Metastatic Breast Cancer?
Population Based Study in British Columbia (n=2150)
Cohort by
year of dx
Total n=2152

Median
survival
days
p value

199192
(1)

199455
(2)

199798
(3)

1999-01
(4)

438

450

564

667

Cohort 1+2 vs 3 (0.002)

Similar
Baseline
Characteristics,
Except Later
Cohorts More
Likely To Receive
Adjuvant Chemo
And Have ER+
Disease

Cohort 3 vs 4 (0.04)

Does not include dramatic improvement in HER2+ MBC

Chia et al Cancer 2007

Goals of Therapy
Prolong survival
Control symptoms
Minimize toxicity from therapy

Goals are
not
mutually
exclusive

Biopsy should be obtained in metastatic setting to confirm

diagnosis and repeat receptor unless clinical situation is
unequivocal and procedure would be associated with undue risk.

Sites of Metastatic Breast Cancer

Locoregional - Skin and Nodes

Bone and Bone Marrow
Liver
Lung
Pleura
Pericardium
Brain and Meninges
Adrenals
Retroperitoneum
Stomach and Intestinal Tract

Different Patterns for different biologic subtypes in general sense

but very variable from patient to patient
Hormone receptor positive bone
Lobular serosal surfaces

Site of First Recurrence

Site of First
Recurrence

Triple
negative
(n=61)

All
other
(n=294)

Bone only

10 (16%)

116 (39%)

0.0006

Viscera only

39 (64%)

122 (41%)

0.001

Bone and viscera

12 (20%)

56 (19%)

0.9

Dent et al, BCRT 2008

Site(s) of Initial
Recurrence/Metastasis
Lung/pleura

48 (41%)

Liver

34 (29%)

Bone

28 (24%)

Breast/chest wall

28 (24%)

Soft tissue/distant lymph nodes

25 (22%)

Regional lymph nodes

17 (15%)

CNS

16 (14%)
Lin et al, Cancer 2008

Site(s) of Initial and Subsequent

Recurrence/Metastasis
Lung/pleura

74 (64%)

Liver

58 (50%)

CNS

53 (46%)

Bone

49 (42%)

Breast/chest wall

38 (33%)

Soft tissue/distant lymph nodes

37 (32%)

Regional lymph nodes

22 (19%)

Local Therapy of Metastatic Breast Cancer

Occasional role for surgery in MBC
Chest wall lesion
Isolated pulmonary nodule
Limited brain metastases
Hepatic metastases (UNPROVEN)
Use of radiation remains common, but common than in the
past because of widespread use of bisphosphonates

When to Consider Local Therapy

Disease is truly localized
Local symptoms are present and low
chance of palliation with systemic rx
Impending localized complication (spinal
cord comp, fracture)

Role of Breast Surgery in Setting of Metastatic

Disease
16,000+ patients who presented with stage IV disease in
National Cancer Data Bases
42% had no breast surgery
58% had partial or total mastectomy

Khan, et al Surgery 2002

3 year OS
Free surgical margins
Involved margins

35%
26%

HR 0.61 [0.58-0.65] if free surgical margin controlling for

sites and volume of disease
At least two additional studies with similar findings.

Hormonal Therapy
Generally initial treatment if disease is
hormone receptor positive
Less likely to use hormonal therapy if:
Disease is HER2+
Impending visceral crisis
More extensive prior hormonal therapy (e.g.
tamoxifen and AI with progression on AI)

Hormonal Therapy Options for

Patients with MBC
Premenopausal
Tamoxifen
Oophorectomy/LHRH
agonist
Tamoxifen + LHRH
AI + LHRH

Postmenopausal
AI (and maybe more
than one)
Tamoxifen
Fulvestrant
Megesterol Acetate
Androgen
Estrogen

Benefit of Ovarian Ablation in MBC

Tamoxifen
161 pts. with ER+
and MBC

Buserelin

Median f/u 7.3 years

76% of patients DOD

Combination

RR

PFS

OS

Tamoxifen

28% 5.6 m

2.9 y

18%

Buserelin

34% 6.3 m

2.5 y

14%

Combination

48% 9.7 m

3.7 y

34%

p Value

0.11

0.01

0.03

Klijn JGM et al., JNCL 2000; 92:903-911.

5-year Survival

Overall Survival

Hormonal Therapy in Premenopausal Women

OS vs Tam vs OS + Tam

Klijn, et al. JNCI 2000

LHRH+TAM vs LHRH+ANA in
Prememopausal ER+
LHRH+TAM

LHRH + ANA

Number

n=58

n=61

OR rate

53%

80%

0.002

Median Duration

8.3m

12.1m

0.05

Median Survival

14.3

18.9m

0.001

Remains unpublished and unconfirmed!

Abstr. 13 Milla-Santos (Barcelona)

Aromatase Inhibitor vs Tamoxifen in 1st

Line Setting
No. Pts
CR + PR
CR+PR+S*
TTP mths

Anastrozole

Letrozole

Exemestane

353

907

371

21% vs17% 30% vs 20%

45% vs 30%

59% vs
46%

49% vs 38%

---

11.1vs 5.6

9.4vs 6.0

9.9 vs 5.8

Nabholtz et al Mourisden et al

Paridaens et al

All three agents at least as good as tamoxifen

Until Proven Otherwise:

Anastrozole = Letrozole = Exemestane
(in first-line setting)

Exemestane vs Anastrozole in Visceral MBC

Exemestane (n=61)

Anastrozole (n=60)

CR

3(5%)

2(3%)

PR

5 (8%)

6 (10%)

SD > 6 months

15 (25%)

8 (13%)

Clinical Benefit

23 (38%)

23 (38%)

Underpowered study, no striking difference, but clinical benefit

in women with visceral disease worth noting
Cameron D et al, in press

Response to Exemestane
After Second-Line AI Failure
Prior AI

Aminoglutethimide

CR
PR
ORR
SD >6 mo
Clinical benefit

(n=136)
2 1.5%
9 6.6%
11 8.1%
26 19.1%
37 27.2%

Lnning PE, et al. J Clin Oncol. 2000;18:2234-2244.

NSAI
(n=105)
1 1.0%
4 3.8%
5 4.8%
16 15.2%
21 20.0%

All AIs
(N=241)
3 1.2%
13 5.4%
16 6.6%
42 17.4%
58 24.0%

Fulvestrant vs Anastrozole in MBC

Fulvestrant

F vs A (Europe)

F vs A (NA)

No. Patients

451

400

CR+PR

21% v 16%

Both 18%

Clinical benefit

Both 45%

42% v 36%

Med response

14.3 v 14.0 mths

19.3 v 10.5

Median TTP

5.5 v 5.1 mths

5.4 vs 3.4

Osborne and Robertson BCRT 64:27 2000

Randomized Trial of Fulvestrant vs

Tamoxifen
Best response

Number of patients (%)

Fulvestrant Tamoxifen
(N=313)
(N=274)

Complete response (CR)

30 (9.6)

19 (6.9)

Partial response (PR)

69 (22.0)

74 (27.0)

Objective response (CR + PR)

99 (31.6)

93 (33.9)

Stable disease (SD) 24 weeks

71 (22.7)

77 (28.1)

170 (54.3)

170 (62.0)

p-value

0.45

Clinical Benefit
(CR + PR + SD >24 wks)

0.03

Trend for improved TTP with tamoxifen (HR 1.18, p=0.08)

Fulvestrant vs. Exemestane After Prior AI: Results

Fulvestrant
(N=351)

Exemestane
(N=342)

P Value

3.7

3.7

0.6531

20 (7.4%)

18 (6.7%)

0.7364

87 (32. 2%)

85 (31.5%)

0.8534

Median Duration of
Response (months)

13.5

9.8

NR

Median Duration of
Clinical
Benefit (months)

9.3

8.3

NR

TTP (months)
ORR, N (%)
Clinical Benefit Rate,* N
(%)

Gradishar, et al. 29th Annual SABCS. December 15, 2006 (abstr 12).

Treatment Algorithms for Postmenopausal Women

Adjuvant Tamoxifen

Adjuvant Aromatase Inhibitor

Aromatase Inhibitor for

MBC

Faslodex

Fulvestrant
Megace

Tamoxifen

High dose
estrogen

1. Allow adequate time to observe a response to rx.

Consider a trial of endocrine rx withdrawal

Optimization of hormonal therapy a major research priority.

Two Ongoing CALGB Trials

PI: Harold Burstein

2nd line
Hormonal rx

Fulvestrant + placebo

HER-2
1+, 2+, 3+

R
Fulvestrant + lapatinib

1st line
Hormonal rx

AI/Tam + placebo

Assess
Prior adj rx

PI: Maura Dickler

AI/Tam + bevacizumab

Chemotherapy for MBC

A Wide Array of Active Agents
Anthracycline and
similar

Doxorubicin
Epirubicin
Doxil
Epirubicin

Taxanes
Paclitaxel
Docetaxel
Nab-paclitaxel

Vinca alkaloids
Vinorelbine
Vinblastine

Antimetabolites
Methotrexate
5-FU
Capecitabine
Gemcitabine
CPT-11
Alkylating agents
Cyclophosphamide
Thiotepa
Platinum agents
Epothilones
Ixabepilone

Chemotherapy Approach
Differs by Subtype

HER2 +

HER2 inhibition +
chemotherapy

Triple
Negative

ER+
(but endocrine resistant)

Chemotherapy +/- Bevacizumab

Is There a Standard First-Line Agent?

Anthracyclines and taxanes often considered firstline agents, but now used increasing in adj setting
No evidence that precise sequence of therapies
affects overall survival or QOL
Response rates more influenced by line of therapy
than specific agent
Treatment decisions can often be individualized to
patient
NCCN breast panel has avoided recommending
specific first-line agents

Single Agent Treatment

vs
Combination Chemotherapy

WHERE DO WE STAND?

Single Agent vs Combination Treatment

Doxorubicin vs Paclitaxel vs Combination

Met breast cancer

No prior chemo for MBC
No prior doxorubicin
n=739

Doxorubicin 60 mg/m2
every 3 weeks

Paclitaxel

Paclitaxel 175 mg/m2

every 3 weeks

Doxorubicin

Doxorubicin 50 mg/m2
Paclitaxel 150 mg/m2
every 3 weeks
Sledge et al, JCO 2003

ECOG Trial of A T vs T A vs AT
RESPONSE

TTP

SURVIVAL

CROSSOVER RR

Doxorubicin

34%

6.2 mo.

20.1 mo.

D to P
20%

Paclitaxel

33%

5.9 mo.

22.2 mo.

P to D
14%

Doxorubicin
+ Paclitaxel

46%

8.0 mo.

22.4 mo.

NA

P < .004

P < .009

NS

Sledge et al, JCO 2003

No diff in QOL
Biggest drop in QOL seen in those with best at baseline

Docetaxel vs Docetaxel/Capecitabine
511 patients, all with prior anthracycline
Docetaxel 100 mg/m2 q 3

Randomize
Docetaxel 75 mg/m2 q 3 weeks +
Capecitabine 2500 g/m2/d x 14

Efficacy

Docetaxel

Docetaxel + Capecitabine

RR

30% [24-36%]

42% [35-48%]

TTP

4.2 months

6.1 months

* Median survival

11.1 months

13.7 months

(OShaughnessy et al, JCO 2002)

(log rank p=0.0119)

AT vs AC in Metastatic Breast Cancer

429 pts rx as first line therapy
Median age = 53, KPS 90%
Randomized to:
Docetaxel 75mg/m2 Doxorubicin 50 mg/m2, q 3 wks
Cytoxan 600 mg/m2 Doxorubicin 60 mg/m2, q 3 wks

Nabholtz, JCO 2003; 21:968

AT vs AC in Metastatic Breast Cancer

RR
TTF
OS

AT
59%
25.6 wks
22.5 mo

AC
47%
23.7 wks
21.7 mo

Nabholtz, JCO 2003; 21:968

Combination vs Single Agent

No Right or Wrong Answer
Combination
Higher RR
Longer TTP
Survival
QOL
Easier to customize
Less wasted toxicity

Single Agent

Is there a best taxane?

Is there a best way to give taxanes?

Phase III: Docetaxel vs Paclitaxel

Every 3 Week Schedule
Docetaxel

Paclitaxel

Response Rate

37%

26%

p=.02

Median TTP (mos)

5.7

3.6

p<.0001

Median OS (mos)

15.4

12.7

p=.03

Jones, S.E. et al. J Clin Oncol; 23:5542-5551 2005

CALGB 9840: Results

N=576
Response
TTP
Survival

Weekly P
40%
9 months
24 months

Standard P

p value

28%

0.017

5 months

0.0008

16 months

0.17

NO BENEFIT FOR TRASTUZUMAB IN HER-2 NEG DISEASE

Seidman et al, JCO 2008

ABI-007 (nab-paclitaxel) vs Paclitaxel

Time to Tumor Progression
Abraxane (n=219)
Paclitaxel (n=214)

Proportion not progressed

1.00

RR 33% vs 19% p < 0.001

0.75

Abraxane median: 21.9 weeks

p=0.029

0.50

0.25

Taxol median: 16.1 weeks

0

0.00

Time to progression (months)

*Censored.
OShaughnessy J, et al. San Antonio Breast Cancer Symposium. 2003; abstr 44;

10

11

12

Phase III Trial of Capecitabine vs

Ixabepilone + Capecitabine
N=752
All patients with previous exposure to anthracycline and
resistance to taxane
Median time to progression

Capecitabine

4.2 months [3.8-4.5]

Cape + Ixabepilone

5.8 months [5.5-7.0]

P=0.0003

Overall Response Rate

Capecitabine

23%

Cape + Ixabepilone

42%

P=0.0001
Vhadat et al, ASCO 2007

CALGB 40502: Randomized Comparison of 3

Antimicrotubule Agents for First-Line MBC

R
A
N
D
O
M
I
Z
E
Baseline Block Collection
Frozen Tumor if Possible
Baseline Blood Collection

Paclitaxel 90 mg/m2 weekly*

ALL WITH
BEVACIZUMAB
10 MG/KG q 2 wk

ABI-007 100 mg/m2 weekly*

Ixabepilone 16 mg/m2 weekly*
Serial Blood for:
Caveolin-1
Circulating Cells

PI Rugo (UCSF), Lyss (St Louis), Moreno (Mayo)

Angiogenesis and Breast Cancer

Preclinical evidence strongly suggests a key role for
angiogenesis in tumor growth and development of
metastases
Clinical studies have suggested a correlation between
microvessel density and/or VEGF expression and poor
clinical outcome
Undisputed activity in other malignancies

Phase III MBC Trial PFS

Bevacizumab and Capecitabine vs Capecitabine
1.0

Proportion event-free

Capecitabine
0.8

Months
HR (stratified)

0.6

4.17

Capecitabine +
Bevacizumab
4.86
0.98 (NS)

Addition of bevacizumab led to

10% improvement in RR

0.4

0.2

0
0

10 11 12 13 14 15 16

Progression-free survival (mo)*

Miller K et al. JCO 23:792-799 2005.

ECOG 2100: Paclitaxel +/Bevacizumab

Stratify:
DFI < 24 mos. vs. > 24 mos.
< 3 vs. > 3 metastatic sites
Adjuvant chemotherapy yes vs. no
ER+ vs. ER- vs. ER unknown
R
A
N
D
O
M
I
Z
E

Paclitaxel + Bevacizumab

Paclitaxel

Miller et al. SABCS 2005 #3

28-day cycle:
Paclitaxel 90 mg/m2 D1, 8 and 15
Bevacizumab 10 mg/kg D1 and 15

Response Rates: Paclitaxel vs Paclitaxel +

Bevacizumab
P<0.0001

P<0.0001

Overall Response Rate

Paclitaxel
Pac + Bev

40

37.7%
29.9%

30
20

16%
13.8%

10
339

341

262

236

0
All patients

Measurable Disease
Miller et al. NEJM 2007

Progression Free Survival

Paclitaxel vs Paclitaxel + Bevacizumab
Pac. + Bev. 11.4 months

1.0

Paclitaxel

6.11 months

PFS Probability

0.8

HR = 0.51 (0.43-0.62)

0.6

Log Rank Test p<0.0001

0.4

0.2

0.0
0
Miller et al. NEJM, 2007

12

18

Months

24

30

484 events reported

AVADO: progression-free survival

(ITT population)
Placebo +
docetaxel (n=241)

HR + 95% CI (unstratified)
HR + 95% CI (stratified*)
8.0

Median

HR + 95% CI (unstratified)

0.79 (0.630.98)
p=0.0318

HR + 95% CI (stratified*)

0.69 (0.540.89)
p=0.0035

Median

8.7

PFS estimate

8.0

Bev 15 +
docetaxel (n=247)

0.72 (0.570.90)
p=0.0099
0.61 (0.480.78)
p<0.0001
8.8

PFS estimate

1.0

1.0

0.8

0.8

0.6

0.6

0.4

0.4

0.2

0.2
0

0
0

Placebo +
docetaxel (n=241)

Bev 7.5 +
docetaxel (n=248)

12
Months

18

mg/kg q3w; *Data censored for non-protocol therapy before PD

12
Months

18

Use of Bevacizumab in Clinical

Practice
As first-line therapy with paclitaxel or (perhaps) with
other agent for which there is toxicity data
Avoid in patients with refractory disease
At present no evidence that continuation beyond
progression is useful
Preliminary data suggest high level of activity with
trastuzumab, but not ready for off-protocol use
Cost/insurance coverage are a concern

Cetuximab or Cetuximab/Carboplatin in Triple

Negative MBC
TRBCR 001
Initial cetuximab 400 mg/m2
then 250 mg/m2 weekly
On PD, carboplatin
AUC 2 weekly, 3 of 4 weeks

Patients with measurable

TN MBC
R
R
3 prior chemotherapies
No prior platinum or
EGFR inhibitor

Carey. SABCS. 2007 (abstr 307).

Initial cetuximab 400 mg/m2

then 250 mg/m2 weekly
Carboplatin AUC 2 weekly,
3 of 4 weeks

Cetuximab in Triple Negative MBC:

Clinical Efficacy
Best
Response
CR

Cetuximab Alone
(n=31)
0

PR

2 (6%)

SD

5 (16%)

Clinical Benefit

3 (10%)

Carey. SABCS. 2007 (abstr 307).

Phase II Study of Carboplatin/Cetuximab

Clinical Efficacy of Combination Therapy
Approximately
50% has 1-2 reg.

Carbo/Cetux
(N=71)

All
(N=95)

CR

1 (1.4%)

1 (1%)

PR

11 (15%)

15 (16%)

Line of therapy
did not affect
likelihood of
response

SD

16 (23%)

22 (23%)

44% EGFR +

ORR

17%

17%

CB

31%

29%

Carey et al,
ASCO 2008

It is Safe to Use Investigational Agents Early in the

Treatment of Patients with Metastatic Breast Cancer
365 women, previously untreated with chemotherapy
for metastatic breast cancer
Randomized to:
Phase II agent x 4 cycles CAF
CAF

Phase II agents:
Trimetrexate, melphalan, amonafide, carboplatin,
elsamitrucin
Costanza, CALGB, JCO 1999;17:1397

Initial Treatment with Phase II Agents vs Initial

Treatment with CAF

Costanza, CALGB, JCO 1999;17:1397

Metastatic Breast Cancer: What Have We Accomplished

and Learned In 30 years of Clinical Investigation?

Hormonal and chemotherapy do not cure most pts with MBC, and have had a modest
effect on overall survival, but remain the mainstay of therapy for most patients with
HER2- disease

Dose Intensity of chemotherapy past a point of efficacy, doesnt help

Single agent therapy can improve quality of life without compromising survival
You dont have to suffer to benefit

Very different agents have similar response rates in first line setting, so it may make
sense to use best tolerated early
You dont have to suffer to benefit

We must learn to determine who will respond to a particular therapy - and administer
it only to those patients, saving others needless toxicity

Biologic (targeted) therapies offer new hope - but we need to figure out how to better
and more quickly identify targets, develop agents directed at those targets, and test
them safely but more efficiently

Many New Agents and Approaches

Angiogenesis inhibitors
SRC inhibitors
PI3K inhibitors
PARP inhibitors
Many others

Olaparib in Mutation Carriers: RESULTS

Olaparib (n=27)
400 mg bid
41%

Olaparib (n=27)
100 mg bid
22%

Complete Response

4%

Partial
Response
Median Time To
Progression

37%

22%

5.7 months
[4.6-7.4]

3.8 months
[1.-5.5]

Overall Response

Dose appears to matter wth higher response rate at 400 mg bid

Prior therapy did not affect response
Patients with both BRCA1 and BRCA2 responded to treatment

Tutt et al
ASCO 2009

Gem/Carbo +/- BSI-201

MBC
Triple Negative
Prior Chemo
N=120

Gemcitabine 1000 mg/m2 d 1,8

Carbo AUC 2 d 1,8
CYCLES EVERY 21 DAYS
Gemcitabine 1000 mg/m2 d 1,8
Carbo AUC 2 d 1,8
BSI-201 5.6 mg/kg d 1,4,8, 11

RESTAGE EVERY 2 CYCLES

OShaugnessy et al, ASC0 2009

Carbo/Gem +/- BSI-201:

Progression-Free Survival
BSI-201 + Gem/Carbo (n = 57)
Median PFS = 6.9 months
Gem/Carbo (n = 59)
Median PFS = 3.3 months
P < 0.0001
HR = 0.342 (95% CI, 0.200-0.584)

OShaugnessy et al, ASC0 2009

Carbo/Gem +/- BSI-201:

Overall Survival
BSI-201 + Gem/Carbo (n = 57)
Median OS = 9.2 months
8

Gem/Carbo (n = 59)
Median OS = 5.7 months
P = 0.0005
HR = 0.348 (95% CI, 0.189-0.649)

OShaugnessy et al, ASC0 2009

Treatment of MBC: Where Now?

The next generation of targeted therapies
appears to be surfacing
Many complex questions about how best to
evaluate these agents measuring target is key
Chemotherapy and hormonal therapy still the
cornerstone of therapy for most patients for the
near future --- optimization of both important
Must be careful not to discard new agents
prematurely
Great promise in the years ahead

Questions

1. Which of the following regimens represent

acceptable first-line treatment for a postmenopausal
women with hormone receptor positive breast cancer?

A.
B.
C.
D.
E.
F.

Letrozole
Anastrozole
Exemestane
High dose estrogen
Megesterol acetate
Tamoxifen

Answers
1) A only
2) A, B, and C
3) All of the above
4) A, B, C, F

Question 1: Explanation
Treatment with the aromatase inhibitors
(letrozole, ansastrozole, and exemestane
represent appropriate first-line treatment.
Tamoxifen remains an acceptable alternative,
and is probably the preferred treatment in a
patients who has received an aromatase
inhibitor in the adjuvant setting. Neither high
dose estrogen nor megesterol acetate are
appropriate first-line treatments as each has
more toxicity that the aromatase inhibitors or
tamoxifen.

2. When chemotherapy is administered in the first- or

second-line setting, combination therapy should
always be used.

A. True
B. False

Question 2: Explanation
False is the correct answer. Although combination
chemotherapy is generally associated with higher
response rates and longer time to progression than
treatment with single agents, combination therapy
does not improve survival when cross-over is allowed
and is associated with greater toxicity. Either
combination therapy or single agent treatment
represents appropriate clinical care, and the approach
can be individualized to the patients disease status
and preferences.

3. Bevacizumab should be given in combination with

chemotherapy for metastatic breast cancer and
should be continued with each and every regimen?

A. True
B. False

Question 3: Explanation
Bevacizumab has been shown to improve the
response rate and time to progression when added to
standard paclitaxel in the first-line setting. It has yet
to be shown to improve overall survival. There is no
clinical evidence, at this time, that it should be
continued beyond progression with successive
chemotherapy regimens. Given the toxicity
associated with bevacizumab and the high cost
associated with the agent, the continuation of
bevacizumab after progression should be discouraged
at this point in time.