Weekly Adriamycin versus VAC in advanced breast cancer. A randomized trial

Weekly Adriamycin Versus VAC in Advanced Breast Cancer. A Randomized Trial S. GUNDERSEN,* *General .$e,bartment

Department.

S. KVINSSLASD,t

The AVorategian Radium

of Oncology, Regional

FIospital,

0. KLEPP,:

Hospital,

Trondheim;

S. KV.ZL@Y,*

Oslo: tDepartment

$ Office for

Clinical

E. I,TJSD$

and

of Oncology. Haukeland

H. H@ST*

Hospital.

Tria1.s. The ,Vor~~egian Radium

Bergen:

Hospital,

Oslo. .lil ru ‘”1’

Abstract-In

a pospectizje

randomised

treated either with Adriamycin (\‘AC).

studv 128 patients

(20 mgiweek)

uxith advanced breast cancer- were

or aincristine. Adrianyin

and cvclophosphamide

iln objective response ulas obtained in 3 1 and 35% of patients in the tu,o grouks.

ujas no .tign$cant Adriamycin

difference

was well tolerated.

and transient. In appox. had alopecia

N’hen subjective

40%

.side effects

re,gard to nausea, TIlC patients.

occurred, thev u’er.e usual!v slight

of the patients no side-effects

at all were obseraed. Eight per cent

requiring a ulig. Onlv slight ryelosuppression

this had no practical

There

with regard to duration of response or surz~ir,al. Il’eeklJ: lorcl dose

implications.

vomiting and alofiecia.

It is concluded

could be seen in a j&et patients

and

,CIost or all of I’AC patient,) experienced severe toxicit,: rcith Also nyelosuppression

that weekb

was more pronounced

doses of ,4drianpcin

adL#anced breast cancer is as effectirle a.s the VA4C combination

among

a.7 srngle agent therakv for

delir’ered ermervthird week. with

considerab~v less touicitv.

INTRODUCTION AI)RIAMYCIN is one

of the

otherapeutic

in

Usually i.c.

agents

vincristine,

or FAC)

vious prospective

study

the response

Besides

alopecia

most

cancer.

with other

drugs,

patients

and

cvcry

3 weeks.

to VAC

hone

experienced

with

nausea

weekly apy

low dose

could

studies Adriamycin

[l]. and

rate

and

in advanced

breast

lished

undertaken

data)

effective

without

cancer.

indicated

as single

be comparatively

to response

Hospital,

have

with

serious

therregard

toxicity

In a pilot study

at The Norwegian

9 out of 24 pretreated

that

agent

patients

]2]

(WCC)

another

initiate

background

a prospective

weekly

Adriamycin

breast

cancer.

it was

which

randomized (Awkly)

study

and VAC

bctwcen

could

osteoblastic

lesions

the disease

were

previously

4 April 1986. Supported by ‘I‘he Norw=gian Cancer Society. Address reprint requests to Dr. Stein Gundersrn, Grncral Dcpartmcnt, ‘l‘hr Norwegian Radium Hospital, Montrbello. 03 IO Oslo 3. Norway.

required.

were

to the excluded.

or cvaluable.

lcptomcningeal only

excluded. with

medical

adherence

schedule,

as the

treated

Patients

or other

prccludr

were measurable

Patirnts affection

or

manifestation

Furthermore

4driamycin

of

patients

did not enter

the study. patients and

had

previously

rcceivcd

hormone

were

considered

hormone

resistant.

to initial

bone

isotope

and

measurements

obtained tion

treatment

examination.

and/or those

bone

of

liver

scan,

count, survey

who had

wcrc

by liver func-

ultrasound

sonography

was performed. symptoms

X-ray,

radiographs lesions

If indicated

computertomography patients

undcrwcnt chest

indicator

in all patients.

tests,

all patients

Blood

scan and/or

computertomography Arcrptrd

(plt)

were

metastascs,

Prior

in advanced

4 X lo”/1 and platelet

Metastases

All

to

white

with

treatment

felt justified

wet-r

initial

of neoplasm,

or assessment

physical this

cancer

lo”/1

treatment brain

1983 a total

breast

A pretreatment

ofa

type

December

advanced

conditions

Radium rcspond-

with

of 2 125 X

(unpub-

cd. With

1982 until

into the study.

cell count

Radium

vomiting. Non-randomized

entered count

depression,

scvcre

June

of 128 patients

5-fluo-

was 35%

marrow

From

In a prc-

at The Norwegian rate

and

chcm-

breast

cyclophosphamide

(VAC

Hospital

effective

advanced

it is given in combination

rouracil

PATIENTS AND METHODS

most

was

Brain

or scans

performed or signs

in

sugges-

tive of central nervous system metastases. Patients were allocated by random numbers

to

1432

S. Gundersen et al.

either Adriamycin 20 mg/wcek (Awkly) or vincristine 2 mg, Adriamycin 50 mg/m2 and cyclophosphamide 600 mg/m2 (VAC) every 3 weeks (Table 1). There was no stratification. Blood counts were performed before each course of chemotherapy, both for Awkly and VAC. Nadir values betwen VAC courses were not determined. When WCC and/or plt counts before start of a new course were between 3.9-3.0 X lo”/1 and 124-100 X log/1 respectively, doses of cyclophosphamide and Adriamycin were reduced by the corresponding 25% and for values 99-75 x 109/l 2.9-2.0 X 109/l and dose reduction was 50%. For lower values treatment was postponed for 1 week. The stipulated maximal cumulative dose of Adriamycin in the Awkly regime was 750mg/m2, and in the VAC regime 500 mg/m’ (Table 1). Responding patients were treated until the stipulated maximal cumulated dose of Adriamycin and then received maintenance therapy with methotrexate 50 mg and cyclophosphamide 600 mg/m’ every 4 weeks for a total duration of chemotherapy of 2 yr. Patients who did not respond (progressive disease or no change after 3 months of treatment) received a combination of 5-fluorouracil 1000 mg/m2 day 1 and 2 and Mitomycin-C 6 mg/m’ day 2 every 3 weeks (FuMi). Main patient characteristics are summarized in Tables 3 and 4. There were no significant differences between the two groups with regard to important prognostic factors except that more Awkly patients had received adjuvant chemotherapy than VAC patients (17/62 vs. 8/66, P = 0.05). Although significant this must have occurred by chance and didn’t favour Awkly patients. The criteria used for remission were those recommended by WHO [3]. The duration of PR was calculated from start of treatment until progression, while CR was calculated from the time CR could be documented.

STATISTICAL METHODS The comparability of the two treatment groups with respect to baseline variables was assessed by performing chi-squared tests or Fischers exact test

Table

Awkly -

VAC -

1.

Treatment

for categorical variables and two-sample Student’s t-tests for means. Survival curves were calculated by the actuarial life table method, and significance testing based on log-rank tests [4]. Survival was calculated from start of treatment and calculated by the life Table method. Differences between the groups were analyzed by the log rank test [4]. RESULTS All the 128 patients were considered evaluable for response, survival and toxicity. Main patient characteristics are summarized in Tables 2 and 3. One patient had received 5-fluorouracil for treatment of metastases, and 25 had received adjuvant chemotherapy, usually CMF for 1 yr (Table 4). Response rates were 31% for Awkly and 36% for VAC (P = 0.62) (Table 5). Among patients that previously had adjuvant CMF for 1 yr 3/8 VAC and 4/17 Awkly patients responded. The percentage difference in response (CR+PR) is 5.7% between VAC and Awkly with 95% confidence limits of + 10.7% and 22.2%. Median duration of complete remissions were 11.3 months (+) for Awkly patients and 8.0 months (+) for VAC patients. For partial remissions, the figures were 5.0 months and 7.0 months respectively (Table 6). There was no significant difference in survival

Table

2.

Main patient

characteristics Awkly

VAC

62 59 3 59 19 39 11 46 33

66 56 3 63 20 45 11 48

16

16

No. of patients Mean age, yr Premenopausal Postmenopausal ER positive (> 10 pmol/g protein) ER unknown PgR positive (> 10 pmol/g protein) PgR unknown Disease-free interval (mean, months) Time from first metastases until randomization (mean, months)

Table 3.

29

Number of sites and dominant site of metastases Awkly n=62

%

VAC R = 66

%

30 26 6

48 42 10

34 27 5

52 41 8

13 19 30

21 31 48

15 13 38

23 20 58

regimes

Adriamycin 20 mg q weekly (max. cum. dose 750 mg/m*)

Number 1 2 3

of sites

Vincristine 2 mg Adriamycin 50 mg/m2 q 3 weeks (max. cum. dose 500 mg/m’) Cyclophosphamide 600 mg/ml

Dominant site Soft tissue Skeletal Visceral

Weekly Adriamycin Table 4.

Versus K4C

Previous treatment

loo

.4wkly

VAC

(n = 62)

(n = 66)

Chemotherapy: Mjuvant

(C&IF

Advanced

disrasc

Hormone

thrrapy:

(‘l‘amoxiphen

1 yi

17

8

1

0

(5fluorouracil)

with

or without

(.aStr;ltloll)

62

66

6

I1

Radiotherapy:

*-.

Mrlomycln

?? --m

VAC

III

II

0

c

test P-049

Log rank

4

2

II

6

8

IO

12

14

I

II

‘6

18

1

I 2u

22

24

Time (months)

Table

5.

Response

Awkly

V.4C

I, = 62

n = 66 3 I%

8

CR

6

PR

13

16

NC:

Ii

27

PI)

26

1.i

Table

6.

Duration

36%

25 21

10 3+

56

xi

I’ c. 0.005

Vomiting

.1

6

43

ti.>

I’ < 0.001

8

i

B one

.AMkl) median

(*l)j

Alopecia

qf response (months)

range

II i

+

(&x3)

8.0 +

(3-26,

PR

5.0

+

(2-14)

7.0

(l&l(i)

+

Depression

6

I0

Neuropathia

0

0

*Patirnts

with

patients the

two groups

start

of therapy

The

response

20%

(Fig.

(56 patients

are

related

response

FuMi

is non-cross-resistant

from dose

so far

1984,

for Awkly

patients

60-1280

with

or respon-

mg.

For

was

dose

376 mg

patients

377 mg with of Awkly

or negligible side-effects, while patients experienced some degree 7). Approximately Awkly

group

usuallycourses.

that

one third

expcricncrd

patients

some

of Awkly patients.

patients, Alopecia

in contrast requiring

metastases. values

reduction

occurred

at

one

one fifth of VAC

or plt below not

Serious

no

in the

of nausea, or more by less to 65% a wig

was

seen among less than 10% of Awkly patients as opposed to 80% of VAC patients. Among the five

WCC

These

were

trombocytes ured.

Two time

ncccs-

or

or dose more

Counts

below.

patients

the lowest

due

and

sccondarv

liver

2.8 and

values

recorded.

of Awkly marrow

of

values

at

X lO”/l

or

mctastases 2.9

X IO”/1 were

course to bone

evidence

with

on

125

4.0

X lO”/l. Values not

and not

in

a

few

that could

was postponed depression.

cardiotosicity

observed. Neuropathia

patients. be ascribed

of

mcas-

was

observed in either group, However, cardiac tion fraction studies have only been done changes

for

of W’CC

Five per cent ofAwkl{,

WCC

No planned

Clinical

plt

course

or plt pretreatment

below

or reduced

alopecia,

and

course

infection

more

or

lO”/l.

at one

had

1.5 X lo”/1 or 75 c 1O”/l respectively

seen.

course

125 x

who

patients.

had

one

L’(I P = 0.x I(, P = 0.oo.i

of WCC

patients of

13 I :3

of a planned

ranging mean

7’4 P -e 0.001

group

were not reported.

almost all VAC of toxicity (Table degree

Awkly

liver

bleeding

had

of the patients

in the

of Adrithe

2

mt’tastaws

postponement

were

a range

lasting for a few hours after one However, vomiting was reported

10%

of VAC

sitating

had 40%

had

approx.

mg.

Approximately

than

no

AwklylVAC.

mean

V’AC

was

indicates

four

liver

Pretreatment

was

therapy This

the

(FuMi)

evaluablc)

with

December

from

time of diagnosis.

therapy

previously.

of Adriamycin

80-960

lint

to primary

se/no

amycin

calculated

1) or from

to second

differences

Until

whether

L’

marrow

range

<:R

between

I

I’ c 1l.001

None Nausea

not ejrclately

Electrocardiographic to :\driamycin

was not seen among

were

Avykly patients

1434

S. Gundersen et al.

while

paresthesia

of VAC

of hand

or feet was seen in 20%

patients.

ported The

DISCUSSION The

groups

to age, There ents

of patients

disease

metastases

free

balanced

interval

is no significant

receiving rate,

a small

has little

from

an earlier

Hospital

The

to a relatively until

start

[l]. rate

The

advanced

stage

were

in

quently

disease

in the Awkly

a somewhat observed

for Awkly

Thirteen group

longer out

were

treatment (P = 0.03,

of the

recorded as opposed Fisher

some

cases

been

discontinued

treatment

was

for the be attri-

first mcta-

of disease

This

and

evaluable

could

to objective

patients

more test).

for Awkly too early.

study,

and with a WCC

VAC

patients notion

agent

every

Awkly on

normal counts

We

in

may have is sup-

week.

therapeutic solely

therapeutic cancer

aim

is optimal

and

from

negligible with

than

liver

patients

patients

regular

also for Awkly

therapy.

that

properly

cancer,

and

the

in cancer

of weekly however,

Awkly

evaluated should

improvement

of treatment

cancer

combination

patients

been

on the

as

side-effects

VAC

for these

life. This is very important,

experi-

breast

side-effects

advantage

to

in this

of Adriamycin

The

following

as a general principle

employed The

remains

patients

doses

to emphasize

has

breast

included

X lo”/1 on Awkly.

However,

like

only

advanced

not

are advisable

would

regimen

poss-

It is also pertinent

as the VAC

and

induced

liver mctastases,

more

liver,

all VAC

Awkly

for advanced

third

endure

blood

of

liver metastases,

to 0.9

therapy

are less than

with

in almost

cases

to be as effective

patients.

to VAC.

and

weekly

most

is

dif-

vomiting

extensive

for

that

3 months

single

regime

observed

important

patient

drop

metastascs

reflect

in the

one

enced

toxicity

observed

five

two regimes

most

to toxicity.

that

the

the 40%.

to nausea,

four had extensive

out

seem

The

were the

where

for the Awkly

considerable

regard

for fre-

Accordingly,

This

In

study

to be around

between

patients.

the

remission

than

to 8/24 among Exact

which

patients.

Awkly

more

as compared

19 remissions after

alopecia

delivered

(16 months),

reported

group. time

is with

In conclusion,

response. Progressive

VAC

point

reason

considered

among

Norwegian

from

to the

as shown rate

seems

lack of toxicity

ference

alopecia,

an ongoing

differences

ibly contributing

can possibly

long interval

to

recorded

The

of chemotherapy

all patients

main

to detect

response

to that from

pati-

or survival.

response

study

(35%)

stases

comparatively

for Awkly

as opposed

first

relation

power

interval.

low response

buted

in

statistical

is comparable

prospective

relatively

between

VAC

in treatment

for VAC

fact that

time

of remission

by the wide confidence

Radium

and

or

duration

difference

(36%)

well according

difference

Awkly

But the study

from

rate

is the relative

to randomization.

response

by data

response

in

not

be

therapy.

Adriamycin in quality

of

as the present

of advanced

palliation.

REFERENCES 1. Kvalery S, Gundersen S, Foss; SD, Eliassen G, Sjcrlie I, Hest H. Vincristine, Adriamycin, Cyclophosphamide (VAC) versus Prednimustine, Methotrexate, 5-FU (PMF) in advanced breast cancer. 3rd. EORTC Breast Cancer Working Conference, Amsterdam 1983. 2. Weiss AT, Metter GE, Fletcher WS, Wilson WL, Crage TB, Ramirez G. Studies on Adriamycin using a weekly regimen demonstrating its clinical effectiveness and lack of cardiac toxicity. Cancer Treat Rep July 1976, 60, 813-822. 3. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981, 4’7, 207-214. 4. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Manta1 N, McPherson K, Peto J, Smith PG. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Br J Cancer 1977, 13, 89-94.

breast