Folinic acid and 5-fluorouracil as adjuvant chemotherapy in colon cancer

GASTROENTEROLOGY 1994;106:699-906

Folinic Acid and 5-Fluorouracil as Adjuvant Chemotherapy Colon Cancer GUIDO

FRANCINI,*

ROBERTO

SALVATORE

ARMENIO,§

ANTONIETTA

AQUINO,*

LORENZO

MARIANI,”

and MARCO

PETRIOLI,*

GABRIELLO GIUSEPPE

DOMENICO

LUCIANO

TANZINI,§ MARZOCCA,’

DE SANDO,”

LORENZINI,’

STEFANIA

MANCINI,?

MARSILI,*

SERENELLA SERGIO

SERGIO

in

ClVlTELLl,5

BOVENGA,”

LORENZI?

*Institute of Medical Pathology, Medical Oncology Division, S. Maria della Scala Hospital; ‘General Surgery institute, and %linical Surgery Institute, Nuovo Policlinico Hospital; University of Siena; “General Surgery Division, Misericordia Hospital, Unita Sanitaria Locale n. 28, Grosseto. Italy

Background/Aims: Colon cancer is one of the major health problems in industrialized countries, and its incidence appears to be increasing. Surgical resectability is the most important prognostic determinant, although despite apparently curative surgery, recurrent tumors are common. Metastatic disease cannot be cured, and thus, there is a need for better adjuvant therapies. Methods:Two hundred and thirty-nine patients with surgically resected colon cancer in Dukes’ stage Bz or C were randomly assigned to chemotherapy or observation alone to determine whether adjuvant chemotherapy could effectively reduce the rate of cancer recurrence. One hundred and twenty-one patients in stage Bz and 118 patients in stage C were enrolled in the study. Adjuvant treatment consisted of folinic acid 200 mg/m’, intravenously, plus Huorouracil 400 mg/m’, intravenously, on days l-5 every 4 weeks for 12 cycles. Results: In stage B2, no significant difference between the adjuvant arm and the observation arm was noted. In stage C, adjuvant chemotherapy produced an advantage over observation in terms of a reduction in cancer recurrence rate with prolongation of a disease-free interval (P = 0.0016) and an improvement in overall survival (P = 0.0025). Conclusions: This study shows that folinic acid plus Sfluorouracil adjuvant chemotherapy is effective in patients with surgically resected Dukes’ stage C colon carcinoma.

C

olon cancer is one of the world’s major health prob-

lems, and the mainstay of therapy has been the surgical approach. The surgical pathological stage of the resected tumor is the most important prognostic determinant, and Dukes’ classification (or one of its modifications) is a commonly used staging system. About 90%95% of the patients with Dukes’ A and B, colon cancer are cured by surgical resection alone, but the great majority of patients present with Dukes’ stage BZ (invasion of serosa or pericolonic

fat) or C (metastasis

to regional

lymph

nodes), which

have a significantly

The failure of surgical

therapy

to the presence

of residual

micrometastases,

and there

oping

adjuvant

paring and

surgery

occult

disease

alone with

the majority

due

and distant

interest

in devel-

that will improve

prognosis

Several trials have been completed

immunotherapy,

However,

risk of

alone is probably

is much

treatments

in these patients.

higher

1.2

disease recurrence.

chemotherapy,

either

alone

com-

radiotherapy,

or in combination.

of these studies

failed to show a

significant advantage of adjuvant therapy over observation. Recently, a large study from the National Intergroup significant

by

Moertel

advantage

et

al.

showed

for a treatment

an

unequivocal

with 5-fluorouracil

(5-FU) plus levamisole of surgically resected colon cancer in Dukes’ stage C.3 Another study published in 1992 reported a significant advantage for patients in Dukes’ stage C treated with portal-vein adjuvant therapy (5-FU plus heparin).4 One of the major problems confronting physicians the treatment of colon cancer is chemoresistance.‘-’

in 5-

FU is the most active drug currently available for this disease, and its action is potentiated when it is combined with folinic acid (FA), which acts as a precursor to the folate cofactor for thymidylate synthetase.*.” Indeed, several current trials are attempting to determine the role of FA plus 5-FU as adjuvant chemotherapy, and preliminary results seem to be very promising.1°

the

After initial reports concerning the successful treatment of advanced colon carcinoma with combined FA and 5-FU,“9” we began a randomized study to evaluate Abbreviations used in this paper: CA 19-9, gastrointestinal antigen; CEA, carcinoembrional antigen; Cl, confidence interval; 5FU, 5fluorouracil; FA, folinic acid. 0 1994 by the American Gastroenterological Association 0016-5065/94/$3.00

900

FRANCINI

ET AL.

this schedule study

GASTROENTEROLOGY

as adjuvant

was to evaluate

reducing

chemotherapy. the effectiveness

the recurrence

resected

colon

observation

cancer

rate in patients in Dukes’ stage

The aim of this

minimum

of FA/5-FU

(epicolic,

in

with surgically

caval). Of the

B2 and C over

randomly

alone.

Materials and Methods The original

design

called

and 0.22, respectively,

with a significance

power of 80%.”

Despite

in recurrence

the present

results provide

mation

the potential

effectiveness

FU regimen.

Moreover,

the observed

rate of 0.17 of accrual due

important

infor-

of the FA and 5-

differences

were suffi-

ciently great to justify early reporting. The patients ological

were enrolled

diagnosis

had undergone

the purpose,

procedure,

their informed motherapy

disease.

All of the eligible

consent

before being randomly

Division. three

by means of a pre-established was entirely

The surgical

surgical

surgical

teams

technique.

chemotherapy patients

conducted

resection

therapy

according

3 months

of

who received

adjuvant

None of the

such as radiation.

of 12 cycles of FA 200 mglm*,

at 4-week

intervals.

Treatment

than 3 weeks after surgery. Patients whose cancer was located within

began

IV,

no later

12 cm of the anal

verge were excluded from the study. The primary aim of the study was to determine

recurrence

interval and survival were also evaluated. time was 4.5 years (range,

2.5-7.5

years).

12 months months

physical

examination,

and liver ultrasonography,

thereafter.

Colonoscopy

every

niques (chest radiograph, magnetic

lung,

was performed

and bone scan every 12 months. computed

resonance

liver, abdomen,

recurrence

brain,

ploratory

laparotomy

every 6

The imaging

tomography,

imaging,

colonoscopy,

bone

of disease recurrence

investigated

tech-

ultrasonogra-

or bone. All suspected

were histologically

scan) in the

cases of

by means of an ex-

in cases of abdominal

recurrence,

fine-

needle guided

biopsy in cases of liver and lung metastases

biopsy

fiberoptic

during

colonoscopy

of recurrence,

the tumoral

was reported.

For early

markers carcinoembryonal

(CEA) and gastrointestinal

measured

or

in cases of local recur-

rence. Only the first site of recurrence diagnosis

antigen

before surgery and at monthly

(CA 19-9)

intervals

were

thereafter.‘*

Statistics The 5-year estimates performed

using

significance

of the

patients

were enrolled

be-

are summarized

in Table 1. There was a good balance between the subgroups, although there were more well-differentiated tumors present in the treatment arm than in the control arm (49 vs. 45 in stage B, and 46 vs. 43 in stage C). Many of the stage C tumors to, or invasion of, surrounding

organs. Patients with stage C were stratified according to the number of regional lymph nodes involved (~4 vs. >4). A

and survival

were

of Kaplan

and

method

was used to assess the statistical

differences

between

survival

tions.15z’6 The Cox proportional-hazards

model

perform

recurrence

multivariate

analyses

as regard

distribu-

was used to rate and

survival.”

Toxicity Toxicity

was evaluated

by means of a five-point

based on World Health Organization mance was measured ventricular

was reduced tween January 1985 and December 1990. The principal characteristics of the patients

of recurrence

the product-limit

Meier. The log rank procedure

ejection

titis, diarrhea,

Patient Characteristics

in both arms showed adherence

of history,

the first year and every 6 months thereafter.

during

Treatment

thirty-nine

consisted

Abdominal computed tomography or magnetic resonance imaging was performed every 6 months in the first year and every

to the same pre-established

(IV), on days 1-5, plus 5-FU 400 mglm*,

Two hundred

58 were

and 60 to observation

in our Medical Oncology

intravenously

follow-up

to adjuvant

Follow-up

antigen

on days l-5,

The median

were

table.

were followed up in our institution.

rate, but disease-free

assigned

blood tests, chest radiograph,

of colon cancer was made by

All of the patients

therapy consisted

to che-

criteria

by the Ethical Committee

received any other initial treatment

Adjuvant

about

assigned

alone after eligibility

The trial, which was approved our Institute,

evi-

were informed

and risks of the study, and each gave

or observation

confirmed

patients

with any postoperative

The patients

60 were

therapy and 61 to the observa-

to adjuvant

were used to reveal the presence

curative en bloc colon cancer resec-

tion, and none of them presented dence of residual

and peri-

B2 lesions,

with stage C lesions,

phy,

in the study as soon as histopath-

was available.

a potentially

stage

randomly

of 80

level of 0.05 and a

the early termination

to loss of funding, regarding

assigned

with

were examined

paraaortic,

Follow-up

for the enrollment

a difference

121 patients

No. 4

alone.

per arm in stage B, and 64 patients per arm in stage

C to be able to detect

nodes for each patient

iliac, intercavoaortic,

tion arm; of the 118 patients

Study Design and Treatment patients

of 10 lymph paracolic,

Vol. 106,

criteria.”

by means of the pre-ejection time, according

was postponed or leukopenia

scale

Cardiac perforperiod/left

to Hassan and Turner.”

by 1 or 2 weeks if grade 2 stomaoccurred.

The chemotherapy

dose

by 50% if the side effects persisted.

Results After a median follow-up time of 4.5 years, 234 patients were evaluable (119 stage B, and 115 stage C). Three patients who were lost to follow-up immediately after surgery and two patients who had died of pulmonary embolism just after randomization were excluded from the analyses. To date, colon cancer has recurred in 30 patients over-

April 1994

ADJUVANT CHEMOTHERAPY IN COLON CANCER

Table 1. Characteristics

of Enrolled Patients Dukes’ stage B2 (n = 121)

chemotherapy

observation

Observation

FA/5-FU

Observation

60 59 55 33 27

61 60 57 27 34

58 57 56 31 27

60 58 59 35 25

-

-

30 28

34 26

39 21

35 26

39 19

37 23

60 60 2 0

61 61

1 0

12 46 15 4 6 1

13 47 18 3 8 0

49 11

45 16

46 12

43 17

and in 48

patients

arm. A total of 12 patients

between

sixth and the ninth cycle of chemotherapy.

control 35%

arm.

(95%

The

relative

confidence

vant treatment to recurrence

significantly (P = 0.005)

estimated

was

18%-52%).

Adju-

reduced the length

of time

1).

64 patients

5-year survival was 79%

had died. The

in the adjuvant

and 65%

in the control arm (P = 0.0044)

reduction

in the death rate by 34% (95%

(Figure

in the

in recurrence

ICI],

(Figure

At the end of follow-up,

5-year recur-

arm and 41%

reduction

interval

the

These patients

were included in the analysis. The estimated in the adjuvant

in the

arm

with a relative CI, 23%-45%)

subgroup

Nineteen

analysis for stage B2 and C are

the observation

arm (15

retroperitoneal, estimated

and 3 lung) experienced

5-year recurrence

in recurrence

was 44%

significant

difference

Univariate

abdominal,

83%

of patients

in the observation

At the end of follow-up, 5-year survival estimates

was a higher

in the adjuvant

to arm

jacent

After

arm.

in the adjuvant

arm

rate of local

a

arm with (Figure

3).

difference

be-

variables,

recurrence

usually reported.?

lymph in the 10.3%

A background

to be an independent

of local recurrence

adjustment

among

prognostic

analyses also showed a significant

in favor of the adjuvant

recurrence

signifi-

(P < 0.05).

for imbalances

multivariate

venting

arm were still alive. The

with

selection procedure revealed adherence and ad-

cant determinant

advantage

in the adjuvant

(P = 0.0016)

arm than one would ordinarily expect:

organ involvement

53 patients

were 89%

in the observation

According

3

interval

and those with less than four regional

arm were free of recurrence.

arm and 49 in the observation and 86%

arm (9 liver,

and 2 local) had recurrences.

5-year estimates, and 77%

in the observation

26%-62%/o),

nodes involved (P = 0.0058).

Eleven of the 59 assessable patients patients

CI,

tween patients with more than four regional lymph nodes

regression

assessable

3

The

arm. The relative reduction

(95%

analysis showed a significant

(6 of 58) vs. 5%-b% in the adju-

recurrences.

in favor of the adjuvant

regard to disease-free

in

6 local,

rate was 34% in the adjuvant

in the control

Stage B2 and 14 of the 60

3 local, 2 retroperito-

liver, 7 abdominal,

arm and 59%

observation

vant arm (10 liver and 1 abdominal)

in the adju-

neal, and 1 lung) and 34 of the 58 assessable patients

There

presented.

of the 57 assessable patients

vant arm (10 liver, 3 abdominal,

involved

2).

In addition,

Stage C

(7 in stage B2

and 5 in stage C) were lost to follow-up

rence rate was 26%

Dukes’ stage C (n = 118)

FA/S-FU Enrolled patients Evaluable patients Age (mean) Male Female No. of lymph nodes l-4 >4 Location of tumor left right Depth of invasion submucosa or muscular serosa Adherence to adjacent organs Invasion into adjacent organs Obstruction Perforation Histological differentiation good poor

all receiving

901

arm in terms of pre-

(P = 0.043).

To date, there were 41 surviving vant arm with

16 deaths,

the observation

arm with

patients

and 27 surviving 31 deaths.

in the adjupatients

in

The estimated

5-

902

GASTROENTEROLOGY Vol. 106. No. 4

FRANCINI ET AL.

diarrhea

(Table

the infusion

2). Chemical

phlebitis

vein of 46 patients

was observed

in

after 2-3 cycles of chemo-

therapy. Treatment

was postponed

for 1-2 weeks in 2 1 patients

(11 in stage B, and 10 in stage C) because of grade 213 diarrhea $!

40

i5 % ap

and/or

stomatitis

and leukopenia.

The chemo-

therapy dose was reduced by 50% in 5 patients (3 in stage B2 and 2 in stage C) because of persistent stomatitis

20

and diarrhea 1

o!,,,,,,,,,,,, 0

I

12

24

I

1141

I1

36

observed.

48

None

threatening

1. Disease-free interval in patients with stage B2 and C ran-

domized with adjuvant FA/SFU or with observation alone. In the FA/ 5FU group (-_), of 116 at-risk patients, 30 relapsed. In the observation group (-----), of 118 at-risk patients, 48 relapsed.

year survival rate was 69% in the adjuvant arm and 43% in the control arm (P = 0.0025), with a relative reduction

(P <

0.05)

included

the number

of the

the patients

care. No cardiotoxicity

patients

side-effects,

experienced

(Figure 4). for survival

of metastatic

nodes,

No

and there

related

deaths.

planned

cycles of chemotherapy.

any

was life-

patient

were no treatment-

refused

to complete

the

Discussion Colon

in death rate by 39% (95% CI, 22%-56%) The factors of prognostic significance

supportive

60

MONTHS

Flgure

after 9 cycles of chemotherapy;

received adequate

cancer is one of the most serious diseases

of our time; the treatment

of advanced

disease is seldom

useful for the patient and disappointing for the oncologist. Since 1982, we have treated many patients with metastatic disease, and although complete remission has been achieved in some cases, disease always recurred in

adherence and adjacent organ involvement, and histological differentiation. Multivariate analysis also showed a significant survival advantage for the adjuvant arm over

long-term follow-up.2o721 Surgery is the main therapy for colon cancer in Dukes’ stage A, B, and C, but many patients present with stages

observation

arm (P = 0.033).

Tumoral rence from or imaging

markers (CEA, CA 19-9) predicted recur1 to 6 months before clinical examination modalities in 68% who experienced liver

BZ and C, which have a high recurrence rate after potentially curative resection. The risk of recurrence is particu-

metastases

and in 36% who experienced

recurrences

in

larly high

in patients

with

metastatic

lymph

nodes at

resection (stage C).22 Consequently, there is great interest in developing adjuvant therapies that will improve disease-free intervals and survival in colon cancer. Many trials have been performed to evaluate the effec-

other sites.

Toxicity

tiveness of adjuvant The toxic effects of the adjuvant chemotherapy were acceptable and consisted chiefly of stomatitis and

radiotherapy,

chemotherapy,

immunotherapy,

either alone or in combination.

and

Some have

100

60-

‘-1

I_

9 -0 - __ L-1

< p

---------t-s.

_

5 v) ap

4o

20-

-.

I,,!,,,

0

I,,,

12

I

24

36

I,,I,,I

-.

48

60

MONTHS

2. Survival of patients with stage B2 and C randomized with adjuvant FA/SFU or with observation alone. In the FA/5-FU group (-), of 116 at-risk patients, 22 died. In the observation group (-----), of 118 at-risk patients, 42 died. Figure

I

0

81.8

I

12

a

I

I

I

24

I

I

36

,,,,,,I

I

48

60

MONTHS

Figure 3. Disease-free interval in patients with stage C randomized with adjuvant FA/5-FU or with observation alone. In the FA/5-FU group (-), of 57 at-risk patients, 19 relapsed. In the observation group (-----), of 58 at-risk patients, 34 relapsed.

April 1994

ADJUVANT CHEMOTHERAPY IN COLON CANCER

nation

seems to be essential

for adjuvant

903

effectiveness,

the mechanism responsible for the interaction between levamisole and 5-FU is still not clearly understood. Another

I-.__

recent

multicenter

trial

advantage in survival for patients treated with portal-vein adjuvant

1-l

--I_______ L____.

heparin)

over surgery

coagulation

system

has shown

a slight

in Dukes’ stage C therapy (5-FU plus

alone.4 The manipulation

may indeed

diminish

of the

secondary

tu-

mor formation. 40241However, the risks and technical difficulties of positioning and maintaining portal-vein cath-

O!,,,,,,,,,,,,,,,,,,,I 0

12

24

36

48

60

eters in place, as well as the complications therapy

MONTHS

in survival. Figure 4. Survival of patients with stage C randomized with adjuvant FA/5-FU or with observation alone. In the FA/S-FU group (-), of 57 at-risk patients, 16 died. In the observation group (---), of 58 at-risk patients, 31 died.

arising

from

itself, perhaps do not justify the small advantage Furthermore,

although

as adjuvant chemotherapy consisting of inflammatory tion, blood coagulation,

extensively

applied

to reduce postembolic response, complement fibrinolysis,

events activa-

and tissue damage,42

the 5-FU-heparin association has not led to consistent results in previous studies.4345 led to a slight reduction in the rate of recurrences, but most have highlighted the considerable toxicity of the treatments and have not shown an objective benefit, particularly in terms of overall surviva1.23-28 A meta-analysis,

The present

trial attempted

to determine

the value of

folinic acid plus 5-FU as an adjuvant treatment. Pharmacological studies have shown that the action of 5-FU is potentiated

by excess intracellular

folates resulting

in a

limited to the results of randomized controlled trials published up to 1987, revealed no significant advantage

tighter binding of the f-luorodeoxyuridylate-reduced folate complex to thymidylate synthase. This leads to the

from the adjuvant

prolonged

Many

trials

postoperative

therapy

of colorectal

have compared use of fluorinated

surgery

cancer.29 alone

pyrimidines

with

the

such as 5-

therapy

studies

colorectal

involved

the

combination

methyl-chloroethylcyclohexylnitrosurea,

of 5-FU or other

and drug

associations. 25233However, none of these trials showed that chemotherapy led to any statistically significant improvement

ported

of thymidylate

combination

seems to be justified

activity,

in comparison

which

is

as an adjuvant

by its significantly

with

5-FU

alone,

greater

in advanced

cancer.4749

In the primary patients

synthase,

synthesis.“.“”

analysis

randomized,

showed a significant

of this

FA

and

difference

study 5-FU

including

all

chemotherapy

in the recurrence

rate in

in survival.

More recent studies have shown a possible step forward in the adjuvant therapy of surgically resected colon cancer. The

for DNA

The use of the FA/5-FU

FU and floxuridine, because these drugs have been shown to be active in metastatic colorectal cancer.30-32 Other have

inhibition

essential

North

Central

the first evidence

Cancer

Treatment

of improved

survival

Group

in patients

a confirmatory National Intergroup Study later showed significant benefits in disease-free intervals and overall survival in patients treated with 5-FU and levamisole.3 has been

used for the treatment

2. Number

of Patients

Showing

Toxicity

re-

treated with levamisole plus 5-FU, and although these interesting results were not considered fully persuasive, 34

Levamisole

Table

Condition

World Health Organization grade

Stage B2 and C (n = 116)

Stomatitis

1 2-3 4 l-2 l-2 1 2-3 4 1 2-3 1 2-3 1 2-3 l-2

96 16 4 43 5 95 18 3 80 13 31 3 79 13 18

Nausea Vomiting Diarrhea

of hel-

minth infections in both domestic animals and humans, and it is presumed to have immunomodulatory activity. 35236It has also been evaluated in several malignant diseases as an adjuvant therapy, but its effectiveness has not been confirmed by any of these studies.3*27,37 Moreover, the use of the 5-FU and levamisole regimen shows no significant advantage over 5-FU alone in the treatment of advanced colorectal cancer.38,39 Although this combi-

Leukopenia Dermatitis Conjunctivitis Alopecia

NOTE. The toxicity scale is the worst World Health Organization grade experienced per patient.

904

FRANCINI ET AL.

GASTROENTEROLOGY Vol. 106. No. 4

favor of the adjuvant

arm after a median

years, with a longer disease-free vival. These data included cancer (it is known

follow-up

interval

of 4

and overall sur-

Dukes’ stage Bz and C colon

that stage B2 has a better prognosis

than stage C). Although

difference

vant arm and observation clusions, detect

between

the adju-

arm was noted in B, patients,

size was too small to allow any definite with

many

more

a significant

tumoral

markers,

patients

difference

being

advantage

FA/S-FU

therapy

achieved

in favor of the adjuvant

alone in reducing interval

It must

of

recurrence

rate with a longer

that the long-term

trials.3,36 This result prognostic

survival

in other

may be explained

in the control

in the treatment

recurstage C

arm in terms

the significant

advantage

of preventing

recurrence

(P = 0.043). These findings ated enhancement colon cancer, residual

suggest

that, in stage C, the FA-medi-

of 5-FU, which is effective in advanced

may also be effective

disease or distant

resection.

against

micrometastases

This seems to be supported

microscopic after surgical

by the observation

of more local recurrences

in the stage C patients

untreated

be emphasized

optimal

group. surgery

However,

was performed

was higher

Local recurrences

perforation,

the depth

wall, and, particularly,

of the

that the same

in all patients.

the rate of local recurrence

arm (10.3%) pect.

It must

in the observation

than one would correlate

with

ordinarily

obstruction

of penetration

through

adherence

to or invasion

exand

the bowel of sur-

rounding organs.51-53 In our study, we observed a normally expected percentage of obstruction, perforation, and invasion of serosa in the observation arm; moreover, patients with rectal cancer (which usually produces a high

local

quently,

recurrence

it is possible

rate)

were

excluded.54

Conse-

that the high local recurrence

rate

in our observation arm was due to the high percentage of tumors with adherence and adjacent organ involvement found to be a significant independent determinant of recurrence also in other studies3 The results

obtained

in patients

with stage C disease

of patients

in a

more homogeneous

The chemotherapy low-grade

mainly

leukopenia.

in the larger

Leukopenia

with

different

reaction

that but

due to the toxicity

plus 5-FU.

usually

Study,

penia and sepsis. Nevertheless, tients prematurely discontinued

leads to

it was seldom although

due to profound

one

leuko-

a large proportion of patreatment after a median and practical

problems

in the use of levamisole-fluorouraci1,3

the combination

do

from the results

Intergroup

death was observed

diar-

side-effects

levamisole,3,55

severe in the National

involved

of stomatitis, These

trial with levamisole

is the toxic

drug-related

tech-

schedules,

with FA plus 5-FU was well-tolerconsisted

not appear to be substantially reported

surgical

of chemotherapy

procedures.

ated, and toxicity

of 5 months

group than in the control group,

analyses confirmed

of the adjuvant

by the

arm.

there were more well-differentiated

multivariate

in the

factors that have influenced

rence rate and survival tumors

and follow-up

dose limitation

control arm was a little lower than that reported

Although

a sig-

arm over ob-

and overall survival.

be noted

unfavorable

a large number

dose and modality

for the prediction

study that allowed

our study, which is much smaller,

preparations,

tests were

procedure

trial

has the advantage of having been performed in a single center, characterized by centralized control of the histo-

rhea, and

disease-free

to accrue

niques,

CEA- and CA 19-P-positive

In stage C, adjuvant

adjuvant

the authors

logical

rate.50 As

in the larger

This latter study was a multicentric

to

recurrence.

servation

those reported

con-

necessary

in recurrence

useful in the follow-up

nificant

with

5-FU and levamisole.3

short time. Conversely

no significant

the sample

are comparable using

whereas

of folinic acid with fluorouracil

did not

give rise to any practical problem. Most of the patients received all 12 planned cycles, and only a small number of patients requested dose-limitation or delay after 9 cycles of chemotherapy. major thanks

Four patients

presenting

toxicity managed to complete to adequate supportive care.56

In conclusion,

with

chemotherapy

we believe that FA and 5-FU adjuvant

therapy can be safely offered to patients with stage C colon cancer. However, the question remains as to whether

the same results may also be achieved

after 6 or

9 cycles of chemotherapy.

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Received November 9, 1992. Accepted November 16, 1993. Address requests for reprints to: Guido Francini, M.D., Institute of Medical Pathology, Division of Medical Oncology, University of Siena, S. Maria della Scala Hospital, Piazza Duomo, 2, 53100 Siena, Italy. Fax: (39) 057743237. Supported in part by grants 89.04691.04 and 92.0217O.PF/39 awarded by the Italian National Research Council (CNR). The authors thank all the general practitioners and Internal Medicine Departments for their cooperation in making this study possible and in particular Professor Luciano Lorenzini, Director of the General Surgery Institute, for his enthusiastic collaboration from the beginning of the study, which allowed the completion of the entire project. The authors take this opportunity to give their best regards to Professor Lorenzini, who is currently Professor Emeritus of Clinical Surgery.