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EUROSCAN, a Randomized Trial of Vitamin A and
N-Acetylcysteine in Patients With Head and Neck Cancer
or Lung Cancer
Nico van Zandwijk, Otilia Dalesio, Ugo Pastorino, Nico de Vries,
Harm van Tinteren
For the European Organization for Research and Treatment of Cancer Head and
Neck and Lung Cancer Cooperative Groups
Background: Preclinical evidence suggests that retinoids and
antioxidants may prevent or delay the occurrence of cancer
in the upper or lower airways, but such effects have not been
reliably established in clinical studies. To assess the chemopreventive effects of vitamin A (retinyl palmitate) and Nacetylcysteine, we conducted a large randomized intervention study in patients with head and neck cancer or with lung
cancer, most of whom had a history of smoking. Methods:
From June 1988 through July 1994, a total of 2592 patients
(60% with head and neck cancer and 40% with lung cancer)
were randomly assigned to receive 1) retinyl palmitate
(300 000 IU daily for 1 year followed by 150 000 IU for a 2nd
year), 2) N-acetylcysteine (600 mg daily for 2 years), 3) both
compounds, or 4) no intervention. All statistical tests were
two-sided. Results: Of the patients, 93.5% had smoked tobacco at sometime in their lives (and 25% continued to
smoke after cancer diagnosis). After a median follow-up of
49 months, 916 patients were reported with an event (recurrence, second primary tumor, or death). No statistically significant difference was observed in overall survival or eventfree survival between patients who received retinyl palmitate
and patients who did not. Similarly, no difference was seen
in overall survival or event-free survival between patients
who received N-acetylcysteine and patients who did not.
There was a lower incidence of second primary tumors in the
no intervention arm, but the difference was not statistically
significant. Conclusion: A 2-year supplementation of retinyl
palmitate and/or N-acetylcysteine resulted in no benefit—in
terms of survival, event-free survival, or second primary
tumors—for patients with head and neck cancer or with
lung cancer, most of whom were previous or current smokers. [J Natl Cancer Inst 2000;92:977–86]
The link between tobacco exposure and cancer of the aerodigestive tract, which accounts for more than 30% of all cancer
deaths, is indisputable (1,2). Although in recent years smoking
prevention and cessation programs have achieved appreciable
results, the mortality from aerodigestive tract cancer is still unacceptably high. Therefore, other preventive strategies are urgently needed. Epidemiologic and experimental data (3–5) have
suggested that chemoprevention of aerodigestive tract cancer is
feasible, but the evidence of a beneficial effect in humans is still
limited. Compounds with potential chemopreventive properties,
such as retinoids and antioxidants, have been investigated by use
of nearly all of the available systems for testing anticarcinogenic
activity. Retinoids exert a strong regulatory effect on cell proliferation and differentiation and can inhibit malignant transJournal of the National Cancer Institute, Vol. 92, No. 12, June 21, 2000
formation and suppress tumor promotion, particularly in the
presence of carcinogens from tobacco smoke, such as benzo[a]pyrene (6,7).
Tobacco smoke is also a source of oxidative free radicals that
can damage DNA (8). Antioxidants have been shown to prevent
cellular damage and the subsequent development of cancer
by neutralizing free radicals (9,10). Interest has arisen, in particular, in N-acetylcysteine, an aminothiol and synthetic precursor of intracellular cysteine and glutathione, which has been
widely used in the past as a mucolytic agent and antidote against
paracetamol (acetaminophen)-induced hepatotoxicity. NAcetylcysteine has proven to be effective in decreasing the direct
mutagenicity of several chemical compounds by inhibiting the in
vivo formation of carcinogen–DNA adducts, DNA damage, and
urethane-induced lung tumors in mice (11–13).
The EUROSCAN Study (i.e., the European Study on Chemoprevention With Vitamin A and N-Acetylcysteine) was designed to test whether vitamin A (retinyl palmitate) and Nacetylcysteine could improve the prognosis of patients treated
for head and neck cancer or for lung cancer by preventing second primary tumors (14). Both categories of patients have a high
risk of developing a second cancer and represent a relevant
population for secondary preventive measures (15). Two earlier,
albeit relatively small, studies of 13-cis-retinoic acid and retinyl
palmitate in the same groups of patients (16,17) suggested that
these agents had protective activity, but large randomized chemoprevention trials with vitamin A and ␤-carotene in smokers
(18,19) failed to show any preventive effect.
PATIENTS
AND
METHODS
Study Design
The two agents studied have different mechanisms of action, and the combination was judged to be feasible without dose reductions or delays. A two-bytwo factorial design was chosen to allow the simultaneous investigation of
retinyl palmitate and N-acetylcysteine. Initially, the EUROSCAN Study also
included a pilot study on the effectiveness of six monthly bronchoscopies as a
screening tool for patients with laryngeal cancer. This part of the study was
closed because only a minority of patients agreed to participate (20).
Participants were randomly assigned to one of the following four arms: 1)
retinyl palmitate alone (300 000 IU daily for 1 year followed by 150 000 IU for
Affiliations of authors: N. van Zandwijk, O. Dalesio, H. van Tinteren, The
Netherlands Cancer Institute, Amsterdam; U. Pastorino, European Institute of
Oncology, Milan, Italy; N. de Vries, St. Lucas Hospital, Amsterdam.
Correspondence to: Nico van Zandwijk, M.D., Ph.D., The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands (e-mail:
[email protected]).
See “Appendix” section for list of participants in the EUROSCAN Study.
See “Notes” following “References.”
© Oxford University Press
ARTICLES 977
the 2nd year), 2) N-acetylcysteine alone (600 mg daily for 2 years), 3) the
combination of retinyl palmitate (300 000 IU daily for 1 year followed by
150 000 IU for the 2nd year) and N-acetylcysteine (600 mg daily for 2 years), or
4) no intervention (Fig. 1). The possibility of a placebo-controlled study was
discarded after considering the cost aspects and the distinct characteristics (smell
and side effects) of the two agents in the double-blind approach.
Randomization by the minimization technique (21) was performed centrally
by the European Organization for Research and Treatment of Cancer (EORTC)
Data Center. The patients were stratified according to institution, sex, smoking
(all tobacco) history (smokers versus nonsmokers and never smokers), previous
therapy (surgery, radiotherapy, or chemotherapy), and histology and location of
the primary tumor (larynx, oral cavity, or lung).
Patient Eligibility
To be eligible for the study, patients had to have non-small-cell lung cancer
(stages pT1–2, N0–1, and T3N0, according to the 1987 edition of the tumor–
node–metastasis [TNM] staging system, published by the Union Internationale
Contre le Cancer (22), cancer of the larynx (Tis, T1–3, and N0–1), or cancer of
the oral cavity (T1–2 and N0–1); had to have a performance status (World Health
Organization [WHO]) 0–2; and had to be treated with curative intent. Patients
with recurrent disease, synchronous multiple tumors, previous malignant disease, abnormal liver or renal function, hypertriglyceridemia, hypercholesterolemia, diabetes mellitus, hypertension, and recent or active peptic ulcer were
considered to be unsuitable for the study. Informed consent from all patients was
to be obtained according to institutional regulations. From June 1988 through
July 1994, a total of 2592 patients (60% with head and neck cancer and 40% with
lung cancer) from 81 institutions in 15 countries were randomly assigned.
Evaluation of End Points
Minimal follow-up requirements during the first 2 years after randomization
consisted of three monthly follow-up visits, with chest x-rays every 6 months.
For patients with laryngeal cancer, ear, nose, and throat examinations included
repeated laryngoscopies. For patients with oral cancer, follow-up investigations
included inspection of the oral cavity; no routine laryngoscopy was performed in
this category of patients. From years 3 through 10 after randomization, follow-up
was scheduled at 6-month intervals and chest x-rays were scheduled yearly. At
every follow-up visit, patients were asked about pill intake, side effects, concomitant medications, and smoking habits. Patients taking retinyl palmitate were
regularly checked for levels of serum enzymes, cholesterol, and triglycerides.
Primary end points were event-free survival, overall survival, and the occurrence of a second primary tumor. Carcinomas of the head and neck, lung,
esophagus, and urinary bladder were considered to be tobacco-related second
primary tumors. The study coordinators reviewed all first events. When inconsistencies or doubts arose, additional information was requested from the responsible physician, and the study coordinators discussed the case until a consensus was reached.
Statistical Considerations
The sample size was chosen to provide 90% power to detect a decrease from
10% to 5% in the rate of (tobacco-related) second primary tumors at 5 years
(significance level ⳱ .05; two-sided log-rank test). The number was increased to
take into account a possible dilution effect caused by 10% crossing-over (e.g.,
10% of the patients randomly assigned to retinyl palmitate not taking their pills
and 10% of the patients assigned to the no retinyl palmitate arms taking retinyl
palmitate). With continuous follow-up, sufficient number of events (recurrences,
second primary tumors, and deaths) would be observed to allow the detection of
a 20% reduction in the hazard ratios with 80% power (significance level ⳱ .05;
two-sided log-rank test). Therefore, at least 2000 patients were to be entered and
followed for at least 5 years (500 patients per arm).
In the factorial design, the effect of N-acetylcysteine could be evaluated by
comparing patients randomly assigned to receive N-acetylcysteine (half with
retinyl palmitate and half without retinyl palmitate) with patients randomly
assigned not to receive N-acetylcysteine (half with retinyl palmitate and half
without retinyl palmitate). This comparison was done by stratifying by the presence or absence of retinyl palmitate. In a similar way, the effect of retinyl
palmitate was evaluated by stratifying by the presence or absence of Nacetylcysteine.
Event-free survival, time to second primary tumor, and survival curves were
constructed by the Kaplan–Meier technique (23) and were compared by the
log-rank test (24). The interaction between the effects of N-acetylcysteine and
those of retinyl palmitate was tested with a proportional hazards model. Also,
analyses of four arms were performed. All analyses were intention-to-treat
analyses. All statistical tests were two-sided, and P values of results referred to
as statistically significant were less than .05.
RESULTS
Patients
Fig. 1. CONSORT diagram.
978 ARTICLES
Of the 2592 patients who were randomly assigned, 19 (0.7%)
were excluded from all tables and analyses because no information was received after registration as depicted in the CONSORT
diagram (Fig. 1). Of the remaining 2573 patients, 1290 were
assigned to retinyl palmitate arms (647 to retinyl palmitate alone
and 643 to retinyl palmitate and N-acetylcysteine) and 1283
were assigned to no retinyl palmitate arms (641 to no treatment
and 642 to N-acetylcysteine alone). The same patients can also
be grouped with respect to treatment with N-acetylcysteine as
follows: 1285 patients were assigned to N-acetylcysteine arms,
and 1288 patients were assigned to no N-acetylcysteine arms.
Table 1 shows the characteristics of patients as a function of
treatment. Sixty percent of the patients had head and neck cancer
(1065 patients had laryngeal cancer, and 485 had oral cancer),
and 40% (1023 patients) had lung cancer. The majority of patients had been treated for a stage I tumor. The median age was
61 years, 13.0% were female, and 6.5% reported that they had
never smoked. In the majority of patients, the primary treatment
consisted of surgery alone or surgery in combination with raJournal of the National Cancer Institute, Vol. 92, No. 12, June 21, 2000
Table 1. Patient characteristics at randomization and treatment
Treatment*
Patient characteristics at randomization
Total
No. (%)
Retinyl + NAC
Retinyl
NAC
No drugs
Total No. of patients
Male
Female
643
560
83
647
563
84
642
556
86
641
559
82
Median age, y (range)
61 (23–83)
61 (23–83)
61 (28–86)
60 (19–91)
601
42
605
42
598
44
601
40
2405 (93.5)
168 (6.5)
150
74
41
143
88
39
134
87
47
127
97
38
554 (52.0)
346 (32.5)
165 (15.5)
47
55
21
56
41
26
40
50
30
51
48
20
194 (40.0)
194 (40.0)
97 (20.0)
179
53
23
196
38
20
197
39
18
204
37
19
776 (75.9)
167 (16.3)
80 (7.8)
Prior treatment, No. of patients‡
Surgery
RT
Surgery + RT
357
202
84
376
184
87
370
183
89
372
177
92
1475 (57.3)
746 (29.0)
352 (13.7)
Months between treatment and randomization
Unknown
<2
2–12
>12
316
230
97
331
209
107
1
337
194
110
314
219
108
1 (0.0)
1298 (50.4)
852 (33.1)
422 (16.4)
No. of former/current smokers
No. of never smokers
Site of tumor, No. of patients†
Larynx
Stage I
Stage II
Stage III
Oral cavity
Stage I
Stage II
Stage III
Lung
Stage I
Stage II
Stage III
2573
2238 (87.0)
335 (13.0)
61 (19–91)
*Retinyl ⳱ retinyl palmitate; NAC ⳱ N-acetylcysteine.
†According to tumor–node–metastasis (TNM) classification (Union Internationale Contre le Cancer, 1987).
‡Eighty-seven patients (3.4%) received chemotherapy in addition to local treatment (mainly before surgery). RT ⳱ radiation therapy.
diotherapy. A minority (3.4%) of patients received chemotherapy in addition to local treatment. Half of the patients were
enrolled in the study shortly after treatment (within 2 months),
and 16.4% of the patients had been treated for longer periods
before randomization (>12 months).
Follow-up
In total, more than 19 000 control visits were reported. Seventy-seven percent of these visits were on schedule. The mean
follow-up intensity (calculated per patient as the number of days
in follow-up divided by the number of follow-up visits) was 189
days in the combined arm, 179 days in the retinyl palmitate
alone arm, 186 days in the N-acetylcysteine alone arm, and
somewhat longer (193 days) in the no treatment arm. The total
follow-up was 8923 person-years (person-years ⳱ the total observation time added over all subjects, expressed in years) and
was well balanced across treatment arms (2213 years in the
retinyl palmitate alone arm, 2249 years in the retinyl palmitate
and N-acetylcysteine arm, 2230 years in the N-acetylcysteine
alone arm, and 2232 years in the no treatment arm). The year of
last follow-up was distributed similarly across treatment arms.
Of the 93.5% of the patients who enrolled in the study with
a smoking history, 25% continued to smoke after the diagnosis
(9.4% admitted that they continued to smoke, and 15.6% reported periods when they resumed smoking) and 72.3% had
permanently stopped (no information was obtained for 2.7% of
the patients). These percentages were similar in all four arms of
the study.
Journal of the National Cancer Institute, Vol. 92, No. 12, June 21, 2000
Compliance, Side Effects, and Concomitant Medication
Of the 1932 patients randomly assigned to receive trial medication, 444 (23%) did not complete the intended 2-year intervention period. Of the 643 patients randomly assigned to receive
retinyl palmitate and N-acetylcysteine, 162 (25.2%) stopped
treatment; of the 647 patients randomly assigned to receive retinyl palmitate only, 167 (25.8%) stopped treatment; and of the
642 patients randomly assigned to receive N-acetylcysteine only,
115 (17.9%) stopped treatment. Stopping treatment was more
frequent in the two groups assigned to retinyl palmitate
(P<.001). For 250 (13%) of 1932 patients, the drug intake was
recorded as being irregular at least once during the 2-year intervention.
Overall, retinyl palmitate elicited more side effects than Nacetylcysteine (P<.001). Side effects were reported by 45% of
the patients in the two retinyl palmitate arms and by 24% of the
patients in the N-acetylcysteine alone arm. Typical side effects
of retinyl palmitate were mucocutaneous (dryness, desquamation, itching, bleeding, and hair loss). Side effects of the Nacetylcysteine arms were more frequently related to the digestive tract (mainly dyspepsia). Severe side effects were also more
frequent in the retinyl palmitate arms (Table 2).
On a few occasions, “other” side effects (e.g., anemia, dizziness, dyspnea, mental symptoms, chills, diffuse pain, and vertigo) were reported. These effects, however, were considered to
be unrelated to the study medication.
Co-medication was recorded on the follow-up forms of 52%
ARTICLES 979
Table 2. Worst degree of toxicity per patient*
Treatment
Retinyl + NAC
Type of toxocity
Gastrointestinal
Skin
Malaise
Transient liver enzyme elevation
Hypercholesterolemia
Bone pain
Other
Retinyl
NAC
Grade 3
Grade 4
Total No.
Grade 3
Grade 4
Total No.
Grade 3
Grade 4
Total No.
Grand
total No.
22
23
—
—
1
1
3
25
20
1
3
2
1
5
47
43
1
3
3
2
8
13
28
1
—
—
2
10
19
22
4
2
2
—
5
32
50
5
2
2
2
15
19
5
1
1
—
—
2
25
6
1
—
—
—
1
44
11
2
1
—
—
3
123
104
8
6
5
4
26
*Retinyl ⳱ retinyl palmitate; NAC ⳱ N-acetylcysteine.
of the patients. From these 1338 patients, a sample of 342 (26%),
balanced for treatment groups and institution, was selected. The
names of the co-medications were translated into generic terms
according to the Anatomical Therapeutic Chemical Classification (25), and the co-medications were labeled if they belonged
to a category with chemopreventive potential (vitamins, various
brands of N-acetylcysteine, and other antioxidants). Of all the
medications specified, 129 of 3125 compounds were found to
belong to the same category as the study drugs (antioxidants or
vitamin A-like). Within the sample, 15 (4%) of 342 patients
were taking these co-medications.
Event-Free Survival, Overall Survival, and Second
Primary Tumors
At 5 years, 58% of the patients with lung cancer, 83% of the
patients with cancer of the larynx, and 77% of the patients with
oral cancer were alive (Fig. 2).
Fig. 3 presents the survival curves for groups that did or did
not receive N-acetylcysteine and for groups that did or did not
receive retinyl palmitate. There were 328 deaths in the groups
that received N-acetylcysteine and 304 deaths in the groups that
did not. There were 318 deaths in the groups that received retinyl
palmitate and 314 deaths in the groups that did not. For both
compounds, no statistically significant differences in survival
Fig. 2. Overall survival by site of the primary tumor.
980 ARTICLES
were detected (P = .925). The statistical test for interactions was
not statistically significant, indicating that the effect of retinyl
palmitate on survival did not depend on the presence or absence
of N-acetylcysteine. Comparison of survival curves, considering
the four arms of the study as separate groups, also did not show
statistically significant differences.
Table 3 summarizes the first events (recurrence, second primary tumor, or death) observed in the four arms. A total of 632
patients were reported dead. Among the 1290 patients randomly
assigned to receive retinyl palmitate, there were 465 first events;
among the 1283 patients assigned to receive no retinyl palmitate,
there were 451 first events. Among the 1285 patients assigned to
receive N-acetylcysteine, there were 468 first events; among the
1288 patients assigned to receive no N-acetylcysteine, there
were 448 first events. After a median follow-up of 49 months,
916 (36%) of the 2573 patients were reported with at least one
event. In 133 (15%) patients, the first event was death. In 572
(62%) patients, the first event was tumor recurrence. In 211
(23%) patients, the first event was a second primary tumor (116
in the N-acetylcysteine groups, 95 in the no N-acetylcysteine
groups, 115 in the retinyl palmitate groups, and 96 in the no
retinyl palmitate groups). In five of these patients, however,
even after re-evaluation, it remained unclear whether the event
was a second primary tumor or a recurrence of disease. In 154
patients (83 in the N-acetylcysteine groups, 71 in
the no N-acetylcysteine groups, 77 in the retinyl
palmitate groups, and 77 in the no retinyl palmitate groups), the second primary tumor was tobacco related. Twenty-nine additional second primary tumors were reported after recurrence of
disease (six in the group receiving retinyl palmitate and N-acetylcysteine, seven in the group receiving retinyl palmitate, seven in the group receiving N-acetylcysteine, and nine in the group
receiving no intervention). There was a lower,
but not statistically significant, incidence of second primary tumors in the no intervention arm.
The incidence rate for all second primary tumors
was 0.027 per person per year, and the rate for
tobacco-related second primary tumors was 0.019
per person per year.
Table 4 summarizes the type of second primary tumor as first event by the site of the primary tumor. The most frequent sites for second
primary tumor were the lung and the head and
neck regions. Event-free survival curves are preJournal of the National Cancer Institute, Vol. 92, No. 12, June 21, 2000
a second primary tumor from recurrent disease,
analyses of time until local failure or second primary tumor were also performed. These analyses
revealed no statistically significant differences
when all four arms were considered individually
or two by two. Analyses considering all second
primary tumors, regardless of whether they occurred as a first event or after a recurrence, gave
similar results (log-rank test for the global comparison of the four arms, P = .054).
In an attempt to consider actual drug intake,
the same analyses were also performed by taking
into account compliance as baseline covariates.
These analyses showed consistently similar results, suggesting that lack of compliance did
not play a major role in the negativity of the
results.
Event-free survival, survival, and time to second primary tumor were compared by treatment
(N-acetylcysteine versus no N-acetylcysteine and
retinyl palmitate versus no retinyl palmitate)
within subgroups. The subgroups were defined
by the presence or absence of the other treatment,
site of disease, prior treatment, performance status, sex, smoking habits, and interval between
treatment of the primary tumor and random assignment. These analyses should be considered
exploratory because they were not planned before
the study was initiated.
For the groups receiving N-acetylcysteine, the
hazard ratios of event-free survival, survival, and
tobacco-related second primary tumor are summarized in Fig. 5, A–C. For the groups receiving
retinyl palmitate or no retinyl palmitate, the hazard ratios of event-free survival, survival, and tobacco-related second primary tumor are summarized in Fig. 5, D–F. The confidence intervals for
all subgroups cross the no-effect line, indicating
Fig. 3. A) Overall survival by treatment (N-acetylcysteine [NAC] versus no N-acetylcysteine). B) no differences beyond what could be consistent
with chance for these groups. In addition, analyOverall survival by treatment (retinyl palmitate [retinyl] versus no retinyl palmitate).
ses by stage of disease within the three tumor
sites were performed and did not suggest any
sented in Fig. 4. No statistically significant differences were particular heterogeneity of results (data not shown).
observed when analyzed according to the factorial design (Nacetylcysteine versus no N-acetylcysteine, P ⳱ .631; retinyl DISCUSSION
In contrast to expectations, the EUROSCAN Study has not
palmitate versus no retinyl palmitate, P ⳱ .672) or when analyzed by the four separate arms (P ⳱ .750), and no statistically shown any benefit for a 2-year supplementation with retinyl
significant interaction was found between retinyl palmitate and palmitate and/or N-acetylcysteine in a population at risk for
second primary tumors and tumor recurrences in the upper and
N-acetylcysteine (P ⳱ .365).
Log-rank test results of time to second primary tumor and lower airways. This population was predominantly made up of
time to tobacco-related second primary tumor for N- former or current smokers. This observation was made when the
acetylcysteine versus no N-acetylcysteine stratifying for retinyl whole group was analyzed or when patients with head and neck
palmitate were not statistically significantly different (P ⳱ .190 cancer or lung cancer were analyzed separately. The 2-year duand P ⳱ .394, respectively). Similar results were found for ration of the intervention and the dosage of the trial medications
retinyl palmitate versus no retinyl palmitate stratifying for N- appear appropriate, considering that the relatively large number
acetylcysteine (P ⳱ .173 and P ⳱ .978, respectively). The tests of patients experiencing side effects resulted in approximately a
for interactions were, however, statistically significant (P ⳱ quarter of the patients not completing the 2-year intervention
.012 and P ⳱ .039, respectively). When all four arms were period. No statistically significant differences in survival or
considered, the number of second primary tumors (tobacco- event-free survival were found between the patients when those
related and overall) was lower in the control group (log-rank receiving retinyl palmitate were compared with those receiving
tests for the global comparisons of four arms P ⳱ .174 and P ⳱ no retinyl palmitate, when those receiving N-acetylcysteine were
.025, respectively). Considering the difficulties in differentiating compared with those receiving no N-acetylcysteine, and when
Journal of the National Cancer Institute, Vol. 92, No. 12, June 21, 2000
ARTICLES 981
Table 3. Events by treatment*
Retinyl + NAC
Follow-up status
No.
%
No. of patients
643
No. of deaths
161
No. of patients with at least one event
Retinyl
NAC
No.
%
100.0
647
25.0
157
231
35.9
78
60
10
54
35
29
Type of first event, No. of patients
Local/regional recurrence
Distant metastases
Local recurrence + distant metastases
SPT†
Local recurrence + SPT
Tobacco-related SPT (% from SPTs)
Death
No drugs
No.
%
100.0
642
24.3
167
234
36.2
33.8
26.0
4.3
23.4
92
39
7
61
39.3
16.7
3.0
26.1
64.8
12.6
42
35
68.9
15.0
Total
No.
%
No.
%
100.0
641
100.0
2573
100.0
26.0
147
22.9
632
24.6
237
36.9
214
33.4
916
35.6
68
53
16
61
1
48
38
28.7
22.4
6.8
25.7
0.4
77.4
16.0
93
45
11
32
2
29
31
43.5
21.0
5.1
15.0
0.9
85.3
14.5
331
197
44
208
3
154
133
36.1
21.5
4.8
22.7
0.3
73.0
14.5
*The numbers according to the factorial design (N-acetylcysteine [NAC] versus no NAC and retinyl palmitate [retinyl] versus no retinyl palmitate) can be obtained
by adding the appropriate columns of Table 4.
†STP ⳱ second primary tumor.
Table 4. Site of second primary tumor as first event by the site of the
initial tumor
Site of initial tumor
Larynx
Oral cavity
Lung
No.
%
No.
%
No.
Total
88
100.0
50
100.0
73
Tobacco-related SPTs*
Head and neck
Esophagus
Lung
Urinary bladder
Kidney
Unknown
16
3
37
2
1
18.2
3.4
42.0
2.3
1.1
22
2
16
44.0
4.0
32.0
8
1
39
5
1
11.0
1.4
53.4
6.8
1.4
1
2.0
46
6
92
7
2
1
21.8
2.8
43.6
3.3
0.9
0.5
5
1
10.0
2.0
12
16.4
1
1
1
2.0
2.0
2.0
1
2
1.4
2.7
4
5.5
27
3
9
5
1
12
12.8
1.4
4.3
2.4
0.5
5.7
Other SPTs
Gastrointestinal
Nasal cavity
Lymphoma/leukemia
Breast
Soft-tissue sarcoma
Prostate
10
2
8
2
11.4
2.3
9.1
2.3
7
8.0
%
Total
No.
%
100.0 211 100.0
*SPT ⳱ second primary tumor.
those in the four treatment groups were considered separately.
The distribution of end points according to the four arms (Table
4) revealed a lower incidence of second primary tumors in the no
intervention group compared with the intervention arms. The
lower incidence of second primary tumors appears to be counterbalanced by a higher frequency of relapses and could perhaps
also be partly explained by the lower follow-up frequency in the
no intervention arm.
The incidence of second primary tumors in the EUROSCAN
Study was approximately what was described in previous series
of patients (15,26), with the exception of a recent report (27) on
a similar group of patients with lung cancer who had a considerably higher rate. Differentiation between second primary tumors and recurrences (especially when the new lesion occurs
near the original tumor site) or between second primary tumor
and solitary metastasis (in case of similar histology) is difficult
and sometimes impossible (15). Ideally for a definite diagnosis,
new molecular methods (28) should have been used. However,
this technology was not yet available for implementation in a
large multicenter trial, such as the EUROSCAN Study. Al982 ARTICLES
though all first events in the study were centrally reviewed, a
certain degree of misclassification cannot be excluded. Therefore, emphasis was put on incontestable end points, such as
overall survival and event-free survival.
Results of the EUROSCAN Study do not confirm the positive
outcomes of previous studies with retinyl palmitate (17) and
13-cis-retinoic acid (16), suggesting preventive activity in patients who have had non-small-cell lung cancer or head and neck
cancer treated with curative intent. These studies were small and
had a shorter follow-up (32 and 46 months versus 49 months)
and a shorter intervention period. Two other relatively small
studies (29,30) in which patients with head and neck cancer were
treated with retinoids (retinyl palmitate and etretinate) have also
failed to show a decrease in the number of second primary
tumors. It is, therefore, not surprising that doubt about the potential of vitamin A to prevent cancer has increased (31).
Other large-scale prevention studies in noncancer populations
have pointed to the complexity of the chemoprevention approach. An unexpected high frequency of lung cancer was found
in the intervention arms of two major placebo-controlled trials of
␤-carotene in populations of predominantly cigarette smokers—
the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study and the Beta-Carotene and Retinol Efficacy Trial
(CARET) (18,19). In a third large double-blind study of 22 071
healthy males, who were mainly nonsmokers, again no preventive effect of long-term (12 years) supplementation with ␤-carotene was observed (32). In this study, an increased incidence
of lung cancer associated with ␤-carotene prescription was not
observed, which led to the conclusion that ␤-carotene might
elicit adverse effects only in smokers (33). Recent animal experiments (34) seem to confirm this suggestion. In addition, in
the EUROSCAN Study, a negative effect of the prescription of
retinyl palmitate or N-acetylcysteine on the incidence of second
primary tumors cannot be excluded. The fact that fewer second
primary tumors were seen when the N-acetylcysteine and retinyl
palmitate were combined, however, suggests an artifact, perhaps
caused by the multiplicity of analyses and a consequent increase
in the probabilities of error.
In the 1980s when the EUROSCAN Study was planned, comparative trials with traditional clinical end points were considered the best means to test candidate chemopreventive agents. In
the light of current knowledge, it might be questioned at what
Journal of the National Cancer Institute, Vol. 92, No. 12, June 21, 2000
Data management and statistics: A. Kirkpatrick
(European Organization for Research and Treatment of
Cancer [EORTC] Data Center, Brussels, Belgium); O.
Dalesio, J. Dijkstra, and H. van Tinteren (The Netherlands Cancer Institute, Amsterdam); and R. Parentela
(Istituto dei Tumori, Milan, Italy)
Advisor: S. Piantadosi (The Johns Hopkins Hospital, Baltimore, MD)
The study took place during the chairmanships of G.
B. Snow and J.-L. Lefebvre (EORTC Head and Neck
Cooperative Group) and J. G. McVie, N. van Zandwijk, and G. Giaccone (EORTC Lung Cancer Cooperative Group).
The participants who collaborated in the
EUROSCAN Study are, in order of number of patients
accrued in the study, as follows: G. B. Snow, M. P.
Copper, and N. de Vries (Free University, Amsterdam,
The Netherlands); G. J. Hordijk and H. Lubsen (Academic Hospital, Utrecht, The Netherlands); U. Pastorino, C. Grandi, M. Infante, and P. Salvatori (Ist
Nazionale per la studio dei Tumori, Milan, Italy); F. J.
M. Hilgers, A. J. M. Balm, and N. van Zandwijk (The
Netherlands Cancer Institute, Amsterdam); J. Jerman
(University of Ljubljana, Slovenia); I. Spasova (Institute of Respiratory Diseases, Prague, Czechoslovakia);
R. G. J. R. A. Vanderschueren (St. Antonius Ziekenhuis, Nieuwegein, The Netherlands); F. Lunghi (Monselice Hospital, Padua, Italy); J. Castella (Hospital de
la Santa Creu I Sant Pau, Barcelona, Spain); G. Chiesa
and M. Maioli (Ospedale Niguarda Ca Granda, Milan,
Italy); G. P. M. ten Velde (Academic Hospital Maastricht, The Netherlands); M. Maffioli and R. Piantanida
(Ospedale di Circolo, Varese, Italy); H. Maier (Universität Heidelberg, Germany); H. Szpirglas (Centre
Hospitaliere Universitaire Pitié Salpétrière, Paris,
France); J. P. van Meerbeeck (Universitair Ziekenhuis Antwerpen, Edegem, Belgium); A. Dundar
(Gulhane M. Medical Academy, Ankara, Turkey);
J. Pawlega, M. Krzysztof, and K. Krzemieniecki
(Institut Onkologii, Krakow, Poland); P. Giannobi
(Nuovo Ospedale San Gerardo, Monza, Italy); L.
Barzan (Centro di Riferimento Oncologico, Aviano
Pordenone, Italy); E. Jassem (Medical Academy of
Fig. 4. A) Time to first event by treatment (N-acetylcysteine [NAC] versus no N-acetylcysteine).
Gdánsk, Poland); Z. Skacel (2nd Clinic for TuberB) Time to first event by treatment (retinyl palmitate [retinyl] versus no retinyl palmitate).
culosis and Chest Diseases, Prague, Czechoslovakia);
V. M. S. A. Vieira (Hospital Pulido Valente, Lisbon,
stage large-scale, randomized studies should be initiated. Recent Portugal); M. Virag (Klinici Bolnicki Centar, Zagreb, Croatia); G.
developments in molecular biology have provided the opportu- Andry (Institut Jules Bordet, Brussels, Belgium); F. M. L. H. G. Palmen
nity for carefully designed developmental protocols through (St. Elizabeth Ziekenhuis, Tilburg, The Netherlands); C. Domenge (Inwhich potential chemopreventive agents could be guided stitute Gustave Roussy, Villejuif, France); F. Cianfriglia (Istituto
through phase I and II studies using intermediate end points that Regina Elena, Rome, Italy); G. Scagliotti (Universita di Torino,
Orbassano, Italy); S. Staemars (Mutterhaus der Borromaerinnen, Trier,
could lead to a more rational selection of agents for comparative
Germany); A. Personeni (Ospedali Riuniti di Bergamo, Italy); T. S. van
studies (35).
der Werf (Akademisch Ziekenhuis, Groningen, The Netherlands);
Carcinogenesis is a multistep process occurring over many C. Berardi (Ospedale di Garbagnate Milanese, Milan, Italy); P. Drings
years, with a latent period (i.e., the period between the start of (Thoraxklinik Rohrbach, Heidelberg, Germany); B. Cottier (Clattercarcinogenesis and the occurrence of clinical cancer) that has bridge Hospital, Merseyside, U.K.); K. Bujko (Oncology Centre Instibeen estimated to be at least 10 years long. Therefore, subjects tute, Warszawa, Poland); G. Ralza (Clinica ORL, Trieste, Italy); S. J.
in cancer prevention trials, such as the EUROSCAN Study, Brockmeier (Klinikum rechts der Isar, Munich, Germany); T. Lewinski
should be followed for periods of at least 10 years to reach (M. Slodowska-Curie Cancer Center, Warszawa, Poland); P. Espana
(Clinica Puerta de Hierro, Madrid, Spain); R. Bastus (Hospital de
definite conclusions.
Mutua de Terrassa, Barcelona, Spain); A. Ravaioli and E. Pasquini
APPENDIX: PARTICIPANTS IN THE EUROSCAN STUDY (Ospedale Civile Rimini Div Oncologia, Italy); M. Clerici (Ospedale
San Carlo Borromeo, Milan, Italy); J.-M. Brechot (Hôtel-Dieu de
Study coordinators: U. Pastorino (European Institute of Oncology, Paris, France); W. Bergler (Klinikum der stadt Mannheim, Germany);
Milan, Italy), N. de Vries (St. Lucas Hospital, Amsterdam, The Neth- J.-L. Lefebvre (Centre Oscar Lambert, Lille, France); G. S. Kho
erlands), and N. van Zandwijk (The Netherlands Cancer Institute, Am- (Dijkzigt Hospital, Rotterdam, The Netherlands); J. Dolensky (Thosterdam).
mayer’s Teaching Hospital, Prague, Czechoslovakia); F. van Breukelen
Journal of the National Cancer Institute, Vol. 92, No. 12, June 21, 2000
ARTICLES 983
Fig. 5. A–C) Event ratios by treatment (N-acetylcysteine [NAC] versus no N-acetylcysteine) within subgroups of patients. A) First event.
B) Mortality. C) Second primary cancer (tobacco related). For each
subgroup and each end point, the ratio of the appropriate hazard rates
of the treatment (N-acetylcysteine) versus the control (no Nacetylcysteine) is plotted as a solid square. Its size is proportional to
the amount of information concerned, so that subgroups with more
patients and events are represented by larger squares. The vertical
lines correspond to ratios of 1.0 that appear when results of treatment
and control are similar. Ranges smaller than 1.0 (to the left of the
vertical lines) are compatible with better results in the treatment arm;
ranges larger than 1.0 favor the control arm. A confidence interval
(99% for each subgroup) is depicted for every ratio as a horizontal
line through the square. If a confidence interval contains the 1.0, then
the vertical 1.0 line and the confidence interval line cross and the
comparison of treatment results in the particular group is not statistically significant at 1%. This level of significance was chosen to take
into account the increased probability of error due to multiple testing.
The overall result of N-acetylcysteine versus no N-acetylcysteine and
its 95% confidence interval is plotted as a diamond. D–F) Event ratios
by treatment (retinyl palmitate [retinyl] versus no retinyl palmitate)
within subgroups of patients. D) First event. E) Mortality. F) Second
primary cancer (tobacco related). Obs ⳱ observed events; Exp ⳱
expected events; O – E ⳱ observed minus expected; CI ⳱ confidence
interval; RT ⳱ radiation therapy; PS ⳱ Eastern Cooperative Oncology Group/World Health Organization performance status. **Time
since treatment of primary tumor.
984 ARTICLES
Journal of the National Cancer Institute, Vol. 92, No. 12, June 21, 2000
Journal of the National Cancer Institute, Vol. 92, No. 12, June 21, 2000
ARTICLES 985
(Spaarne Ziekenhuis, Haarlem, The Netherlands); and X. Panis (Centre
Jean Godinot, Reims, France).
(22)
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NOTES
The authors are the writing committee for the EUROSCAN Study. The writing committee assumes responsibility for the integrity of this manuscript on
behalf of the participants in the EUROSCAN Study (see “Appendix” section
preceding “References”).
The EUROSCAN Study was funded by support from the European Organization for Research and Treatment of Cancer (EORTC) to the EORTC Data
Center and from The Netherlands Cancer Institute to the Biometrics Department
and by three separate grants from the European Commission—Directorate General V—Programme “Europe Against Cancer.” Financial support for meetings
was received from Zambon (Milan, Italy).
Zambon provided N-acetylcysteine, and Mucos (Geretsried, Germany) provided retinyl palmitate.
Manuscript received July 19, 1999; revised March 29, 2000; accepted April
13, 2000.
Journal of the National Cancer Institute, Vol. 92, No. 12, June 21, 2000