letters to the editor
Is it deleterious to delay the start
of adjuvant chemotherapy in
colon cancer stage III?
Annals of Oncology
chemotherapy can for ethical reasons never be tested in
a randomised trial, since a delay beyond what is reasonable
for postoperative recovery can only be detrimental.
After the USA consensus statement in 1990, several groups
wanted more documentation before acceptance of routine
adjuvant therapy for stage III, and randomised trials, including
a surgery-alone group, were initiated [6, 9, 18, 19]. In the
Nordic countries, discussions led to a pragmatic trial design,
so that any results would be relevant for the general population
considered for treatment.
From 1991 to 1997, 708 patients with colon cancer stage III
were randomly assigned to receive surgery alone (n = 364) or
surgery plus chemotherapy (5-FU/levamisole, 5-FU/leucovorin
or 5-FU/leucovorin + levamisole, n = 344). An absolute
difference in 5-year survival of 7% favouring the adjuvant
group was found [19]. This difference did not reach statistical
significance (P = 0.15) but did not differ from the previous
surgery-alone trials or from a pooled analysis of seven
randomised trials [20]. The study thus supports that a small
gain is seen from adjuvant 5-FU-based therapy.
In Sweden, having the most pragmatic design, randomisation
and treatment initiation should be as early as possible, or
preferably within 49 days. When data were analysed, it was
found that one-third of the patients started treatment after
8 weeks (57 + days). It was speculated [19] that this delay
could be one reason why a clear survival gain was not seen.
The overall results of the 494 stage III patients randomised in
Sweden (Figure 1) were identical to those in the entire
Nordic cohort (data not shown). Patient characteristics, time
to randomisation and start of adjuvant therapy are presented
in Table 1. There was no difference in overall survival according
to whether randomisation was carried out within 7 weeks or
not. A difference, however, was seen according to when
treatment was initiated (Figure 2). Patients who had their
treatment initiated beyond 8 weeks appeared to have no gain
from the chemotherapy.
The evidence base for gains from adjuvant chemotherapy
in colon cancer stage III is at level I, according to ASCO
Cumulative Proportion Surviving (Kaplan-Meier)
Colon cancer stage III
p=0,19
Postoperative chemotherapy using modulated 5-fluorouracil
(5-FU) to patients operated for a colon cancer stage III can
prevent recurrences in some individuals and thereby improve
survival. These gains have been seen in randomised trials
published 10–15 years ago. In the trials having a surgery-alone
group, the treatment was generally initiated within 35 days,
and the maximum number of days allowed was 56 [1–8]. In
one trial, patients who did not start treatment within the
stipulated 42 days were excluded [8]. In contrast, later trials
comparing different regimen have allowed intervals up to
56 days or more [9–12]. In routine practice, this interval is
frequently longer than in the trials. The potential importance
of this interval was recently discussed [13]. Further, several
abstracts at American Society of Clinical Oncology (ASCO)
symposia in 2007 presented results from retrospective
analyses [14–17]. The relevance of timing of adjuvant
400 | letters to the editor
Cumulative Proportion Surviving
1,0
0,9
0,8
0,7
adj chemo
no adj chemo
0,6
0,5
0,4
0,3
0
1
2
3
4
5
6
7
8
9
10
Time, years
Figure 1. Overall survival in patients with colon cancer stage III from
Sweden randomised to surgery alone (n = 263) or surgery with adjuvant
chemotherapy (n = 231).
Volume 19 | No. 2 | February 2008
letters to the editor
Annals of Oncology
Table 1. Characteristics of Swedish patients with colon cancer stage III
Surgery + CT
Surgery
Surgery + CT
Treatment start
All
n = 263
Patient characteristics
Age (median, range)
Sex
Male
Female
Time to randomisation (days)
Time to treatment start (days)
n = 231
£56 days
>56 days
n = 149
n = 82
P value
66 (32–77)
65 (27–75)
65 (29–75)
65 (42–75)
P = 0.65
140
123
30 (6–126)
–
125
106
34 (5–97)
50 (10–117)
76
73
27 (5–51)
40 (10–56)
49
33
50 (14–97)
67 (57–117)
P = 0.85
P = 0.93
– = not relevant.
CT, chemotherapy.
Cumulative Proportion Surviving (Kaplan-Meier)
Colon cancer stage III
p=0.25
Cumulative Proportion Surviving
1,0
0,9
0,8
surgery only
< 56 days
> 56 days
0,7
0,6
0,5
0,4
0,3
0
1
2
3
4
5
6
7
8
9
10
Time, years
Figure 2. Overall survival according to whether the adjuvant
chemotherapy was initiated within 56 days (n = 149) or not (n = 82) in
relation to survival in the group randomised to surgery alone. Thirteen
patients who did not start adjuvant chemotherapy, although randomised
to this, and seven patients who received adjuvant chemotherapy in the
surgery-alone group were excluded.
guidelines, however, only when the treatment started within
5–6 weeks after the surgery [1–8]. When the relevance of the
time interval was explored, no clear influence was found
according to whether treatment was initiated within 20 [21]
or 28 days [6]. In a British trial, comparing two 5-FU-based
schedules, survival was inferior in those who started their
treatment beyond 8 weeks [22]. Actually, the survival curves
in that trial parallel those presented here. In another study [15],
the risk of death was significantly higher (relative
hazard = 1.33) among those 69 patients who commenced
adjuvant chemotherapy beyond 8 weeks. In contrast, three
other studies [14, 16, 17] could not detect any difference
according to when treatment started. Actually, in one study,
disease-free survival tended to be better in those who started
after 56 days [17]. In an analysis of 4382 patients with colon
cancer using Surveillance, Epidemiology, and End ResultsMedicare data, initiation of chemotherapy >2 months after
Volume 19 | No. 2 | February 2008
surgery influenced overall survival whereas initiation
>3 months had to be present to influence disease-specific
survival. It could not be determined whether the results
were because of chemotherapy timing or other associated
factors [23].
The question of timing cannot be explored prospectively,
and we are left with retrospective analyses. It is obvious that
a very long delay (any beneficial effect will of course be lost
if waiting until a recurrence has occurred) is deleterious.
A delay within reasonable limits, up to 6–7 weeks appears
not important, as recently found [24], whereas a delay longer
than 8 weeks can be negative. No definite cut-off is present,
but with time, the positive but in absolute terms rather
small gain from 6 months of adjuvant chemotherapy
becomes smaller and smaller. We argue that all efforts should
be made to initiate treatment as early as possible after the
surgery and postoperative recovery and, if the delay turns out
to be beyond some 8 weeks, the gain may be too small. It is
likely that the relations between time to treatment initiation
is the same using a combination of 5-FU and oxaliplatin [10],
being slightly more effective than 5-FU alone. In breast cancer,
a similar retrospective analysis indicated that survival was
compromised by delays of >12 weeks after definitive surgery [25].
funding
Swedish Cancer Society and the Stockholm Cancer Society.
Å. Berglund1, B. Cedermark2 & B. Glimelius1,3*
1
Department of Oncology, Radiology and Clinical Immunology, Uppsala
University, Uppsala, 2Department of Surgery, 3Department of Oncology
and Pathology, Karolinska Institutet, Stockholm, Sweden
(*E-mail: [email protected])
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letters to the editor | 401
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doi:10.1093/annonc/mdm582
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