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http://oncology.thelancet.comVol 8 August 2007
given more drug than the dose calculated based on their
body-surface area). The median of the ratio between
actual time and protocol-dictated length of a cycle (56 days
per cycle) was 1·09, which is close to the protocol ideal of
unity, and ranged from 0·79 to 1·63. 1·63 was for a
patient receiving six cycles over an extended duration.
Combining the dose and relative time elements into the
RDIChemo resulted in a median of 0·87 or about 90% of
that intended. About one-third of the patients achieved an
RDIChemo of less than 0·78 (minimum 0·53) and about
one-third more than 0·93 (maximum 1·41). The overall
survival achieved by these groups (after rounding to
convenient boundary values) suggests that those with the
highest-achieved RDIChemo tended to have longer
survival times post completion of chemotherapy (figure 6).
The 3-year postchemotherapy overall survival was 52·1%
(95% CI 33·5–67·9), 64·0% (44·3–78·3), and 90·7%
(67·6–97·6) for the three RDIChemo groups, respectively.
These rates will be affected to a greater or lesser extent by
subsequent treatment, including radiotherapy, and the
effect of these on overall survival will increasingly affect
the ultimate shape of the survival curves as the interval
from the end of chemotherapy increases. Patients
achieving the highest RDIChemo (calculated from the
relative time it took to administer the chemotherapy
against the protocol specification) had a postchemotherapy
5-year overall survival of 76% (95% CI 46·6–91·2)
compared with 64% (44·6–78·4) and 52% (33·3–68·1) in
those in the intermediate and lower dose-intensity groups,
respectively (p=0·04).
The MRI scans of the 40 patients who had survived
4 years beyond treatment were reviewed, 19 had received
radiotherapy. Subtle white matter changes were noted in
two non-metastatic patients, one of whom had received
radiotherapy. 33 children of this subgroup are still alive,
six of whom seem to have stable residual disease at the
end of treatment.
Discussion
Our results show that after primary postoperative
chemotherapy, children younger than 3 years had a 5-year
overall survival of 63·4%, without the use of radiotherapy
in 42% of those treated for non-metastatic disease. For
those with and without metastases at diagnosis,
the
median delay to radiotherapy was 20·3 months, and the
median age at irradiation was 3·6 years. This study did
not identify age or histological grading as prognostic
factors, but did identify that metastatic disease predicted
poor survival. Finally, in contrast to several other reports,
completeness of surgical resection was not identified as a
significant predictor for survival.
There are several possible explanations for the relative
success of this primary chemotherapy strategy. Treatment
intensity of the chemotherapy could be important. The
treatment schedule specified a 14-day treatment interval,
irrespective of blood count. During the planned 1-year
protocol period, there was one peri-operative death, four
patients progressed and died, while ten others relapsed;
in all, 11 patients progressed on treatment. Of the
84 survivors, those achieving optimum RDIChemo had a
post chemotherapy 5-year survival of 76% compared with
52% in those not achieving optimum RDIChemo
(p=0·04).
The effect of non-chemotherapy events, such
as postsurgical neurotoxicity, intercurrent infections,
shunt malfunction and treatment, might have contributed
to the cause of decreases in RDIChemo inferring that
avoidance of these events by enhanced attention to
supportive and preventive care might benefit patients by
permitting optimum RDIChemo to be achieved in a
higher proportion. This highlights the importance of an
integrated and holistic approach to patient care aimed at
maximising nutrition, infection prevention, and opti-
misation of surgical approaches to minimise neurological
risks. The role of dose intensity in the management of
ependymoma deserves further study.
Comparison of survival results of our study against those
reported by other national trials groups using primary
chemotherapy showed that our study had better outcomes
than the French Society of Pediatric Oncology (SFOP)
study (table 6). Our study achieved an event-free survival of
64·4% and 44·9% at 2 and 4 years for non-metastatic
patients, compared with 33% (95% CI 23–44) and 22%
(13–34) at the same time points in the SFOP study.
2
Comparisons in overall survival between these studies
showed less marked differences: 5-year overall survival of
63·4% (52–73) in our trial, compared with 52% (38–65) in
the SFOP series.
2
Such contrasting results between event-
free survival and overall survival reflect the efficacy of
salvage therapies after primary chemotherapy. Our results
were better than those from the US Pediatric Oncology
Group (POG) 8633 study in which chemotherapy was
delivered to delay, but not avoid, radiotherapy.
3,22
Finally,
comparison to the US Children’s Cancer Group (CCG)-
9921 study shows similar overall survival (59% at 5 years).
5
The effect of age in this very young cohort upon survival
was non-significant, in contrast with the POG study
3,22
and
other groups.
2,4,5
The very young age group, limited age
range studied, and small numbers of patients in cohorts
n Event-free survival (%) Overall survival (%)
“Radiotherapy-
free” survival
3-year
5-year
3-year
5-year
Pediatric Oncology Group
3,22
48 46*
27
58*
40·5
0
Children’s Cancer Group
6
15 26
18
NA
NA
NA
SFOP
2
73 40*
22
68*
52
22
CCG-9921
74 50*
32
65
59
40
St Jude
4
48 69·5
55†
NA
NA
0
This study
89 48
42
79·3
63
42
NA=not available. *Estimated on the basis of exponential survival using the quoted 5-year rates. †Projected survival,
assuming exponential survival rates.The German Paediatric brain tumour studies are not included as they only include
anaplastic (grade III) tumours on Hirntumor Säuglinge und Kleinkinder (HIT-SKK) protocols.
Table 6
: Outcomes of major studies of ependymoma in young children