paediatrics Brussels 17

Articles

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

48 46* 15 26 73 40* 74 50* 48 69·5 89 48

27 18 22 32

58* NA 68*

40·5

0

Pediatric Oncology Group 3,22 Children’s Cancer Group 6

NA 52 59 NA 63

NA 22 40

SFOP 2

CCG-9921

65 NA

55†

0

St Jude 4

This study

42

79·3

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

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

702

http://oncology.thelancet.com Vol 8 August 2007