Twenty-five years of treatment for childhood acute lymphoblastic leukaemia in Western Australia: how do we compare?

Between 1983 and 2008, all Western Australian children with newly diagnosed acute lymphoblastic leukaemia (ALL) were treated at Perth’s Princess Margaret Hospital for Children (PMH) under 15 consecutive protocols from trials conducted by the North American Children’s Cancer Group (CCG).

The CCG (now part of the Children’s Oncology Group) was a cooperative research group of more than 120 centres in the United States, Canada and Australia. More than 16 000 children have been treated in CCG randomised controlled trials for ALL since 1968.1 The event-free survival (EFS) of children with ALL has risen from 15% to over 80% during the past four decades. This can be attributed to the intensification of therapy with agents previously shown to be effective in the treatment of ALL in a series of randomised controlled trials performed by the dozen or so international, multicentre, cooperative groups in high-income countries around the world. EFS is predicted based on clinical and biological or disease variables, and treatment intensity is modified according to EFS to maximise cure while minimising toxicity. It is notable that few new drugs have contributed to this improvement in outcome (rather, there has been better use of existing drugs and improved supportive care) and that the CCG studies are not sponsored by the pharmaceutical industry.

In 1983, the Total Care Unit for Children with Cancer at PMH became an associate member of the CCG and began to treat patients with ALL according to CCG protocols. By 1992 the unit had fulfilled the requirements for compliance and audit, and was accepted as the first non-North American full member of the CCG enrolling patients in the study.

The last CCG ALL protocol (CCG 1991) closed to accrual in January 2005, and by early 2008, all patients had completed their therapy and were in follow-up. In 2000, the CCG joined with the other large cooperative group for the management of children with cancer and leukaemia in North America, the Pediatric Oncology Group, and formed the Children’s Oncology Group (COG). Randomised trials of treatment for children with ALL continue within the COG, but there are as yet no mature data for analysis.

The incidence of childhood ALL in WA is similar to that in other Western populations — 3.7 per 100 000 person-years.2 Despite being the commonest childhood malignancy, only 15–20 new patients aged under 16 years are diagnosed with ALL in WA each year. This low incidence makes meaningful, Phase III, randomised controlled trials of treatment impossible, and highlights the importance of membership of a large cooperative clinical trials group so that many hundreds of patients can be studied within a reasonable time frame. Without membership of CCG, the small cohort of patients in WA may have been treated according to the best available evidence, such as that of the most recently published peer-reviewed trials of therapy. Even within the large cooperative groups, the time taken from opening a Phase III randomised clinical trial for ALL to the publication of a manuscript is about 10 years. Thus children treated according to the latest published research would receive therapy about 10 years out of date compared with children treated in the clinical trial.

However, as well as reporting overall improvements in outcomes of CCG patients with successive trials of therapy, it is important for us to review the outcomes of our Western Australian patients separately, to ensure that they are achieving equivalent success. As we contribute only 1%–2% of patients in the entire CCG cohort, it is possible that our patients are faring comparatively badly within the larger cohort.

In this study, we aimed to review the outcomes of all children who began treatment at PMH between 1983 and 2005 to determine survival according to treatment protocol, and to compare this with the published results for the entire CCG cohort.

For the period 1983 to 2008, records of children aged 0–16 years with ALL were reviewed retrospectively with respect to date of diagnosis, treatment protocol and outcome. Fifteen protocols were used in treatment. Each successive ALL study accrued patients for about 5 years.

Patients diagnosed before 1992 were treated according to the best arm of the previous closed study — the standard arm of the current open protocol. After 1992, 212 children were treated at PMH, of whom 146 (69%) consented to be enrolled in the current randomised study and 66 (31%) were treated off-study on the standard arm. Reasons for children not being enrolled in the study included lack of an available study open at the time of diagnosis, patient ineligibility (eg, prior treatment with corticosteroids) and parents’ decisions for reasons such as a perceived increased burden of therapy on some experimental arms.

Long-term follow-up was assessed in the Total Care Unit’s “late effects” clinics from 5 years after diagnosis and, after about 10 years in remission, by annual postal questionnaire.

The entire cohort of children treated at PMH for ALL under CCG protocols from 1983 to 2008 numbered 311; 133 were female (43%) and 178 were male (57%). There were 85 events among the overall cohort: 72 relapses, 11 deaths in remission (some following allogeneic haemopoietic stem-cell transplantation) and two diagnoses of a second malignant neoplasm (one of chronic myelomonocytic leukaemia and the other of malignant astrocytoma).

Box 1 shows that the PMH cohort had a superior outcome for female patients, consistent with that observed in other CCG studies.1

Four-year EFS for the entire PMH cohort increased from 66% (SE, 6%) for 1983–1987 to 88% (SE, 6%) for 2002–2005, while overall survival over the same period improved from 78% (SE, 5%) to 94% (SE, 4%). EFS by period is illustrated in Box 2.

The EFS of Western Australian children with ALL treated at PMH over 25 years according to CCG protocols are equivalent to the outcomes of the larger CCG cohort. These results reassure us that we are delivering effective anti-leukaemic therapy and supportive care to our patients with ALL.

As PMH is the only paediatric hospital in WA, all newly diagnosed patients with ALL are referred to the Total Care Unit for Children with Cancer for treatment. The small population of WA coupled with the relatively low incidence of ALL result in very small numbers of patients on any treatment protocol.

Our retrospective study has some limitations. Children treated “on study” at PMH after 1992 are also included in the CCG survival data. However, as they make up less than 2% of the entire CCG cohort, this bias was considered negligible. Second, our analysis was unable to examine prognostic factors of the PMH cohort within each treatment protocol group, and the groups may not be equivalent for important prognostic factors such as age or WCC. This may be the reason for a better outcome for PMH patients treated according to the intermediate-risk protocol CCG 105. Before 1992, PMH patients were treated on the standard arm of the current protocol and in all but one CCG ALL study, the experimental arm was the better arm of the study. We may, therefore, have expected the outcome for PMH patients to have been poorer than for the CCG as a whole for these studies, yet no definite trend was seen. The differences in outcome between PMH and the whole CCG cohort for each remaining study are neither statistically nor clinically significant.

The small numbers of patients in each risk-stratified treatment group of PMH patients and the large standard errors associated with the survival data in such small cohorts highlight the statistical power of large cohorts when treatment centres work cooperatively, as in the CCG. Only with large numbers of patients is there enough statistical power for randomisation between standard and experimental treatments to show a difference in outcome within a reasonable time frame. The CCG study cohorts are of adequate sample size to detect moderate treatment differences of the order of a 25%–30% reduction in hazard, even when the difference in EFS between arms is only a small percentage.1 Such a sample size ensures that useful interventions that boost EFS are identified and are used to direct future treatment.

The national and international cooperation in obtaining such results has been an enormous feat of organisation. All children with cancer in Australia are now offered the opportunity to take part in clinical trials from North America and Europe. Our continued cooperation with other international centres is essential to continue to improve survival for these children. Barriers to participating in international multicentre cooperative group trials include regulatory hurdles (which prevent Australian centres from benefiting from the centralised ethics submission process available to US centres), transport costs and time delays in shipping specimens to central laboratories for testing.

Finally, while there is no doubt that paediatric patients with cancer and leukaemia are best treated in large, randomised, international, cooperative group trials, the lack of government funding for data management and the lack of individual academic recognition for such participation may lead clinical researchers to pursue smaller trials, perhaps to the detriment of Australian patients.16

1 Event-free survival of children treated at Princess Margaret Hospital on Children’s Cancer Group protocols, 1983–2008

2 Event-free survival of patients treated at Princess Margaret Hospital on Children’s Cancer Group protocols during five periods, 1983–2007