We've known for some time that
pediatric cancer survivors carry a burden of extra risk
of new cancers for years after achieving a cure. Several
studies have identified that risk — even characterized
the likeliest types — but truly long-term followup
is a rarity. In the case of acute lymphoblastic leukemia
(ALL), which produces more child survivors than almost
any other serious cancer, we may have been misled into
error by this short follow-up, according to researchers
at St Jude Children's Research Hospital in Memphis,
writing in the Journal of the American Medical Association.
A
LONGER LOOK
An early spike in myeloid leukemia is a well-known phenomenon
in ALL survivors. But this rash of secondary cancers
tends to level out about five years after the patient
enters remission and then fall off, declining to normal
levels after about 15 years — the extreme limit
of follow-up in most pediatric cancer survivors to date.
Now, the JAMA study has
uncovered a whole second wave of tumours, some of them
severe, occurring up to 30 years after children enter
remission for ALL. In fact, the elevation in risk of
secondary cancers appears to be climbing ever faster
as the patient ages, and risk is higher after the 15-year
mark than before.
Doctors from St Jude reviewed the
records of 2,169 patients who participated in the hospital's
leukemia treatment trials between 1962 and 1998. Average
follow-up was 18.7 years, the maximum follow-up was
41 years, and the total period reviewed was a whopping
29,179 person-years.
By no means did all of these patients
achieve lasting remission from their original disease.
Of the 879 whose leukemia recurred, three-quarters were
dead when the study started. Of those who survived a
recurrence of ALL, nearly a quarter went on to develop
a second neoplasm.
But a clearer picture emerges from
the patients who really did achieve lasting cure (10
years free of ALL). Of these 1,290, 9.5% developed a
second neoplasm, and 85.2% did not. The rest died cancer-free,
of unrelated causes.
TUMOUR
BREAKDOWN
The researchers found the usual, expected spike of acute
myeloid leukemias clustered rather tightly around the
three-year mark, which accounted for 30% of the secondary
neoplasms. Also to be expected based on previous research,
was some elevation in risk of central nervous system
(CNS) tumours. But this proved a bigger problem than
conventional wisdom might suggest. Ultimately ALL survivors
suffered as many CNS tumours as they did myeloid leukemias.
Fortunately, nearly half of these were meningiomas,
which are considered very treatable.
The earliest meningioma cropped
up 13 years after the patient had entered remission
— which is probably why this trend has stayed under
the radar for so long. Other types of CNS tumour occurred
sooner.
Then came the real surprise. Starting
around 15 years after remission, an unusually large
number of carcinomas began to crop up. Half were basal
cell, but the remainder were more serious. The list
of secondary cancers was rounded out by a handful of
sarcomas and lymphomas, small in number but still much
more than would be expected in an age-matched random
population.
Carcinomas ultimately accounted
for 24.4% of patients' secondary tumours, almost as
large a group as the myeloid leukemias. CNS tumours
accounted for 30.9%. The true threat to these patients
is best seen when the less dangerous cancers —
basal cell and meningiomas — are excluded and only
the remainder considered. In the thirty years following
ALL remission, these patients were 13.5 times more likely
than the general population to develop one of these
dangerous cancers.
That's not to say that the study
authors play down the significance of basal cell carcinomas
or meningiomas. "Even though they are low-grade tumours
and are considered curable, they may cause significant
health issues," said lead author Dr Nobuko Hijiya. Meningiomas
can cause neurological problems and basal cell carcinomas
frequently recur. "So it's very important that clinicians
are aware of this new finding," he added.
The overall cumulative frequency
of cancer in this study was 4.17% in the first 15 years
after ALL remission; 5.37% at 20 years; and 10.85% at
30. Most of these very late tumours were meningiomas
and basal cell, but the risk of a serious carcinoma
or sarcoma was still 2.4 times higher in these patients
20-30 years after remission than in the general population.
CANCER-CAUSING
Tx?
The authors noted a trend, again just short of significance,
for more secondary cancers in patients who had received
alkylating agents for their ALL — begging the question
of whether patients' excess risk of secondary tumours
is a product of the original cancer, or of its treatment.
The patients enrolled in this trial
were initially treated between 1962 and 1998. Obviously
leukemia treatment has changed a lot in those years,
with survival rates climbing from 4% to 80%. The St
Jude doctors describe post-1979 treatment as the modern
era.
Unfortunately, these later patients
couldn't be followed up for as long. One way of testing
the long-term dangers of current therapy is to measure
the effect of cranial/craniospinal irradiation on secondary
tumours. This treatment used to be standard for ALL,
but is nowadays only used for relapses at St Jude and
many other hospitals. In fact, as far as the more serious
secondary tumours were concerned, all of the excess
risk was concentrated in patients who had been irradiated.
So there's reason to believe today's patients face a
somewhat brighter future.
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