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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 9 (May 1), 2000:
pp. 2770-2775
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Secondary neoplasms subsequent to Berlin-Frankfurt-Münster
therapy of acute lymphoblastic leukemia in childhood: significantly
lower risk without cranial radiotherapy
Lutz Löning,
Martin Zimmermann,
Alfred Reiter,
Peter Kaatsch,
Günter Henze,
Hansjörg Riehm, and
Martin Schrappe
From the Department of Pediatric Hematology and Oncology, Hannover
Medical School, Hannover; the Department of Pediatric Oncology,
University Children's Hospital Giessen; the Department of Pediatric
Oncology, University Hospital Rudolf-Virchow, Charité Berlin; and
the German Childhood Cancer Registry, University Mainz, Germany.
 |
Abstract |
Secondary neoplasms (SNs) represent serious late
complications after successful treatment of malignant diseases. To
evaluate the rate and type of SNs after Berlin-Frankfurt-Münster
(BFM) treatment in children with acute lymphoblastic leukemia (ALL), we
analyzed the data from the BFM database and the German Childhood Cancer
Registry (GCCR). Between April 1979 and April 1995, 5006 children with
B-precursor or T-ALL were enrolled in 5 ALL-BFM multicenter trials. The
median follow-up time from diagnosis was 5.7 years (range 1.5-18 years). By December 1997, 52 SNs were documented, including 16 acute
myeloid leukemias (AMLs), 13 neoplasms of the central
nervous system (CNS), and 23 other neoplasms. Compared with the expected numbers estimated from incidence rates derived from
the GCCR, this represented a 14-fold increase for all cancers and a
19-fold increase for CNS tumors. SNs developed 0.9 to 15 years (median:
6 years) after the diagnosis of ALL; 46 patients were in first complete
remission (CR). The overall cumulative risk of SNs at 15 years was
3.3% (95% confidence interval [CI]: 1.6%-5.1%) and 2.9% (95%
CI: 1.6%-4.2%) in first CR. The risk was 3.5% (95% CI: 1.5%-5.5%)
after treatment, including cranial irradiation and significantly lower
in nonirradiated patients: 1.2% (95% CI: 0.2%-2.3%;
P = .048). The development of secondary AML was not
associated with the use of any specific cytotoxic agent. Considering
the high-survival rate of this large unselected ALL cohort, the risk of
SN is relatively low, though higher, especially after cranial
irradiation, than in the general population. Long-term follow-up is
mandatory, and further SNs with longer latency periods are to be expected.
(Blood. 2000;95:2770-2775)
© 2000 by The American Society of Hematology.
| |
Introduction |
Intensive multimodal therapy has improved the survival
of many patients with different types of neoplasms in childhood.
The treatment of children with acute lymphoblastic leukemia (ALL) has become increasingly successful with an overall survival rate of
almost 80% in the last Berlin-Frankfurt-Münster (BFM)
study.1 However, the immunosuppressive and cytotoxic
therapy necessary to achieve this improvement increases the risk of
subsequent complications. One of the severe late effects is the
occurrence of a second cancer. Compared with age-matched controls,
individuals with a history of childhood cancer have been estimated to
have a 10- to 20-fold greater risk of developing a secondary malignant
neoplasm.2 Genetic predisposition, previously administered
chemotherapy, and/or radiotherapy are considered the most important
risk factors.
To determine the occurrence and type of secondary neoplasm (SN) among
children with ALL previously treated by 1 of the ALL-BFM protocols
since 1979 and to identify possible risk factors, we analyzed data from
the BFM database and the German Childhood Cancer Registry (GCCR).
| |
Patients and methods |
Between April 1979 and April 1995, 5006 children up to 20 years of
age with newly diagnosed B-precursor or T-cell ALL enrolled in 1 of the
5 BFM multicenter trials (ALL-BFM 79, 81, 83, 86, and 90) for
previously untreated ALL were included in the current study. Of the
patients, 57% were male, and the median age at diagnosis was 4.8 years
(range: 5 days-20 years). Informed consent from the guardians was
obtained for every patient. In all trials, patients were stratified and
randomized into well-defined subgroups. In trial ALL-BFM 79, patients
were stratified according to their risk index (RI), based on white
blood cell count, central nervous system leukemia (CNS-L), mediastinal
mass, age, and cytochemical reaction.3 In trial ALL-BFM 81 and 83, patients were stratified by leukemic cell burden (RF) only,
based on peripheral blast count, liver, and spleen size at the time of
diagnosis.4,5 In trials ALL-BFM 86 and 90, the initial
response to prednisone ( = number of lymphoblasts in blood after a
7-day exposure to prednisone) was used as an overriding stratification
factor in addition to the leukemic cell burden at
diagnosis.5,6
Details of the treatment regimens have been previously
published.3-7 The cumulative doses of the important
treatment elements are listed in Table 1.
Mean administered cyclophosphamide dose was 3000 mg/m2
(range: 2000-5000 mg/m2), mean anthracycline dose was 240 mg/m2 (range: 120-280 mg/m2).
Epipodophyllotoxins, only part of some ALL high-risk regimes, were
administered up to 1.6 g/m2. Major treatment changes
between the trials mainly concerned the high-risk regimen, except for
the intravenous methotrexate (IV MTX) and cranial irradiation (CRT)
dosages. Cyclophosphamide or ifosphamide and anthracyclines were part
of the treatment for all patients. Treatment after relapse was taken
into consideration when applicable. This included epipodophyllotoxins
and alkylating agents for all relapsed patients.
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|
Table 1.
Cumulative doses of selected chemotherapeutic agents and
radiation of ALL-BFM trials 79 to 90 according to the risk groups
|
|
To determine the occurrence of late effects, the follow-up status was
ascertained at least every 2 years (last update: December 1997).
Standardized forms to be completed by the treating institution are used
for follow-up, verifying the date of the most recent contact and the
status of each patient. Additionally, the BFM study group was notified
of all SNs after ALL, diagnosed in 1980 or later, registered by the
GCCR.8 Supplemental information, including a verification
of the diagnosis, surgical and pathology reports, records of radiation
therapy, and patient's outcome, was obtained for all reported cases of SN.
Survival and event-free survival (EFS) were calculated from the time of
initial diagnosis of ALL to death of any cause or first event
(nonresponse, relapse, death of any cause) or last follow-up. The risk
of SN was estimated by cumulative incidence functions9 for
SN and death as causes of failure. Ninety-five percent confidence
intervals (95% CI) were calculated using standard methods. Comparisons
were performed using the 95% CI for the difference between 15-year
point estimates for the incidence functions. In addition, standardized
incidence rate ratios (SIRs), defined as the ratio of the number of
observed divided by the number of expected cancers, were used to
measure the difference in cancer occurrence between the study group and
the general population.10 Confidence intervals were
computed by the method of Byar.10 The number of SNs
expected to occur was estimated from standardized incidence rates
derived from the GCCR statistics between 1992 and
1996.11,12
The contribution of presenting features or treatment components to the
development of SN was estimated with the Cox proportional-hazards model.13 The clinical and biologic features that were
analyzed included age, sex, leukocyte count, CNS involvement,
prednisone response, and immunophenotype.
Drugs specifically analyzed for impact on SN were epipodophyllotoxins,
cyclophosphamide/ifosphamide, anthracyclines, and radiotherapy. The
dosage of CRT was coded as follows: 0 for no RT, 1 for 12 Gy, and 2 for
at least 18 Gy. Radiotherapy as part of the relapse strategy was
included as a time-dependent variable in the model.
| |
Results |
The estimated overall survival rate for children previously treated
for ALL with 1 of the ALL-BFM 79 to 90 protocols was 76% (SE: 1%)
after 15 years. The EFS was 68% (SE: 1%) (Figure
1). Of the study population, 98% achieved
complete remission and 23.2% of the children suffered a relapse. Of
all the patients, 3% died before or while in remission and 1%
developed an SN. Nine percent were reported as being lost to follow-up.
At the time of analysis the median follow-up after diagnosis of ALL was
5.7 years (range 1.5-18 years), with a total of 28 605 person-years of
follow-up.
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| Fig 1.
Kaplan-Meier estimate of
survival and event-free survival for
the study population of the
trials ALL-BFM 79 to 90. The solid line
indicates survival (N = 5006; 969 events); the dotted line,
event-free survival (N = 5006; 1371 events).
|
|
As of December 1997, a total of 52 SNs had been observed. Most
frequent, in decreasing order, were acute myeloid leukemias (AMLs)
(31%), CNS tumors (25%), lymphomas (12%), and thyroid cancers (6%)
(Table 2). The clinical characteristics of
the patients, summarized in Table 3, showed
no difference between all the patients and those who developed an SN
with regard to sex, age, initial white blood count (WBC), tumor load
(RF), and prednisone response, although boys and infants had a slightly
(but not statistically significant) higher risk for developing an SN,
as well as patients presented with T-cell and CNS leukemias.
The median time from initiation of primary treatment to diagnosis of
the SN was 6 years (range 11 months-15 years) and varied according to
the type of SN (Figure 2). The median time
span for AML was 3.8 years (range 1-11.5 years), and 7.9 years (range
4-13 years) for CNS tumors. Types of SN differed also, according to the
age at diagnosis of ALL. Tumors of the CNS were the most common SNs
among children below the age of 7 years at diagnosis of ALL. The
cumulative probability that a CNS tumor would develop in these patients
was 1.5% (95% CI: 0.2%-2.7%) after 15 years, significantly higher
compared with the risk of 0.1% (95% CI: 0%-0.3%) in patients 7 years of age or older (P = .03). In contrast, incidence for AML was in the same range for these age groups.
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| Fig 2.
Time interval from
diagnosis of ALL to the
diagnosis of SN. Median time interval, box:
25%-57% quartile; bars encompass the range
|
|
SN developed in 46 patients during the first complete hematologic
remission. Six patients had previously been treated for ALL relapse, of
whom 4 patients had received bone marrow transplantation (BMT). Three
patients had isolated bone marrow relapses, 2 had an isolated relapse
in the testes, and 1 in the CNS. In the whole study population, a total
of 291 BMTs had been performed during the observation time.
The overall cumulative incidence of developing an SN was 0.5% (95%
CI: 0.4%-0.6%) after 5 years, 1.5% (95% CI: 1.3%-1.9%) after 10 years, and 3.3% (95% CI: 1.6%-5.1%) after 15 years from the
diagnosis of ALL (Figure 3). The
corresponding cumulative risk in patients during the first complete
remission (CR) was 0.5%, 1.3%, and 2.9% (95% CI: 1.6%-4.2%),
respectively. It was 3.9% (95% CI: 0.2%-10%) after 15 years in
relapsed patients. If low-grade meningiomas and skin cancers were
excluded from the analysis, the cumulative risk was 2.4% (95% CI:
1.7%-3.0%) at 15 years. Separate consideration of AML and CNS tumors,
the 2 largest groups of SN in our cohort, showed a cumulative risk of 0.2% at 5 years, 0.4% at 10 years, and 0.6% (95% CI: 0.2%-1.1%) at 15 years for developing an AML, and 0.1%, 0.4%, and 1.0% (95% CI: 0.4%-1.8%) at 5, 10, and 15 years for developing a CNS tumor. Thus, after 10 years, the cumulative risk of secondary CNS tumors exceeds that of secondary AML, although the absolute number of CNS
tumors is lower.
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| Fig 3.
Cumulative risk of
developing SN for patients
after treatment for ALL. CI: 95%
confidence interval.
|
|
The comparison of the observed SNs with the expected cancer rates in
the general population was carried out based on population rates
derived from the GCCR.11,12 In a total of 28 605
person-years at risk, the expected incidence of new neoplasms would
have been 3.7 (SIR: 14.1; 95% CI: 10.7-17.8), of new leukemia and
lymphomas 1.8 (SIR: 12.8; 95% CI: 7.9-18.4), and of new CNS tumors 0.7 (SIR: 18.6; 95% CI: 9.8-29.4). This represents a 14-fold increase of all cancers and a 19-fold increase of neoplasms of the CNS.
In most cases of SN, there was no family history suggesting cancer
predisposition: in 26 patients, the history was negative; in 16 cases,
no report was received; and in 10, 1 first- or second-degree relative
was suffering from a malignant disease. If all patients from the BFM
database with a report on family history were considered in statistical
analysis, a positive history is more frequent in patients with SN
compared with all patients treated for ALL. Although the cumulative
risk of developing an SN in patients with a positive family history is
more than twice as high as in patients with a negative family history
(1.2% vs 3.1%), there is no statistical significance.
Forty-five (87%) SNs occurred in patients who had received CRT, either
during frontline therapy or during relapse therapy. The median dose of
irradiation was 12 Gy (range: 12-30 Gy). All patients with secondary
CNS tumors, except 1 boy with a meningioma, and all patients with
secondary thyroid cancer had undergone CRT. The estimated risk of
developing an SN 15 years after the diagnosis of ALL was 3.5% (95%
CI: 1.5%-5.5%) among patients who had received radiation therapy,
significantly higher when compared with 1.2% (95% CI: 0.2%-2.3%)
among nonirradiated patients (Table 4;
Figure 4). For developing a CNS tumor, the
relation was 1.3% versus 0.1%; for developing an AML, it was 0.6% in
both groups. In the subgroup of patients during first CR, the
cumulative risk after irradiation was 3.3% and 1.0% in nonirradiated
patients. Among all irradiated patients (CRT performed either in
frontline or in relapse therapy) the risk was 1.7% after cranial
irradiation with 12 Gy, and 3.2% after irradiation with at least 18 Gy.
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| Fig 4.
Cumulative risk of
developing SN according to
radiation therapy (RT). The dotted line
represents the irradiated subgroup, and the solid line
nonirradiated patients.
|
|
By Cox stepwise regression, 3 parameters reached statistical
significance: initial CRT, CNS involvement, and administration of
epipodophyllotoxins in frontline therapy. Risk ratios (RR) and CIs are
given here for the regression model, including only these variables:
initial CRT (RR 1.5, CI: 1.01-2.3, P = .04), CNS involvement
(RR 3.1, CI: 1.1-8.7, P = .03), and administration of
epipodophyllotoxins in frontline therapy (RR: 2.6, CI: 1.3-5.4, P = .01). The risk ratios for these parameters were in the
same range when a Cox model was calculated for each of these parameters alone (RT: 1.7, CI 1.1-2.5; CNS: 4.0, CI 1.5-11.2; and
epipodophyllotoxins: 3.0, CI 1.4-6.2).
The analysis of treatment exposures failed to demonstrate a
relationship between the different BFM trials and the cumulative risk,
as well as between single chemotherapeutic agents (dose of
cyclophosphamide/ifosphamide or anthracycline) and the cumulative incidence of SN after 15 years (Table 5),
with the exception of epipodopyhyllotoxins. Comparing the cumulative
incidences of SN for patients treated or not treated with
epipodophyllotoxins, no difference was found. In Cox regression,
however, the use of epipodopyhyllotoxins in frontline treatment had a
significant impact on the incidence of second malignancies. When
including the relapse therapy, this parameter is losing significance.
Considering the patients with secondary AML, it is remarkable that 12 of 16 patients received no epipodophyllotoxins, a cumulative dose of less than or equal to 3000 mg/m2 cyclophosphamide, and less
than or equal to 240 mg/m2 anthracyclines. Only 3 patients
with secondary AML have been treated with epipodophyllotoxin (0.45-1.3 mg/m2). The other so-treated patients developed very
different types of SN.
At the time of the analysis, 26 patients (50%) with SN were alive. The
clinical outcome of patients with AML has especially been dismal.
Eleven of 16 children entered remission after receiving AML therapy,
but only 3 patients have remained in remission so far. The median
survival time was 6 months. Compared with that, approximately half of
the patients with CNS tumors can be expected to be long-term survivors
after surgical treatment and/or intensive chemotherapy. The median
survival time for patients with CNS tumors was 14 months.
| |
Discussion |
The risk of an SN in childhood cancer survivors may be influenced by
genetic and other predisposing factors, as well as by the treatment
given for the primary disease. The risk to develop an SN has always to
be viewed in the context of the survival probability provided by a
given treatment protocol, as low survival will result in fewer SNs.
Although the lifetime incidence of SNs has not yet been defined, within
the first 20 years of initial diagnosis of childhood cancer it is in
the order of 3% to 12%, according to the Late Effect Study Group
(LESG).14 The nationwide GCCR observed (for a period of 15 years up to 1995) 127 children with secondary neoplasms.12
For the first 15 years of life, the estimated cumulative risk of
developing an SN within 10 years after the first malignancy was 1.9%
(95% CI: 1.5%-2.3%), and the overall SIR for an SN was 12.5 (95% CI: 10.4-14.9). CNS tumors after ALL (13% of all SNs) and
after other CNS tumors (9%), and leukemia after leukemia (10%) were
the most frequently reported combinations.
A few studies have attempted to describe the overall risk of SN among
children with ALL. In 1991, Nygaard et al15 from Norway found an overall cumulative risk of 2.9% (SE: 1.4%) by 20 years after
diagnosis in a group of 895 patients, treated between 1958 and 1985. Neglia et al16 from the Children's Cancer Group (CCG) reviewed 9720 cases of ALL since 1972. They observed 43 SNs, after a
median follow-up of 4.7 years, including 24 neoplasms of the CNS, 10 new leukemias and lymphomas, and 9 other neoplasms. The estimated
cumulative risk was 2.5% (95% CI: 1.7%-3.4%) 15 years after
diagnosis, whereas Pratt et al17 observed 20 SNs in a group
of 1815 patients and estimated a cumulative risk of 5% during that
interval. In view of a longer follow-up time, the cumulative risk of
3.3% (95% CI: 1.6%-5.1%) after intensive BFM therapy is comparable
to these results. The cumulative incidence of an SN before another
first event in our data (2.8%) was nearly the same as the one reported
by Dalton et al (2.7%).18 The incidence of secondary brain
tumors (1.0% at 15 years) is comparable to the results of Walter et al
(1.39% at 20 years).19
Therapy-related SNs have been identified in patients receiving
radiotherapy, chemotherapy, or combined modality therapy for a variety
of primary neoplasms. Several studies have documented a clear
relationship between prior therapeutic irradiation and the occurrence
of CNS tumors,19-22 sarcomas of bone,23 and
thyroid cancers.24 Our study identified radiation therapy
as a significant risk factor, which was not found in the data of Dalton
et al.18 Also in the nonirradiated group no SN was
observed; however, a statistically significant difference in the
cumulative risk, compared with the irradiated group, could not be
demonstrated. This could be explained by the shorter follow-up of the
nonirradiated cohort. As shown in Figure 4, there is no evidence that
the cumulative risk of developing an SN has reached a plateau 15 years
after diagnosis in the irradiated group of our cohort, suggesting a continuing effect of irradiation on the rates of SN. Even among nonirradiated patients, it is at this time unknown whether the reduced
cumulative risk will remain constant, or whether SNs might arise after
a longer latency period. The standard dose for preventive irradiation
of 12 Gy was introduced in the BFM trials in the mid-1980s (Table 1).
Analysis of the data demonstrates a relationship between the dose of
cranial irradiation (12 Gy vs 18 Gy and more) and the incidence of SN
(Table 4), although the difference between the single dosage groups was
not statistically significant. Furthermore, the impact of CNS-targeted
chemotherapy still remains unknown.
Multiagent chemotherapy as part of multimodality therapy for malignant
disease has increased the difficulty of assessing which agents might
play a causative role in the development of SNs. Alkylating agents, and
more recently DNA-topoisomerase II inhibitors, have been linked to the
development of secondary AML and myelodysplastic syndrome
(MDS).25-28 Compared with the results of
Neglia et al,16 using intensive
nonepipodophyllotoxin-containing treatment regimens, we noted similar
rates of SN, but a higher rate of AML, which on the other side was
clearly below the rate reported by Pui et al.25 In that
study, the estimated risk was 3.8% to develop acute nonlymphocytic
leukemia, occurring within 6 years. In contrast to their conclusions
and the results of other studies, this investigation could not
demonstrate a clear relationship between the dose of cyclophosphamide/ifosphamide or anthracyclines and the occurrence of
SNs or special types of SN. Epipodophyllotoxin in frontline therapy was
administered only in high-risk patients (10% of all patients). There
was no difference in cumulative incidence rates, but a significantly
increased RR in a Cox model for patients treated with
epipodophyllotoxins in frontline therapy. The interpretation of these
data remains difficult because an explorative type of analysis has been
used, the number of SNs after epipodophyllotoxin was small, and there
are known (risk-adapted therapy) and possible unknown interactions
between biologic features and different treatment modalities.
Other risk factors for inducing SN comprise genetic predisposition and
possible combinations. According to the reports of the Late Effects
Study Group,29 some combinations of tumors seem to be
related to underlying genetic syndromes. It has been suggested that
genetically determined susceptibility is involved in the association
observed between brain tumors and leukemia/lymphoma. Increased
incidence of leukemia in the first-degree relatives of patients with
CNS tumors and a 2.8-fold increased risk was reported among
siblings,30 as well as CNS tumors in relatives of patients
with leukemia, are raising the possibility of a link between ALL and
brain tumors.31,32 SNs may also result from a specific
combination of age, genetics, first malignancy, and therapy. In
retinoblastoma, for example, exposure to alkylating agents and
radiation potentiates an already markedly elevated risk of
SN.23 Furthermore, the biologic characteristics of the blast cells may be associated with the development of secondary malignancy. In 1989, Pui et al33 reported a substantial
risk of secondary AML in patients with T-cell immunophenotype, but this
correlation has disappeared with longer follow-up and the accrual
of additional cases.25 Also, in our study, SN was more likely to occur in patients with T-cell leukemia, although the cumulative risk was not significantly increased.
In conclusion, we confirm that considering the high-survival rate of
this large, unselected ALL cohort, the risk of developing an SN after
ALL-BFM therapy is relatively low, although higher, especially after
radiation therapy, than in the general population. In particular, young
children are at increased risk when irradiation has been
used. The intensive chemotherapy regimens used during these studies do
not predict a higher risk as reported in other studies.15-19,25 AML and CNS tumors are the most common SNs.
In view of the long latency periods and long life expectancy of
individuals treated in childhood, long and careful follow-up of these
patients is warranted, especially for patients after irradiation and
for those with T-cell phenotype, with a positive family history for
cancer. This follow-up will also facilitate the evaluation of the role
of low-dose cranial irradiation (12 Gy), other CNS-targeted
chemotherapy, and genetic predisposition determining the risk of SN.
Efforts to identify the causative cancerogenic factors should continue,
and future treatment protocols should take these factors into account
to maximize the chances of a long and healthy life, while preserving
efficacy of treatment of the primary malignancy.
| |
Acknowledgments |
We thank U. Meyer and N. Götz for preparing the data of the
ALL-BFM studies, and J. Meyers for proofreading the text. We also thank
all the investigators and staff involved for their continuous
cooperation with the BFM study center.
| |
Footnotes |
Submitted July 26, 1999; accepted January 4, 2000.
Supported in part by grants from the Deutsche Krebshilfe and the
Madeleine Schickedanz Kinderkrebs-Stiftung.
Reprints: Martin Schrappe, Hannover Medical School, Department
of Pediatric Hematology/Oncology, 30623 Hannover, Germany; e-mail:
schrappe.martin{at}mh-hannover.de.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Abstract
Introduction