Late Effects Study
NWTS 4941L Progress Report - Page 1
Study Progress Report
Study Number and Title: NWTS 4941L, NWTS Late Effects Study
Study Chair: Daniel M. Green, MD
Study Statistician: Wendy Leisenring, Sc.D
Data Frozen: November 5, 2015
I. Study Purpose and Objectives:
1. To determine the incidence of life-threatening medical conditions in survivors of Wilms tumor;
specifically a) congestive heart failure; b) second malignant neoplasms (SMNs); c) renal failure; and
d) chronic restrictive pulmonary disease. To relate the risks of these events to the type and amount of
radiation and chemotherapy received, to disease factors and to host factors. To compare the incidence
of SMNs to that expected from national rates.
2. To determine mortality rates in former Wilms tumor patients, and to compare these with age, calendar
period and sex-specific national population rates.
3. To determine the risks of serious pregnancy complications and adverse reproductive events in
survivors of Wilms tumor, and to correlate their occurrence with the type and amount of radiation and
chemotherapy. To compare birth rates with those from national statistics.
4. To extend the current Late Effects Study to include patients treated on the latest therapeutic protocol
of the National Wilms Tumor Study Group (NWTS-5, accrual 1995-2002) and to enroll patient
offspring as study participants.
5. To serve as a case-finding resource, identifying the most informative subgroups of Wilms tumor
patients for use by epidemiologists studying risk factors and by molecular biologists studying
mutations in identified or prospective Wilms tumor genes including genes for familial Wilms tumor.
II. Study Progress to Date:
The study is closed to accrual for patients who were originally participants in one of the clinical studies
NWTS 1-4.
Table 1: Disposition of Study Patients Initially Registered on NWTS 1-4
Study disposition
No. %
In current follow-up (follow-up received in the last two years)
1,848 31
Contact made – forms not returned within the last two years
1,519 25
In tracking by DSC
597 10
Institution Lost to follow-up, not released to DSC for direct follow-up
279
5
Lost to follow-up, released to DSC for direct follow-up
542
9
Deceased
548
9
Discontinued (mostly at patient/family request)
310
5
Non-participating Institution
343
6
Total (NWTS 1-4 patients, survived 2+ years from diagnosis)
5,986 100
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NWTS 4941L Progress Report - Page 2
The study is open to accrual for patients from NWTS-5:
Table 2: Status of Protocol at Institutions for Registration of NWTS-5 Patients
Protocol Status at Institution
No.
No. patients eligible
No. patients
institutions
registered
Approved
60
971
604
Declined / Closed
108
1008
522
Expired
40
560
311
208
2,539
1,437
Total
Table 3: Distribution of NWTS 1-5 Registrants by Gender and Ethnicity
Native
American
Hawaiian or
Indian or
Black or
Other
Native
African
Pacific
Other or
Gender Alaskan Asian
American
Islander
White Hispanic Unknown Total
22
52
660
3 2,825
340
12 3,914
Female
17
40
554
6 2,629
264
12 3,522
Male
39
92
1,214
9 5,454
604
24 7,436
Total
Target accrual for patients on NWTS-5 is 2,077, approximately the number of patients known to have
survived two years from institutions that had submitted the protocol to their IRB at the time accrual
began. Accrual started in February, 2002 and continues to date.
Figure 1
NWTS-5 Accrual Chart
3000
Number of Patients
2500
2000
Actual Patients Accrued
1500
Expected Patients Accrued
1000
500
0
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
Year of Study
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NWTS 4941L Progress Report - Page 3
Table 5: Summary of Pregnancy/Offspring Ascertained with Medical Records
Number of
reported
Pregnancies
Gestation
less than
20 Weeks
not a
Live
Birth
In
Progress
or
unknown
duration
and
outcome
Gestation
greater
than 19
Weeks or
Live
Birth
Questionnaires
Requested
3,614
526
239
2,849
2,455
Releases
Signed
Mother's
Records
Requested
Mother's
Records
Received
Mother's
Records
Reviewed
1,575 1,398
1,361
1,267
1,267
Questionnaires
Returned
Child's
Records
Requested
Child's
Records
Received
Child's
Records
Reviewed
1,351 1,244
1,244
IIA. Study Chair Commentary on Study Conduct and Progress
The study has progressed well. For patients registered on NWTS - 1, - 2, - 3, and - 4, passive refusals
(contact made – forms not returned) accounted for 25% of eligible subjects and failure of the original
treating institution to permit the DSC to initiate direct follow-up of eligible subjects accounted for 5% of
eligible subjects. Nine percent were lost to follow-up and another 5% have requested discontinuation of
follow-up. During the funding gap between November, 2011 and August, 2012, follow-up fell behind.
The DSC established an online version of the Annual Status Report Form through the website of the
survey research firm Survey Monkey, which is now linked to the NWTS website. This was intended in
part to return to active follow-up some of those now classed as passive refusal by offering them another
avenue of communication with project personnel.
Accrual of surviving subjects from NWTS - 5 was also affected by the funding hiatus. One hundred-fortyeight institutions refused to participate in this protocol or have allowed their IRB approvals to lapse
(Table 2). The number of NWTS-5 patients currently enrolled on the Late Effects Study (LES) is 1437.
The study continues its strong record of research productivity. The latest analyses of second malignant
neoplasms (SMNs), pregnancy outcomes and end stage renal disease (ESRD) were published during
2010-2012, as was the first analysis of portal hypertension (Section IX). Results of the first NWTS study
of pulmonary complications in survivors were presented at the 9th International Conference (2006) on
Long-Term Complications of Treatment of Children and Adolescents for Cancer and a manuscript has
been published in Pediatric Blood and Cancer (21). Data from the NWTS, the Childhood Cancer Survivor
Study, the British Childhood Cancer Survivor Study and a consortium of Nordic cancer registries were
pooled for an international collaborative study regarding the incidence of and risk factors for SMNs in
Wilms tumor survivors and a manuscript was published in the International Journal of Cancer (14).
Medical records continue to be reviewed for a planned updated analysis of risk factors, including
radiation and chemotherapy doses, for congestive heart failure and cardiomyopathy. In addition NWTS
data were used for the development of a risk predictors for congestive heart failure that has been
published in the Journal of Clinical Oncology (25). Maternal and infant medical records were reviewed
for an update of risk factors for pregnancy complications that was published in the Journal of Clinical
Oncology (15). A new finding was the increased risk of hypertension complicating pregnancy with
increasing dose of abdominal irradiation. Strong circumstantial evidence was developed for a role for
germline WT1 mutation in the etiology of ESRD due to chronic kidney disease (rather than progressive
Wilms tumor) in patients without WT1 associated congenital anomalies and syndromes in a study
published in the Journal of Urology (18). This laid the foundation for a case-control study of WT1
mutation and ESRD that is currently underway in collaboration with Dr. Vicki Huff. The currently
mandated 1-2 year waiting period for renal transplantation following chemotherapy was called into
question by analysis of treatments and outcomes among patients who developed ESRD after Wilms
tumor. A manuscript was published in Cancer (that provides evidence that not only chest irradiation, but
also flank irradiation, may increase the risk of secondary breast cancers (Section VI, 24).
III. Toxicity: Acute toxicity is not monitored in this study
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NWTS 4941L Progress Report - Page 4
IV. Currency of follow-up:
Table 6: NWTS 1-5 Patients Alive at Last Contact and Not Discontinued
Year of Diagnosis
Years since last follow-up
0-1
2-4
5-9
10-14
15+
1969-1974
155
51
59
34
60
1975-1979
241
77
102
61
144
1980-1984
468
163
199
96
255
1985-1989
479
176
237
196
280
1990-1994
495
165
347
265
272
1995-1999
392
199
189
101
28
2000-2002
291
97
112
37
2521
928
1245
790
1039
Total
Total
359
625
1181
1368
1544
909
537
6523
V. History of Study Amendments:
AMENDMENT 6, Approved by CTEP 3/22/2004: The protocol was amended in order to provide
instructions regarding the consent and enrollment of NWTS-5 (protocol 4941/9440) patients onto the
NWTS Late Effects Protocol.
AMENDMENT 7, Approved by CTEP 6/18/2004: The protocol was amended in order to revise the
model consents. The consents were updated to incorporate a detailed question and answer document that
provides patients and families with a comprehensive explanation of what participation in the study
includes.
AMENDMENT 8, Approved by CTEP 04/14/2010: The protocol was amended in order to update the title
page, contact information for NWTS Late Effects Study Committee and Consultants, study monitoring
section, and the model consents. The consents were updated to omit grammatical errors.
AMENDMENT 9, Approved by CTEP 02/11/2014: The protocol was amended in order to update Wendy
Leisenring, ScD, as the Principal Investigator. Norman Breslow, PhD, has been updated to CoInvestigator from the Principal Investigator. The model consents were updated with Dr. Leisenring as the
Principal Investigator and the dates of the study. The study forms were updated to be more concise.
VI. Recent Findings (published since 2005):
This study is currently in its 24th year of operation with NCI R01 grant funding which extends through
July, 2017. Major findings as summarized in the 2011 competing renewal application and developed since
then are as follows:
Overall mortality (2, 23) 1 Evaluation of 8 year follow-up data for patients with Stage I-IV favorable
histology Wilms tumor demonstrated that flank irradiation did not improve survival in spite of its clear
efficacy in preventing local recurrence.(2). This apparent paradox reinforces the importance of evaluating
entire treatment policies with regard to long term outcomes. Based on a recent review of pathology and
surgery records for NWTS-4 patients with Stage II disease of favorable histology, the 8 year overall
survival for those found to have local spillage was 90.3% (95% CI 82.2-94.9%) whereas it was 95.6%
(93.1%, 97.3%) for those without spill.(23)
Late mortality (5, 9, 12) The first systematic study of long term mortality started with an evaluation of the
NWTS ascertainment system by linkage of records for patients from U.S. institutions with the National
1
Numbers in bold indicate publications listed in §IX
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NWTS 4941L Progress Report - Page 5
Death Index (NDI) (5). Records of patients with vital status unknown as of Jan 1, 2000 were submitted to
the NDI in April, 2003. Matches were established for 709 of 789 patients known to have died during
1979-2001 (sensitivity 89.9%) but none of 1052 patients known by NWTS to be alive in 2002 (specificity
100%). Factors independently associated with decreased sensitivity were not having a social security
number known to the NWTS (sensitivity 87.8%), Hispanic ethnicity (76.4%) and foreign birth (56.5%).
Percentages of patients lost to follow-up after ten years were 9.5 for Caucasian, non-Hispanic, 22.4 for
African-American, 25.9 for Hispanic and 35.5 for foreign born. For 2351 patients with 2002 vital status
unknown and 13,166 person years of missing observation between date last seen and 2002, only 18
deaths were ascertained by NDI whereas 79.3 were expected based on NWTS mortality data. Since the
same selection factors were likely associated with NDI failure to match decedents and loss to follow-up
by NWTS, use of the NDI search to fill in missing follow-up data appears unwarranted.
An analysis of cause-specific mortality and comparison with U.S. population rates has been completed
and was published in the Journal of Clinical Oncology. (9) Standardized mortality ratios (SMR)
decreased markedly during the first ten years of follow-up but remained elevated at levels 4-5 times
background even 20 years from diagnosis. The improvement in treatment outcomes is clearly reflected in
5 year survival rates by calendar period of diagnosis; there is also some evidence for a reduction in
mortality due to late effects of treatment, based on relatively small numbers of events. Causes of death are
not well represented on death certificates; in particular, late deaths due to WT are often wrongly identified
as due to SMNs.
A recent update on the survival experience of patients from NWTS-5 with very low risk Wilms tumor
showed no difference in 5-year survival outcomes for those treated with surgery alone vs. surgery plus
chemotherapy, although there were large differences in the 5-year event free survival (EFS) outcomes.
(12)
Second malignant neoplasms (14) Data on 2893 British patients with WT diagnosed during 1962-2002, of
whom 68 with secondary cancers, were received from the UK childhood cancer registry for incorporation
into the database for an international collaborative study on SMNs in survivors of Wilms tumor. These
data were combined with those from the NWTS and the Childhood Cancer Survivor Study (n=8,884, 140
SMNs), and a consortium of Nordic cancer registries (n=1,574, 30 SMNs). The estimated cumulative risk
of a solid tumor at age 40 among those who survived to age 15 without a SMN was 6.7%, and this was
remarkably consistent among the North American, British and Nordic populations. Age specific incidence
of secondary solid tumors increased from about 1 per 1,000 person years (PY) at age 15 to 5 per 1,000 PY
at age 40. Standardized incidence ratios (SIR) for both solid tumors and leukemias were 5.1 and 5.0. For
solid tumors, there is no sign that the SIR is declining with age or years since the Wilms tumor diagnosis.
These results were published in the International Journal of Cancer (14).
Among 2492 female patients from NWTS1-4 known to have survived until age 15, 29 cases of breast
cancer (BC) were identified. Standardized incidence ratios (SIR) relative to SEER rates were 2 cases
observed vs 0.9 expected, or 2/0.9 = 2.2, among 1229 who received no irradiation; 10/1.7=6.0 for 894
who received only abdominal irradiation; and 16/0.6=27.6 for 369 who received chest irradiation to treat
their WT. BC was more likely to have occurred on the side (L or R) of the body to which radiation
therapy (RT) had been given. Treatment with doxorubicin was not independently associated with
increased BC risk. However the risk was increased (SIR 9/0.4=23.6) among 90 patients whose WT
diagnosis occurred at age 10+. Since the standard dose of chest RT radiation is 12 Gy for WT, current
treatment guidelines, suggesting that doses up to 20 Gy are “safe” for childhood cancer patients, may
need revision. A manuscript describing this work was published in Cancer in December of 2014 (24).
End Stage Renal Disease (1, 7, 16, 17) A major contribution from earlier studies was the discovery that
patients with the Wilms tumor, aniridia, genitor-urinary anomaly, mental retardation (WAGR) syndrome
were at high risk of renal failure progressing to end stage renal disease many years following their Wilms
tumor diagnosis. A subsequent investigation involved linkage of records for 5,910 patients to the database
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NWTS 4941L Progress Report - Page 6
of the United States Renal Data System (USRDS). Of the 115 cases of end stage renal disease (ESRD)
identified, 9% were ascertained by NWTS along, 11% by USRDS alone and 80% by both systems. The
cumulative incidence of ESRD for patients who did not have DDS, WAGR or male GU anomalies was
0.6% at 20 years from diagnosis of unilateral Wilms tumor and 12% following diagnosis of bilateral
disease. Most of the ESRD among the latter patients occurred during the first five years and was due to
bilateral nephrectomy. Patients who had manifestations of WT1 alterations, however, had much higher
rates of ESRD (1). This study provided some reassurance regarding the NWTS system for ascertainment
of major medical conditions during long term follow-up.
A French group (Am J Kid Dis 49:793-800, 2007) was motivated by NWTS results to examine the
histology of non-tumor kidney samples from WAGR syndrome patients at the time of initial surgery.
They found a bimodal distribution of glomerular diameters in seven such patients and substantially
smaller average diameters in comparison with non-WAGR WT patients, suggesting a specific defect of
WT1 function in development of the ESRD.
Our latest study of risk factors for ESRD focused on patients who did not have WT1 associated congenital
anomalies (16). Cases of ESRD were separated according to whether they were the result of progressive,
bilateral Wilms tumor (PBWT) requiring surgical removal of all renal tissue or whether the ESRD was
due to other factors collectively termed chronic renal failure (CRF). The risk of ESRD due to PBWT was
largely over by 3 years from diagnosis of bilateral WT, whereas the risk of ESRD-CRF continued to rise
even 25 years from WT diagnosis. The study showed striking associations, with relative risks up to
tenfold, between ESRD-CRF occurrence and the clinicopathologic factors of early age at onset, stromal
predominant histology and the presence of intralobar nephrogenic rests, the same factors thought to be
associated with a WT1 etiology for the Wilms tumor itself (3). It also demonstrated that the risk of ESRDPBWT was over 4 times higher for those whose bilateral disease developed after the initial diagnosis of
Wilms tumor than for those who had bilateral disease at onset. This study was published as a Special
Article in the Journal of Urology (16).
In a study of 28 NWTS patients who received treatment after renal failure (7), there was no evidence for
increased toxicity due to vincristine or doxorubicin but some increase in neutropenia from dactinomycin.
The overall survival of 39% (64% for those in initial treatment at time of renal failure) suggested that cure
is not precluded in such patients.
Time-to-transplant, graft failure and survival rates for 173 NWTS patients who had developed ESRD
were examined and compared to those for an age matched sample of general pediatric patients with ESRD
from the USRDS. (17) Results of this study have been published in Pediatric Nephrology. Fifty-five
patients whose ESRD resulted from progressive bilateral WT (PBWT) experienced high early mortality
from WT that limited their opportunity for transplant (47% at 5 years) and survival (44% at 10 years) in
comparison to population controls. The 118 patients whose ESRD was due to other causes (termed
“chronic kidney disease”), many of whom had WT-associated congenital anomalies, had transplant (77%
at 5 years) and survival (73% at 10 years) outcomes no worse than those for population controls. Graft
failure following transplant was comparable for the two groups. Minority children had twice the median
time to transplant as non-Hispanic whites and twice the mortality rates, also reflecting population trends.
A pilot study was conducted by co-investigator Dr Vicki Huff of our hypothesis that germline WT1
mutations led to ESRD even in patients without known WT1 congenital anomaly syndromes. We
identified 4 such patients among NWTS-5 patients for whom tumor tissue and blood were still available
and matched each to 4-6 controls on duration of follow-up. 3/4 cases and 14/19 controls had adequate
biological material for evaluation; 2/3 cases and 1/14 controls had germline WT1 mutations. Although
these data support the hypothesis, suggesting a 26 fold increase in ESRD risk associated with mutation,
they are too sparse for definitive conclusions.
Pulmonary Complications (4, 22) The records of 6,449 patients treated on National Wilms Tumor Studies
-1, -2, -3, and -4 whose flow sheets or annual status reports documented one of several pulmonary
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NWTS 4941L Progress Report - Page 7
conditions were reviewed. Cases were fully evaluable if pulmonary function test (PFT) results were
available, pulmonary fibrosis was identified on a chest radiograph or was listed as the primary or a
contributing factor to death. Partially evaluable cases were those for whom PFT results could not be
obtained. We evaluated the relationship between RT factors and the occurrence of pulmonary disease
using hazard ratios (HR) and cumulative incidence, treating death as a competing risk. Sixty-four fully
evaluable and 16 partially evaluable cases of pulmonary disease were identified. The cumulative
incidence of pulmonary disease at 15 years since WT diagnosis was 4.0% (95% confidence interval (CI)
2.6-5.4%) among fully evaluable and 4.8% (95% CI 3.3-6.4%) among fully and partially evaluable
patients who received lung RT for PM at initial diagnosis. Rates of pulmonary disease were substantially
higher among those who received lung RT for PM present at initial diagnosis or relapse compared to
those who received no RT or only abdominal RT (hazard ratio (HR) 30.2, 95% CI 16.9-53.9). These
results were published in Pediatric Blood and Cancer. (21)
Portal Hypertension (13) Nineteen of 5,195 patients from studies NWTS-1-4 were identified who
developed portal hypertension. The cumulative risk at 6 years post Wilms tumor diagnosis was 0.7% for
those with right sided tumors and 0.1% for those with left sided tumors. Based on analysis of results from
a nested case-control study, there was a strong association between higher doses of radiation therapy to
the liver (>15 Gy) and the development of portal hypertension. These results were published in the
International Journal of Radiation Oncology, Biology and Physics. (13)
Pregnancy Outcomes (15) The most recent analysis of pregnancy outcomes involved over 1,000
pregnancies with duration of 20 weeks or longer, including 955 liveborn singletons for whom 700 sets of
maternal and offspring medical records were reviewed. This study identified an increased risk of
hypertension complicating pregnancy, and confirmed the previous findings of an increased risk of early or
threatened labor and malposition of the fetus with increasing abdominal irradiation to the mother.
However, by contrast with the earlier study, no statistically significant trend in the number of congenital
anomalies with radiation dose was observed in the offspring of female patients. These data were
published in the Journal of Clinical Oncology (15).
Epidemiologic evidence for genetic heterogeneity (3, 11, 18) Study of the associations between age-atonset distributions, birth weight, tumor centricity, characteristic congenital anomalies and syndromes,
precursor lesions and other clinicopathologic features led NWTS investigators early on to the conclusion
that Wilms tumor arose from a variety of pathogenetic mechanisms. These observations were confirmed
in the laboratory by the finding that WT1 mutations accounted for only a small fraction of Wilms tumors
and that imprinting at the putative WT2 locus likely involved a larger fraction. Phenotypic evidence for
genetic heterogeneity was provided by the striking association of tumors arising in association with the
precursor lesions perlilobar nephrogenic rests (PLNR) and intralobar nephrogenic rests ILNR with ages at
diagnosis and bilateral or unilateral, multicentric disease (3). The slight excess of females in the NWTS
population, their greater mean ages at diagnosis and the apparent biomodality in their age distribution
were explained in part by the relative excess in females compared with males of PLNR vs ILNR
associated tumors. In a more direct examination of genetic heterogeneity, gene expression profiles were
used to cluster patients with very low risk Wilms tumor. The two identified clusters were distinguished by
histology (differentiated epithelial vs mixed), nephrogenic rests (few identified vs. intralobal) and relapse
risk. (11). A further clustering of gene expression profiles identified five subsets showing differences in
their pathologic and clinical features that may lead to the development of subset-specific treatment
strategies.(18)
The NWTS database as a resource (6, 8, 10, 19, 20) The NWTS continues to collaborate with other
investigators conducting a variety of studies of Wilms tumor including both clinical and epidemiological
studies. One important collaboration is a case-control study based on telephone interview of NWTS cases
and controls matched for age and geographic region. One report from this study failed to confirm earlier
reports of an increased risk for Wilms tumor among children exposed to household pesticides, either in
utero or through early childhood. (6) Another noted an increase in risk of Wilms tumors occurring in
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NWTS 4941L Progress Report - Page 8
association with perilobar nephrogenic rests (PLNR) for children with high birth weight. (8) This report
failed to confirm several associations with obstetric factors reported from earlier, smaller studies. In the
most recent report, no consistent association was observed between risk of Wilms tumor in the offspring
and maternal exposure to medical radiation. (10)
Two recent clinically oriented studies investigated the prognostic significance of lung lesions detected by
CT but not CXR, and of lymph node involvement, respectively, in patients with favorable histology
Wilms tumor. (19, 20) These studies demonstrate the continuing importance of the records maintained by
the NWTS Late Effects Study.
Congestive Heart Failure (CHF).
We are collaborating with the Childhood Cancer Survival Study (CCSS) to investigate congestive heart
failure (CHF) in Wilms tumor (WT) survivors on a substudy for which Dr. Chow is the lead investigator.
We confirmed the occurrence of CHF in 104 NWTS patients, of whom 84 were not part of the original
CCSS cohort (childhood cancer cases diagnosed during 1970-86). These 84 patients, and a random
subcohort (n=400), have been used to validate a cardiovascular (CV) risk score developed by Dr Chow
and his collaborators. Dr. Chow and his research staff have completed abstraction of actual doses of
doxorubicin from NWTS charts for 5 year survivors among cases and controls (non-cases in subcohort).
This information has been combined with radiation doses already abstracted by NWTS staff and was used
to validate several CHF prediction models developed based on CCSS data. Depending on the model,
NWTS data demonstrated comparable performance to CCSS data, with AUC=0.72-0.76 for CHF
prediction at age 40 years. A manuscript describing this project has been published in the Journal of
Clinical Oncology (25). The subcohort used for this study will also be used to study other outcomes
(using a case-cohort study design).
In another collaborative project related to CHF, we have carried out analyses to determine the
best anthracycline equivalence formulas for conversion between daunorubicin and doxorubicin doses
based on risk of CHF, rather than hematologic toxicity, which has been the basis for most previous
equivalence formulas. For this project, we are using the same NWTS case-cohort data from the Chow
study above, combined with data from the CCSS (N =12411), the St Jude Lifetime Cohort Study (N =
1695) and the Emma Children’s Hospital Academic Medical Center (AMC) in the Netherlands (N =
1349). In total, there are 273 CHF cases from all sites. This collaboration was led by Elizabeth Feijen,
MS, who was a visiting scholar at the Hutchinson Center from the Netherlands during the spring of 2014
to work with Drs. Chow and Leisenring on this project. Results illustrate a consistently steeper
cardiotoxicity dose response curve for doxorubicin compared with daunorubicin, which contrasts with the
equivalence ratio values generally used today (i.e. those based on hematologic equivalence). These
results were presented at the European Symposium on Late Complications after Childhood Cancer in
September, 2014 and recently published in the Journal of Clinical Oncology (26).
An additional collaboration is underway with the Chemotherapy Cardiotoxicity Collaborative
Group (CCCG) organized by the Oxford (UK) Clinical Trials Study Unit. This will involve patients from
two randomized trials of doxorubicin conducted as part of NWTS 2-3. Data on cardiovascular events,
patient characteristics and WT treatments will be pooled with similar data from other randomized trials of
anthracycline therapy around the world. A shared data file was submitted in June of 2013 and Dr.
Breslow attended a collaborative meeting with the team of investigators in October, 2013. The CCCG
group continues to collect data from other studies and still plans to carry out a combined analysis of the
data.
Newsletter The eleventh edition of the study newsletter, Late Breaking News, was prepared as part of
DSC staff service of providing information and referrals to participant families. The newsletter was
published online (http://www.nwtsg.org/newsletter/newsletter.html) and mailed to study participants in
late 2014.
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NWTS 4941L Progress Report - Page 9
VII. Study Conclusions:





The major medical endpoints (second malignancy, congestive heart failure, pulmonary restrictive
complications, renal failure) that are the focus of this study are uncommon events, even for
Wilms tumor survivors. Most patients treated on modern protocols can look forward to a
relatively normal life following cure. The increased frequency of these events among patients
who received (large doses of) radiation therapy and/or doxorubicin as part of their primary
therapy justifies continuing efforts to identify subgroups of “high risk” patients, so that others
may be spared such therapy.
Patients whose Wilms tumor occurs as a result of a germline WT1 mutation or deletion,
particularly those with the DDS and WAGR congenital malformation syndromes or incomplete
forms of these, have a higher risk of renal failure leading to end stage renal disease. Re-evaluation
of current guidelines that mandate a 2-year delay in transplant following WT treatment in these
patients may be warranted.
Former Wilms tumor patients are generally quite capable of becoming parents of normal children.
Female survivors who received (larger doses of) abdominal radiation therapy experience a
somewhat higher incidence of pregnancy complications and low birth weight deliveries.
The incidence of familial Wilms tumor is low. Survivors may be counseled that the risk of Wilms
tumor in offspring is low.
Wilms tumor is heterogeneous as a pathogenetic entity. Molecular studies are needed to help
discriminate subtypes that cannot now be identified on the basis of precursor lesions.
VIII. Summary – Recommendations and Future Plans:
Since the receipt of the renewed funding from NIH in August of 2012, efforts have focused on restarting
and prioritizing work within the study. Some senior staff members retired, and new staff has been
recruited. As of August 1, 2012, Dr. Wendy Leisenring has taken on the role of PI for the study while Dr.
Breslow enters semi-retirement, though he will maintain an active role as co-investigator. A major effort
has been made to increase participation of NWTS-5 patients; the availability of biological material for
most of these subjects will permit novel hypotheses to be tested as they reach the ages where late effects
occur at higher incidence. Institutions are urged to cooperate with this process. Record matches with the
National Death Index and the United States Renal Data System are planned for future years that will
provide follow-up data to complement the direct follow-up undertaken by NWTS. Similarly, we have
begun the process of acquiring an updated data set from the USRDS to ascertain new cases of ESRD in
our cohort.
IX. Study Publications (since 2005)
1. Breslow NE, Collins AJ, Ritchey ML, Grigoriev YA, Peterson SM, Green, DM: End stage renal
disease in patients with Wilms tumor: Results from the National Wilms Tumor Study Group and
the US Renal Data System. J Urol 174:1972-5, 2005
2. Breslow NE, Beckwith JB, Haase GM, Kalapurakal, JA, Ritchey ML, Shamberger RC, Thomas
PRM, D’Angio GJ, Green DM. Radiation therapy for favorable histology Wilms tumor:
Prevention of flank recurrence did not improve survival on National Wilms Tumor Studies 3 and
4. Int J Rad Biol Onc Phys 65:203-9, 2006.
3. Breslow NE, Beckwith JB, Perlman EJ, Reeve, AE: Age distributions, birth weights, nephrogenic
rests and heterogeneity in the pathogenesis of Wilms tumor. Pediatr Blood/Cancer 47:260-267,
2006.
4. Friedman DL, Qu A, Kalapurakal J, Grigoriev YA, Peterson SM, Norkool PA, Breslow NE:
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5. Cotton CA, Peterson SM, Norkool PA, Breslow NE: Evaluation of mortality in the National
Wilms Tumor Study using the National Death Index. Epidemiol Perspect Innov 4:5, 2007
6. Cooney MA, Daniels JL, Ross JA, Breslow NE, Pollock BH, Olshan AF: Household pesticides
and the risk of Wilms tumor. Environ Health Perspect 115:134-7, 2007.
7. Feusner JH, Ritchey MA, Norkool PA, Takashima JR, Breslow NE, Green DM. Renal failure
does not preclude cure in children receiving chemotherapy for Wilms tumor: A report from the
National Wilms Tumor Study Group. Pediatr/Blood/Cancer 50:242-5, 2008
8. Daniels JL, Pan IF, Olshan NE, Breslow NE, Bunin GR, Ross JA: Obstetric history and birth
characteristics and Wilms tumor: a report from the Children’s Oncology Group. Cancer Causes
Control, 19(10):1103-10, 2008
9. Cotton CA. Peterson S. Norkool PA. Takashima J. Grigoriev Y. Green DM. Breslow NE. Early
and late mortality after diagnosis of Wilms tumor. J Clin Oncol 27:1304-9, 2009
10. Goel R, Olshan AF, Ross JA, Breslow NE, Pollock BH: Maternal exposure to medical radiation
and Wilms tumor in the offspring. A report from the Children’s Oncology Group. Cancer Causes
Control, 20(6):957-63, 2009
11. Sredni ST, Gadd S, Huang CC, Breslow N, Grundy P, Green DM, Dome JS, Shamberger RC,
Beckwith JB, Perlman EJ. Subsets of very low risk Wilms tumor show distinctive gene
expression, histologic and clinical features. Clin Cancer Res, 15(22):6800-9, 2009.
12. Shamberger RC, Anderson JR, Breslow NE, Perlman EJ, Beckwith JB et al., Long term outcomes
for infants with very low risk Wilms tumor treated with surgery alone in National Wilms Tumor
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13. Warwick AB, Kalapurakal JA, Ou SS, Green DM, Norkool PA, Peterson SM, Breslow NE:
Portal hypertension in children with Wilms tumor: a report from the National Wilms Tumor
Study Group. Int J Radiation Oncology Biol Phys, 77(1):210-6, 2010.
14. Breslow NE, Lange JM, Friedman DL, Green DM, Hawkins MM, Murphy MF, Neglia JP, Olsen
JH, Peterson SM, Stiller CA, Robison LL. Secondary malignant neoplasms after Wilms tumor: an
international collaborative study. Int J Cancer 127(3):657-66, 2010.
15. Green DM, Lange JM, Peabody EM, Grigorieva NN, Peterson SM, Kalapurakal JA, Breslow NE.
Pregnancy outcome after treatment for Wilms tumor: a report from the national Wilms tumor
long-term follow-up study. J Clin Oncol,28(17):2824-2830, 2010.
16. Lange J, Peterson SM, Takashima J, Grigoriev Y, Ritchey ML, Shamberger RC, Beckwith JB,
Perlman E, Green DM, Breslow NE. Risk factors for end stage renal disease in non-WT1syndromic Wilms tumor. J Urol, 186:378-386, 2011.
17. Grigoriev Y, Lange J, Peterson SM, Takashima JR, Ritchey ML, Ko D, Feusner JH,
Shamberger RC, Green DM, Breslow NE. Treatments and outcomes for end-stage renal
disease following Wilms tumor. Pediatr Nephrol, 27:1325-1333, 2012
18. Gadd S, Huff V, Huang CC, Ruteshouser EC, Dome JS, Grundy PE, Breslow N, Jennings
L, Green DM, Beckwith JB, Perlman EJ. Clinically relevant subsets identified by gene
expression patterns support a revised ontogenic model of Wilms tumor: a Children's
Oncology Group Study. Neoplasia;14(8):742-56, 2012.
19. Grundy PE, Green DM, Dirks AC, Berendt AE, Breslow NE, Anderson JR, Dome JS.
Clinical significance of pulmonary nodules detected by CT and Not CXR in patients
treated for favorable histology Wilms tumor on national Wilms tumor studies-4 and -5: a
report from the Children's Oncology Group. Pediatr Blood Cancer, 59(4):631-5, 2012.
20. Ehrlich PF, Anderson JR, Ritchey ML, Dome JS, Green DM, Grundy PE, Perlman EJ,
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Kalapurakal JA, Breslow NE, Shamberger RC. Clinicopathologic findings predictive of
relapse in children with stage III favorable-histology Wilms tumor. J Clin Oncol,
31(9):1196-201, 2013
21. Green DM, Lange JM, Qu A, Peterson SM, Kalapurakal JA, Stokes DC, Grigoriev YA,
Takashima JR, Norkool P, Friedman DL, Breslow NE. Pulmonary disease after treatment
for Wilms tumor: A report from the National Wilms Tumor Long-Term Follow-Up
Study. Pediatr Blood Cancer, 60(10):1721-1726, 2013
22. Kalapurakal JA, Perlman EJ, Seibel NL, Ritchey M, Dome JS, Grundy PE. Outcomes of
patients with revised stage I clear cell sarcoma of kidney treated in National Wilms
Tumor Studies 1-5. Int J Radiat Oncol Biol Phys 85:428-431, 2013.
23. Green D, Breslow N, D'Angio G, Malogolowkin M, Ritchey M, Evans A, Beckwith JB,
Perlman E, Shamberger R, Peterson S, Grundy P, Dome J, Thomas P, Kalapurakal J.
Outcome of patients with stage II/favorable histology Wilms tumor with and without
local tumor spill. A report from the National Wilms Tumor Study Group. Pediatr Blood
Cancer, 61(1):134-9, 2014.
24.
Lange JM, Takashima JR, Peterson SM, Kalapurakal JA, Green DM, Breslow NE. Breast
cancer in female Wilms tumor survivors: A report from the National Wilms Tumor Late
Effects Study. Cancer120:3722-30, 2014.
25.
Chow EJ, Chen Y, Kremer LC, Breslow N, Hudson MM, Armstrong GT, Border WL,
Feijen EAM, Green D, Meacham L, Meeske KA, Mulrooney DA, Ness KK, Oeffinger
KC, Sklar CA, Stovall M, van der Pal HJ, Weathers RE, Robison LL, Yasui Y. Individual
prediction of heart failure among childhood cancer survivors. J Clin Oncol, 33:394-402,
2014.
26.
Feijen EA, Leisenring WM, Stratton KL, Ness KK, van der Pal HJ, Caron HN,
Armstrong GT, Green DM, Hudson MM, Oeffinger KC, Robison LL, Stovall M, Kremer
LC, Chow EJ. Equivalence Ratio for Daunorubicin to Doxorubicin in Relation to Late
Heart Failure in Survivors of Childhood Cancer. J Clin Oncol. 33:3774-3780, 2015.
X. Prepared by
Wendy Leisenring ScD (Principal Investigator, Study Statistician)
Daniel Green MD (Study Chair)
Susan Peterson MBA (Project Manager)