The Treaimeni of Wilrns’ Tumor:

Results of the Second National Wilms’ Tumor Study

G. J. D’ANGIO, MD,* A. EVANS, MD,’ N. BRESLOW, PHD,t 6 . BECKWITH, MD,$ H. BISHOP, MD,* V. FAREWELL, PHD,t
W. GOODWIN, MD,§ L. LEAPE, MD,” N. PALMER, MD,# L. SINKS, MD,? W. SUTOW, MD,*’
M. TEFFT, M D , t t AND J. WOLFF, MD**

One-hundred-eighty-eight children up to 16 years of age were randomized in the second National

Wilms’ Tumor Study (NWTS) with tumors that were confined to the kidney and that had been totally
excised (Group I). Most fared well whether treated for six or for 15 months with both actinomycin D
(AMD) and vincristine (VCR). No postoperative radiation therapy (RT) was given. The two-year
relapse-free sur-vival (RFS) and two-year survival rates were 88 and 95%, respectively. Two-hundred-
sixty-eight ran-domized patients with more advanced local lesions (Groups I1 and 111) and 57 with
distant metastases (Group IV) had postoperative RT and were scheduled for 15 months treatment with
either AMD and VCR (Reg. C) or AM D plus VCR plus Adriamycin (Reg. D). The 77% two-year RFS
rate for Reg. D was significantly different from the 63% with Reg. C. As in the first NWTS, patients
with tumors of unfavor-able histology (UH) had a significantly worse prognosis than those with
favorable histology (FH), as did those with positive nodes. Survival rates at two years were 54% for UH
vs. 90% for FH, and 54% vs. 82% for those with and without lymph node involvement.
Cancer 47:2302-2311, 1981.

T HE NATIONALWILMS’TUMORSTUDY(NWTS)
was established in 1969 as a consortium of in-stitutions
concerned with the management of children with cancer. It
was anticipated that data on several hundred children could
be collected each year in this way and permit the study of the
tumor from multiple standpoints, including the trial of
competing treatment
regimens.
From the *Children’s Hospital of Philadelphia, Philadelphia,
Pennsylvania; tFred Hutchinson Cancer Research Center, Seattle,
Washington; $Children’s Orthopedic Hospital, Seattle, Washington;
IU.C.L .A., Los Angeles, California; IITufts New England Medical
Center, Boston, Massachusetts; #Columbus Childrens’ Hospital,
Columbus, Ohio: llGeorgetown University Hospital, Washington,
DC; **M. D. Anderson Hospital, Houston, Texas; ttRhode Island
Hospital, Providence. Rhode Island: and $Columbia University, New
York, New York.
Supported in part by USPHS Grant No. CA 11722.
Principal investigators enrolled in the three participating coopera-
tive study groups, Cancer and Acute Leukemia Group B, Children’s
Cancer Study Group, and Southwest Oncology Group, also received
support from the NIH.
The authors acknowledge the contribution made by the many
surgeons, pediatricians, and radiation therapists who treated these
children and without whom the study would have been impossible.
They also thank Drs. D. Fernbach, B . Jones, and H. B. Othersen, who
became members of the NWTS Committee in the latter days of
NWTS- 2, Drs. R. Shalek and W. Hanson of the Radiological Physics
Center, and J . Meyer, P. Norkool. J. Takashima, J. Larners and D.
Sim of the Data and Statistical Center.
Address for reprints: G . J . D‘ Angio. Children‘s Cancer Research
Center. 3400 Civic Center Blvd., Philadelpia PA 19104.
Accepted for publication October IS, 1980.
Enrollment in the first NWTS (NWTS-1) ended in
1974. The study design and results of several NWTS-1
investigations have been reported.”’” In brief, it was
found in the therapy trials that routine postoperative
radiation therapy (RT) conferred no advantage to babies
under 24 months of age with Group I tumors who also
received cyclic courses of actinomycin D (AMD) over a
period of 15 months. (See Table 1 for the grouping system
employed.) The result in older Group I children was
different. There were more infradiaphragmatic recurrences
in the nonirradiated patients. This eventually resulted in a
worse survival rate because abdominal recurrent disease
proved dif-ficult to control. The combination of AMD and
vin-cristine (VCR) was found to be superior to either agent
alone when given to children with more locally advanced
tumors (Groups I1 and 111). all of whom also received
postoperative irradiation. Preoperative vincristine therapy
was examined in patients with metastases at the time of
diagnosis (Group IV), all of whom received postoperative
RT, AMD, and VCR as well. The results were no better than
for Group IV children who received the same treatments
except for the preoperative VCR. Certain clinicopathologic
characteristics present at diagnosis were identified, which
helped predict treatment outcomes, chief among them being
the presence of anaplastic or sarcomatous histopathologic
features and the involvement of lymph

0008-543X/81/0501/2302 $1.00 Q American Cancer Society

2302
No. 9 RESULTSOF SECONDNWTS . D’Angio et (11.
nodes. Either of these indicated a poor prognosis.‘.’
Other substudies dealt with the epidemiology, diag-
nosis, surgery. and radiation therapy of these chil-
dren .3-l;.!l- l l
The second NWTS (NWTS-2) was built, in part, on
these observations. The study design is shown in Figure
1. Vincristine was added to AMD in the rnanage-ment of
Group I children, none of whom at any age were given
RT. This was done, first, because double agent
chemotherapy had been shown to be best in NWTS-1,
and second, to see whether VCR might substitute for RT
of the tumor bed, using historical data as a measure.
Group I patients were randomized
between those who received short and long courses of
chemotherapy. Group 11, 111, and IV patients were
divided between those who received AMD and VCR,
and those given AMD. VCR, and Adriamycin (ADR) as
a third agent, the activity of ADR against the Wilms‘
tumor having been identified by others during the course
of NWTS-l.12.’3All Group 11, 111, and IV children
received postoperative RT. Group IV patients were given
additional radiation to metastatic sites.
The results of the NWTS-2 therapeutic investiga-tions
are reported here.
Materials and Methods
The procedures and methods used in the second
NWTS generally followed those of the first study.:! The
opening date for Group I patients was October 1, 1974,
and for all other groups, January 1, 1975. Between those
dates and July 15, 1978, a total of 755 children having a
pre- or postoperative diagnosis of Wilms’ tumor were
registered in one of the three categories “randomized,”
“followed,” or “not-on-study.” At the time of registration
each patient was assigned by his physician to one of five
Groups representing different levels of disease extension
(Table I ) .
There were 5 13 children eligible for randomization
who hereafter will be termed “randomized.” These were
the patients for whom the registering institution agreed
to follow all aspects of the study protocol
including randomization of treatment. Stratified ran-
domization by institution, Group, and age was carried
out at six months postsurgery for Group I patients and at
six weeks for Groups 11, 111, and IV. How-ever, some
of the patients in this category were not actually
randomized because of early deaths from toxicity. or,
more commonly, persistence or reap-pearance of disease
prior to the scheduled time for randomization. Such
children are labelled “not assigned” or NA in the data
displays that follow.
The 87 children in the “followed” category were
treated and had data submitted according to protocol,
2303
TABLE1. National Wilms‘ Tumor Study Grouping System
The patient’s group is decided by the surgeon in the operating
room, and is confirmed by the pathologist. If the histologic diagnosis
and grouping will take more than 48 hours, the surgical grouping
stands, the patient is registered, and started on treatment.
Gt-orcp I-Tumor limited to kidney and completely excised
The surface of the renal capsule is intact. The tumor was not
ruptured before or during removal. There is no residual tumor
apparent beyond the margins of excision.
Grorcp 11-Tumor extends beyond the kidney but is completely excised.
There is local extension of the tumor, i . r . , penetration beyond the
pseudocapsule into the peri-renal soft tissues, or peri-aortic lymph
node involvement. The renal vessels outside the kidney substance are
infiltrated or contain tumor thrombus. There is no residual tumor
apparent beyond the margins of excision.
Grorrp 111-Residual nonhematogenous tumor confined to abdomen.
Any one or more occur: (1 ) The tumor has undergone biopsy or
rupture before or during surgery; (2) there are implants on peritoneal
surfaces; (3) there are involved lymph nodes beyond the abdominal
peri-aortic chains; (4) the tumor is not completely removable be-cause
of local infiltration into vital structures.
Grorcp IV-Hematogenous metastases.
Deposits beyond Group 111: r . g . , lung, liver, bone, and brain.
Grorrp V-Bilateral renal involvement either initially or sub-sequently.
but were either ineligible for or declined randomiza-tion
for any of several reasons. Before the study began each
institution had been given the option of electing to
exclude certain categories of patients defined by
u
IVCR 6.7.8wks.I
follow
3,6.9.12,15
VCR 6,7,8wks,
ADR 6 wks. 4 5.
75.105, 135 1011ow
* ~ o r o - o p= day I AM0 15 rnrg/Kg/d i 5
doys 7,14,21,28,35 VCR-15mq/rn2
subsequent courses = AM0 doses 05 obaue. VCR doys 181 5, doses os obave ADR 6
0mg/m2
FIG .1. National Wilms’ Tumor Study-?. Relapse-free survival and
survival curves for Group I patients by randomized treatment
regimen.
2304 CANCERM a y I
Vol. 47
group and age. Twenty such “institutional exclusions” were
assigned to the “followed” category, as were 14 excluded
for medical reasons, 25 for whom the family or physician
refused randomization either at the time of registration or
thereafter, and ten whose randomiza-tion date followed the
termination of the study. Miscel-laneous causes accounted
for the remaining 18 patients followed.
The 155 “not-on-study” patients, for whom only minimal
data were collected, were treated according to local
decisions. These included 35 children who were believed
by the responsible physician to be inoperable and who
therefore received preoperative therapy, making them
ineligible for randomization. Bilateral tumors were found in
34 children, 15 had therapy incompatible with protocol
requirements initiated at another institution, seven were
excluded on the basis of prior institutional agreement (see
above), and in 15 additional cases either the parents or
physician refused to participate. There were 12 cases of
mis-diagnosis, predominantly neuroblastoma and renal cell
car-cinoma, and 1 1 mesoblastic nephomas. Other causes
accounted for smaller numbers of “not-on-study” patients.
The 155 “not-on-study” (NOS) patients were com-pared
with the randomized and followed patients ac-cording to
group, age, histology, sex, and race. N o important
differences were detected except for the dis-tribution
according to group. There were higher pro-portions of
Group 111 and Group IV patients (26.9 and 25.9%),
respectively, in the NOS children than in the randomized or
followed categories. The values for the randomized
children are given below; for the fol-lowed patients, they
are 20.7 and 14.9%, respectively, for Groups I11 and IV.
Institutional elective exclu-sions accounted for the shift of
patients with more advanced disease to the NOS category.
Narrative reports and checklists of the surgery and
pathology findings were submitted for randomized and
followed patients, as was detailed information regarding
the radiation therapy administered. “Flow sheets“ giving
clinical information were submitted at periodic intervals.
These data, using only the 513 randomized patients, form
the basis for all the statis-tical analyses of treatment
effectiveness and toxicity reported below.
Endpoints (ind S t CI tisticrr 1 Proc.edure s
The major endpoint used to evaluate response to
treatment in Group I , 11. and 111 patients is “relapse-free
survival’’ (RFS), defined as the length of time between the
initial surgery and the earliest detection of
1981
abdominal recurrence, distant metastasis, or death (whether
or not tumor related). The anatomic pattern of relapse is
also considered, with relapses to the opera-tive site
distinguished from those occurring elsewhere in the
abdomen or in more remote areas. All but seven of the 513
randomized patients had some follow-up data reported and
are included in the actuarial esti-mates of the relapse-free
survival curves for various patient subgroups.’‘ Patients
with incomplete follow-up are kept in the analyses up to the
last date for which information is available. At the time this
report was prepared, 72 patients were known to have died,
and 262 of the 441 who were alive at last contact had been
followed at least two years. Only 40 had less than one year
of follow-up.
Statistical evaluation of the RFS curves for different
treatment groups was made in terms of the log-rank test,
whereby the observed number of relapses in each treatment
group is compared with an expected number calculated on
the assumption of no difference in re-lapse rates.’“.1hAll
the P values cited below for the comparison of RFS curves
are two-sided and refer to this test.
A frequently used summary statistic is the projected
proportion of patients remaining continuously disease-free
for two years after surgery. In fact, of 112 children who
have relapsed or died, 82 did so in the first year, as did 28
between 13 and 25 months. The two late re-lapses have
occurred at 908 and 923 days postsurgery. one in the lungs
in a Group I1 patient and the other in the contralateral
kidney in a Group I patient.
Nine Group I patients relapsed or died prior to
randomization at six months. Although these events are
shown in the RFS and survival curves, only those
occrrrriiig beyond six iiioiiths (iw corrtitert i n the log -
t u i i I\ c o i i i pcr risoii s o f t 11c trecr t i ~e i i t regin1 e m . One
Group I1 patient died of a pulmonary tumor embolus at
eight days and eight Group IV patients had persistent
metastatic disease at six weeks postsurgery. These patients
were not randomized and were counted in neither the
actuarial curves nor the log-rank compari-sons. Hence,
when comparing the RFS results for Group IV patients
presented below with those of other series, it is important to
remember that they are pre-dicted on the patient being
disease-free at six weeks postsurgery.
Similar analyses were made using death as the endpoint
without regard to cause.
Pretreatment investigations and details of NWTS
surgical, chemotherapy, and radiation therapy pro-cedures
have been reported elsewhere, and are re-peated here
briefly in conjunction with the elements of the study
design.’,”,”’‘’
No . 9 RESULTSOF SECONDNWTS . D'Augio et al.
Study Design
Group I patients were not to be irradiated post-
operatively and were to be given AMD and VCR at the
time of surgery and six weeks, three months and six
months thereafter. After receiving that fourth course,
those who remained free of disease were randomized
either to discontinue therapy (Regimen E) or to continue
three additional three-month double-agent chemotherapy
up to the 15th month (Regimen F). Groups 11, I l l , and
1V were to be given postoperative RT, A M D , and
VCR, with the AMD + VCR repeated every three
months for a total of six courses. Six weeks after surgery,
those who remained disease free were randomized
between two arms (Regimens C and D). Regimen D
patients received ADR at that point and at three-month
intervals thereafter for a total of five ADR courses. Thus,
t h e y received some form of chemo-therapy every six
weeks, whereas the Regimen C children continued only
the three monthly courses of AMD + VCR.
SlI rg c. ry
Radical nephrectomy using a transabdominal ap-
proach was specified. The opposite kidney was to be
exposed and palpated, and a biopsy was done of all
suspicious lymph nodes.
HLidiiitioti Thcirripy ( R T )
RT was to be started within ten days of surgery and
directed to the llank unless there was diffuse tumor spillage
within the peritoneal cavity; in this case the whole abdomen
was to be treated. The age-adjusted RT dose scheme used is
shown in Table 2. Group IV patients also received RT to
metastatic sites as follows:
Piilmoiiciry nietci.3ttcise.s: The whole thorax was to be
irradiated in daily doses ranging from 150-200 rad for
a total dose of 1400 rad. Midway in NWTS-2, com-
bined chemo- and radiation therapy pneumonopathy was
identified in approximately 10% of patients so treated.
Thereafter, it was recommended that the total dose to
the lungs be reduced to 1200 rad.s The portals specified
extended from the lung apices superiorly to the level of
the posterior costophrenic angles inferiorly, the lateral
limits being the thoracic walls. The growth centers of the
proximal humeri were to be blocked; otherwise, there
was to be no shielding.
Lii-er: The liver was to receive in its entirety no more
than 3000 rad in 3%-4 weeks, but supplements of 500-1000
rad were permissible at the discretion of the radiation
therapist, e . ~, .to localized areas of bulky disease.
2305
TABLE2. Total Tumor Dose according to Age
Age (mo) Total tumor dose (rad)
Birth to 18* 1800-2400
19-30 2400- 3000
3 1-40 3000- 3500
41 or more 3500-4000
* I n each age bracket. higher doses are given to older children.
Bruin arid Bone: These areas received 3000 rad with
500- 1000 rad supplements permissible for large tumors.
All treatments were to be given with megavolt equip-
ment or the equivalent. Daily doses were to be 200 rad,
with the recommendation that they be reduced to 150 rad
if large volumes ( i . e . , whole abdomen or whole thorax
plus flank) were to be encompassed. No cor-rection was
to be made for tissue inhomogeneity and all fields were
to be treated daily when multiport plans were being
followed. For instance, both the anterior and the
posterior fields were to be treated each day when paired,
opposing, parallel arrangements were prescribed.
Chemot h ertipy
The frequency and timing of each of the agents are
shown in Figure 1. The doses of the individual agents
follow:
Actinomycin D (AMD)-15 pg/kg/d I.V. for five days
repeated at six weeks and three months and then at three-
month intervals. Groups 11, 111, and IV did not receive
the six weeks' course. (See Fig. 1.)
Vincristine (VCR)- 1.5 mg/M'/d I.V. once weekly for
the first 6-8 weeks, and then two doses in one week at
three-month intervals timed to coincide with the AMD
courses.
Adriamycin (ADR)-60 mg/M'/d I.V. once at three-
month intervals, starting six weeks after surgery.
The doses of all chemotherapeutic agents were re-
duced to one-half for babies under 13 months of age
because the chemotherapy used in NWTS-I proved to be
especially toxic for them.
Results
Groirping
Table 3 shows the distribution of the 513 randomized
patients by Group and regimen. Subtracting the 14 Group
1 patients carried over from 1974, the per-centage
distribution by Group is I-34.9%; II-32.9%; III-20.8rO;
1V-l1.4%. The contrast between this and the distribution
(I-45.4%; II-27.8%; III-19.5%; and IV-7.2%) for
randomized NWTS-1 pa-tients' is statistically significant
(xi1 = 11.56, P = 0.01).
2306 CANCERMay 1 1981 VOl. 47

TABLE3. Baseline Patient Characteristics according to Group and Randomized Treatment Regimen

Age
Regional
No . of Sex 0-23 24-47 48+ Racet Histology: lymph nodest
Group Reg* PtS (% male) R cir 7% (5% nonwhite) (8unfavorable) (% positive)

I NAf 9 77.8 77.8 11.1 11.1 0.0 44.4 0.0

E 88 56.8 60.2 17.1 22.7 15.1 7.8 0.0
F 91 42.9 56.0 23.1 20.9 11.5 4.9 0.0
I NA 1 100.0 0.0 0.0 100.0 0.0 0.0 0.0
C 84 41.6 19.0 32.1 48.8 18.5 11.0 19.2
D 79 50.6 26.6 29.1 44.3 10.8 11.5 25.0
111 C 53 47.2 24.5 37.7 31.1 19.2 14.3 30.6
D 51 47.1 11.8 31.4 56.9 20.0 21.3 20.0
IV NA 8 37.5 12.5 37.5 50.0 16.7 42.9 37.5
C 22 40.9 9.1 31.8 59.1 31.8 20.0 41.4
D 27 48.1 1.4 22.2 70.4 12.0 3.8 57.1
TOTAL 513 48.9 33.5 27.1 39.4 13.1 11.9 17.8

* See Figure 1. t NA = No regimen assigned (see text)

t Unknown values excluded.

The smaller percentage of Group IV patients in the first
study is due at least in part to the fact that they were
randomized on the basis of the preoperative diagnosis,
with those having metastases discovered at surgery
necessarily assigned to the “followed” category. The
difference in the ratio of 1:II patients between the two
studies reflects the option given investigators in NWTS-
2 to “upstage” older patients, or those with large tumors,
so as to ensure that they received radia-tion therapy. This
upstaging is also apparent when one compares the
institutionally assigned Group to that calculated
according to criteria from information supplied on the
surgery and pathology checklists. Excluding 38 patients
distributed among various groups lacking relevant base
line data, 8.8% of 171 Group I patients actually
belonged in Group I1 or 111, a mis-grouping percentage
similar to that observed for NWTS-1 . 2 However, 22.2%
of patients registered as Group I1 were found to have
localized Group I disease, which is almost twice the
misgrouping rate seen for this category on NWTS-1. The
pathology checklist for several other Group I1 patients
indicated the presence of tumor in the margin of surgical
re-section, technically a Group I11 criterion. Neverthe-
less, these deviations from the strict grouping criteria do
not bias the treatment comparisons. The randomiza-tion
process ensures that they are distributed equally among
the treatment groups, and the results for regimen C vs. D
in Group 11-IV patients are not altered in kind if one
excludes from analysis the patients who were apparently
upstaged.
for NWTS-1. Fewer misdiagnoses (1.6%) occurred in the
second study because registration was usually delayed
until after surgery. Of 478 patients for whom slides were
received, 57 were found by the NWTS pathologist (J.
B.B .) to have tumors of “unfavorable” histology: there
were 3 1 monophasic sarcomas, six of diffuse anaplastic
type and 20 with foci of anaplasia. This percentage (1
1.9%) of unfavorable histologic types is identical to that
found on NWTS-1. There were 35 additional patients
whose slides were not avail-able for review. They were
distributed, by group and regimen, as follows: Group I:
E-11, F-9; Groups II/III: C-6, D-5: Group IV: NA-1, C-
2, D-I. These 35 chil-dren with tumors of unknown
histology are included among their favorable histology
cohorts in all analyses. The differences in results
between patients with favorable and unfavorable
histologic characteristics to be recorded below are
accentuated when the 35 pa-tients are excluded from the
analyses.
Overall, 17.8% of NWTS-2 patients were found to
have microscopic tumor in regional lymph nodes. These
two characteristics were found to have the most
profound impact on outcomeXfrom reviews of NWTS-1
data that were being pursued as NWTS-2 progressed.
They are distributed among the treatment groups in a
manner compatible with the randomization, as are the
ages, sexes, and races of the patients (Table 3).
Of the 57 Group IV patients, 47 had pulmonary
metastases only, six had involvement of both lung and
liver, one of lung and bone, and three of liver only.

Protocol Violations
Baseline Characteristics Chemotherapy: A total of 22 randomized patients was
The frequencies of bilateral tumors (4.6%) and meso- treated according to a regimen different from that to which
blastic nephromas (1.5%) are similar to those reported they had been assigned: ten switched from D
No.9 RESULTSO F SECONDNWTS D’Atigio et nl. 2307

to C, two from C to D, four from E to F, and six from F to 100

E. In addition to such switches, major deviations from the
chemotherapy protocol occurred with 3 1 patients: 15 on
regimen D and seven, five, and four on regimens C, E, and
F, respectively. The principal criterion for a “major
deviation” was a 50% or greater reduction in dose of one or
more study drugs during one or more courses without an 90
obvious medical cause such as substantial toxicity.

Rrrtlirrtioti therripy: There were 13 major deviations

reported in the radiation therapy protocol. Two Group I
patients, one E and one F, received a full dose of radiation
to the abdomen. Four Group 11-IV patients failed to receive ; I-
80
any abdominal radiation, one Group 111 received half the LL
W

a
protocol dose preoperatively and there were delays of ten or REGIMEN E REGIMEN F LOG RANK TEST
more days in starting therapy in a few more cases.

The policy followed for all patients with evident

protocol violations was to include them in the analyses
according to their original randomized group, as is con-
sistent with good statistical p r a ~ t i c e . ’Additional~
analyses were performed, which are not reported here, in
which patients were grouped according to the treat-ment
actually received. These had the effect of lessen-ing very
slightly the observed differences among regimens.
Twtrtiiirtit Rc,rrlts
Grorrp I : No statistically significant difference is noted
in the relapse-free survival (RFS) and survival curves for
patients receiving six vs. 15 months of chemotherapy (Fig.
2). Overall, 95% of the 188 Group I children, including
those not randomized at six months, are projected to be
alive at two years and 88% to remain continuously disease-
free until that time. Nine of 20 documented tumor relapses
occurred among 14 patients known to have an unfavorable
histology, and seven of the nine are dead at the time of this
report. The other two patients are surviving for two or more
years. Two more patients (with FH) died with evident
disease. Only five Group I children had abdominal sites
among the first manifestations of recrudescent disease.
Three of these cases, all with favorable histology, involved
the contralateral kidney only, one (with sarcomatous
features) both the liver and bone, and the fifth (with a
sarcomatous lesion) the original tumor bed and distant sites.
All three patients who developed metastases to bone had
tumors of the clear-cell sarcoma variety.; Three of the
patients who relapsed with pulmonary metastases, are
among the 15 Group I patients for whom the surgery or
pathology checklists actually indicated a Group I1 status.
Crorrps 11, Ill titid IV: The results for Groups I1 and 111
are quite similar so that these Groups were combined in the
analysis and presentation of the data.
I I I I I I L I I I I I J
6 12 18 24 30 36 42
MONTHS SINCE INITIAL NEPHRECTOMY
FIG . 2. Relapse-free survival and survival curves for Group I patients
by randomized treatment regimen. Early portions of both sets of curves
show deaths and relapses for patients experiencing those events prior to
the six months‘ randomization. These are not counted in the treatment
comparisons.
However, a breakdown is given according to whether
the tumors were of favorable (FH) or unfavorable (UH)
histologic type, and the NWTS-1 findings with respect to
the grave prognostic impact of the latter is confirmed (Figs.
3 - 5).
When analyzed in terms of RFS (Fig. 3), Group
11-111 FH patients receiving ADR in addition to AMD +
VCR (Regimen D) fare considerably better than those
receiving only AMD and VCR (Regimen
C) . The results for Group 11-111 UH and Group IV
patients are in the same direction, but treatment dif-ferences
for these two categories are not statistically significant on
their own. The percentage of all Group 11-IV patients
randomized to Regimen C who remain disease free at two
years is 62.5%, compared with 77.1% for Regimen D, and
combining the log-rank test results over the three strata
leads to a highly significant P-value of 0.0004.
The difference between the two regimens is less
evident when analyzed using death as the sole endpoint
(Fig. 4). Survival curves for FH Group 11-111 patients
are, in fact, nearly identical for the first two years, after
which an additional four patients on Regimen C have
died compared with none on D. In contrast to the RFS
results, the greatest difference is noted for the survival of
UH Group 11-111 patients. For all
2308 CANCERM a y 1 1981 VOl. 47

100 None of these results is altered materially if cor-

rections are made for the 12 patients who actually
90 received a different treatment from that to which they
W were randomized.
W
a Results according to group: The two-year relapse-
w
v)
00 free survival rates for Groups I, 11, 111, and IV with-
a out reference to the treatment given or other factors
W

g 70 were 88, 78, 70, and 49%, respectively. Two-year sur-

c3
z vival rates in the same order were: 95, 90, 84, and
z 60 54%. These data, like the results of NWTS-I, demon-
Z
z
W strate that the grouping system serves to identify
a
I- patients at low, intermediate, and high risk, but the
5
0
50 differences between Groups 11 and 111 are minor and
a not statistically significant.
W

a 40 Results according to lyrnpli tiode status: The relapse-

free survival (RFS) rates are significantly less for pa-
30 Pts or Deaths PIS or Deolhs
tients with tumor identified in lymph nodes. Results
for patients with evaluable data stratified according

N o Relapses N o Relapses

csbs exp obs exp to various criteria are shown in Tables 4 and 5. The
GROUPIL-Ill
FAVORABLE HISTOCOGY 121 31 21.59 11 1 12 2141 0=0004 RFS rates, all patients considered, are 82.2 and 53.7%
for those without and with positive nodes (P < 0.0001).
They are 80.7 and 56.1%, respectively, (P< 0.001)
when only Group I1 and 111 children are analyzed.
I I , ,I I I, I I It 1 I 1 Toxicity: The most marked depressions of the
0 6 12 18 24 30 36 42 leukocyte and platelet counts and hemoglobin levels
MONTHS SINCE INITIAL NEPHRECTOMY
F H . FAVORA0LE HISTOLOGY, UH: UNFAVORABLE HISTOLOGY
were recorded during the early months of therapy,
especially in Groups 11, 111, and IV, no doubt because
FIG .3 . Relapse-free survival curves by randomized treatment of the initial combined chemo- and radiation therapy
regimen and histology for Group 11-111 patients and for Group IV
patients, any histology. course given these patients. The leukocyte, hemo-
globin, and platelet values after the six-weeks' course
Group 11-IV patients combined, the two-year sur- are shown in Table 6. Regimen D appeared to be the
vival percentages for C vs. D are 72.4 and 84.196, most toxic, as might be expected because it contained
respectively, and the adjusted P-value for testing the the third agent, ADR.
difference is 0.02. There was one cardiac death in a 4-year-old Group IV
patient who had received thoracic RT and a total of
TABLE4 . Relapse-free Survival: Lymph Node Involvement, 330 mg/M2 of ADR. This may have been one example
All Patients (Stratified by Histology) of the enhanced radiation reactions noted in some of
the patients receiving AMD and ADR along with RT.
No. relapses Percent
No. NED$ For instance, liver enlargement of greater or lesser
Histology Nodes* ptst OBS EXP fit 2 yr degree, at times associated with alterations of liver
function tests and thrombocytopenia, was seen in 20
Favorable NEGiNE 326 41 51.6 88.0
POS 67 26 9.4 56.8 among the 325 irradiated patients (6%). These latter
Unfavorable NEGiNE 40 22 26.2 42.5
findings are characteristic of combined therapy hepatic
POS 16 13 8.8 16.7 toxicity.j.IHConjoined toxicities were rarely sufficiently
Unknown NEG/NE 17 3 2.8 81.3
pronounced that major amounts of chemotherapy
POS 1 0 0.2 - were curtailed or discontinued because of adverse ef-
TOTALS NEGiNE 383 66 86.6 82.2 fects in the liver, kidney, or lung despite the known
POS 84 39 18.4 53.1 abilities of AMD and ADR to reactivate latent radi-
* N E = Not examined. ( P < 0.0001) ation damage. 1 9 m Combined modality initial therapy,
however, appeared to be associated with lethal com-
~~~ ~~

t Only for those for whom nodal status is known and for whom plications either directly or indirectly in some patients.
follow-up data are available. Thus, ten patients among the 513 children treated
$ NED = No evidence of disease.
OBS = observed (2%) died of toxicity or infection. Six were in Group 11,
EXP = expected two were Group IV, and there was one in each of the
 No . 9 RESULTSO F SECONDNWTS . D’Angio et (11. 2309

other groups. Three other children succumbed to

toxicity or infection while being treated intensively ....... ...... ,...
after relapse. U-Dl D/FH
....

Discussion
Treatment results obtained in the first National
Wilms’ Tumor Study were used to design NWTS-2.
RT was not found to provide a treatment advantage
to NWTS-I Group I children under two years of age;
the results were less encouraging in older patients, who
developed infradiaphragmatic relapses more frequently
than their irradiated counterparts. It was reasoned
that the efficiency of double-agent adjuvant chemo- 40 t n m C~UH
therapy utilizing actinomycin-D (AMD) and vincristine
(VCR), shown in NWTS-1 Group II/III children, could 3 0 l “ ’ . ’ . A

also be of benefit to Group I patients by not only 6 12 18 24 30 36 42

MONTHS SINCE INITIAL NEPHRECTOMY
destroying microscopic metastatic foci, but also by FH FAVORABLE HISTOLOGY, UH UNFAVORABLE HISTOLOGY
“protecting” the operative site and other intra-ab-
STRATUM REGIMEN C REGIMEN D LOG RANK TEST
dominal locations. Thus, AMD and VCR together NOOF DEATHS NOOF DEATHS
might substitute for RT in providing local control and
lead to better suppression of remote metastases as well.
FAVORABLE HIST PT5 I21
OBS
14
EXP 1202
PTS
Ill
OBS
9
EXP
I098
p:041
GROUPD - ID

Group 1 patients randomized in NWTS-2 fared ex- GROUP U-JD

9 547 4 753 p=005
tremely well. The two-year relapse-free survival rate is UNFAVORABLE HIST 16 I9

GROUP III 22 II 8 21 27 8 1079 p=O 19

88% and survival at two years is 95% with no sug- TOTAL IS9 34 2570 157 21 2930 p:OO2*

gestion that the results depend on duration of treatment 0 ADJUSTED FOR STRATA

or age. The two-year relapse-free survival rate for the

77 N WTS-2 Group I children two years of age or over FIG .4. Survival curves by randomized treatment and regimen
is 89V; it was 77 and 5896, respectively, for their 39 for Groups I1 and 111 by histology and Group IV. any histology.
irradiated and 41 nonirradiated age and group peers in
NWTS-I.’ The two-year survival rates in the same processes were: neuroblastoma ( 5 ) , renal cell car-
order are 97%, 9796, and 91%. It should be recalled cinoma (3), lymphoma ( l ) , and rhabdomyosarcoma (1).
that investigators could elect to “upstage” Group I Unlike NWTS-1, there was no indication that the
children to Group I1 if they were considered to be at older Group I patients had a worse outcome than their
particular risk. I t also should be recalled that there were
nine NWTS-2 Group I patients who relapsed or died TABLE5. Relapse-free Survival: Lymph Node Involvement.
before the six-monl h randomization point. Three of the Group I1 and 111 Patients (Stratified by Histology)
seven children in this subset for whom the histologic No . relapses Percent
type is known had UH. This underscores the fact that No . NEDS
such Group I patients are at high risk and need more Histology Nodes’ ptst OBS EXP ( ( I 2 yr

effective therapy during the early postoperative weeks. Favorable NEG/NE 160 22 30.8 86.5
The incidence of bilateral tumors (4%) and of meso- POS 46 16 7.2 60.6
blastic nephromas (2%) is very much the same as in Unfavorable NEG/NE 24 I? 13.7 47. I
N WTS-I, suggesting that the study population bases POS I1 8 6.3 24.2
were similar. Wrong diagnoses were less frequent in Unknown NEG/NE 4 1 1 .o
NWTS-2 (2 c’s. 5%). This may be an ascertainment POS 0 0 0.0
artifact: investigators in the first but not the second TOTALS NEGiNE 188 35 45.5 80.7
NWTS were requested to register all patients in whom POS 57 24 13.5 56.1
the preoperative diagnosis of Wilms’ tumor was ( P < 0.001)
strongly considered. Thus, the frequency in NWTS-2 * N E = Not examined.
may be a more accurate reflection of an irreducible t Only for those for whom nodal status is known and for whom
minimum of “wrong” preoperative diagnoses. Two of follow-up data are available.
t: NE D = N o evidence of disease.
the 12 NWTS patients had benign conditions (hydro- OBS = observed
nephrosis and polycystic kidney). The ten malignant EXP = expected
23 10 CANCERMay 1 1981 VOl . 47

TABL E6 . Summary of Hematologic Toxicities Encountered phasizes the importance of this determinant. Lymph
Following Six-week Course, by Therapeutic Regimen node involvement also has a strongly negative effect
Leukocyte Platelets on survival.
(9% under (5% under HGB Results are not good in children with metastases at
Group/ No . pts. 1oooi 50,OOOi (% under
regimen* evaluated cu mm) cu mrn) SgilOO ml) diagnosis (Group IV) regardless of histology whether
they received two- or three-agent chemotherapy. The
Group I (all) 168 0.0 4.2 7.1 RFS for Regimens C and D were 43 and 59%, respec-
Group 11-IV/C IS8 1.9 7.2 16.4
Group 11-IVID 140 17.1 7.6 30.9 tively, the differences not achieving statistical sig-
nificance.
* Actual regimen used. The conclusion that Regimen D (triple-agent chemo-
therapy) is superior to AMD + VCR (Regimen C) is
younger counterparts. The two-year relapse-free sur- based on aggregated results for Groups 11, 111, and IV,
vival (RFS) rates for NWTS-1 Group I patients aged although the same advantage appears when the in-
0- 1, and 2 + years were 89 and 6796, respectively. The dividual Groups are considered. It should be noted,
RFS rates for NWTS-2 Group I children similarly however, that the results with Regimen C in NWTS-2
stratified by age and in the same order were 88 and are different from those recorded in NWTS-1. Although
89%. Shifts in the other prognostic factors identified the differences are not statistically significant, better
in NWTS-I, other than age, may become apparent as RFS and TYS were noted in NWTS-I/C children than
late results of NWTS-2 are accumulated, but histologic in their NWTS-2 counterparts. The course of AMD
type and lymph node involvement continue to be the at six weeks was omitted by design in NWTS-2/C, and
most important determining factors. Overall relapse- it was thought possible that dropping the drug at this
free survival and two-year survival (TYS) by histology, early time during the course of treatment might have
been responsible for the discrepancy in result. A review
regardless of group, are shown in Figure 5 , which em-
of patients randomized to receive Regimen C in
NWTS-2 showed that 16 children were given the drug
100 at this time against protocol specifications. When the
FAVORABLE HISTOLOGY
results for those patients in NWTS-21C who did and
9 c.
2
z 90 - L who did not receive AMD at this time were reviewed,
>
a 00 it was found that no major differences could be de-
3
cn tected in either the RFS or TYS rates. N o other reason
for the apparent discrepancy can be identified, em-
phasizing the importance of concurrent, randomized,
W 60 DEATHS '- -; prospective controls in studies of this kind. This
Nopl s Obs Exp -
I__ _
Favorable 456 45 65 17 ------. matter is discussed at greater length elsewhere."
5 0 - Unfavorabla 57 27 683 L ----- ----- These data from NWTS-2 indicate that evaluation
40 - LOG RANK TEST p.0 0000
of prognostic factors must be considered in the light
of the era during which they are being studied. One
reason is that factors once of prognostic import lose
their significance as more effective therapeutic regi-
mens are devised, and relapse-free survival rates and
survival rates climb. Then, only those that indicate
--
6
I
1
\ I % R E L A P S E F R E E SURVIVAL] very poor or very good prognosis become important,
the former because more effective therapy must be
RELAPSES devised, the latter because treatment can be reduced
9
W
60 .' . Favorable456
No pts Obs
76
Exp
10270 without jeopardizing a good clinical result.22
a These several factors are taken into consideration
50t
. __ Unfavorable 57 36 9 22
LOG RANK TEST p=O.OOOO
L .. in the design of the third NWTS (NWTS-3), which was
lr a- ._
0 L. inaugurated May I , 1979. The third study continues
to seek refinements of therapy for those at low risk
d"
and more effective therapeutic regimens for those at
6 12 18 24 30 36 high risk. Thus, patients are stratified according to
MONTHS SINCE INITIAL NEPHRECTOMY histology and stage, and are randomized among dif-
FIG .S . Outcomes according to histology for all Group I-IV Ran- fering chemotherapy and radiotherapy regimens. An-
domized patients. other important part of NWTS-3 is the continuing
No. 9 RESULTSOF SECONDNWTS . D’Angio et 01. 2311

follow-up of NWTS-1 and -2 survivors to detect the late
effects of the treatments administered those children .u
REFERENCES
1. D’Angio GJ, Beckwith J B , Bishop H C et ul . The National
Wilms‘ Tumor Study: a progress report. Proc Nut/ Cancer Conf
1973: 7:67-7-636.
2 . D‘Angio GJ, Evans AE . Breslow N r t trl. The treatment of Wilms’
Tumor. Results o f t h e National Wilms’ Tumor Study. Cancer 1976;
38:633-646.
3. Tefft M. D‘Angio G J , Grant W. Postoperative radiation therapy for
residual Wilms‘ tumor. Review of Group 111 patients in the National
Wilms’ Tumor Study. Cuncer 1976: 37:2768-2772.
4. Pendergrass TW . Congenital anomalies in children with Wilms‘
tumor. Crrtrc.rr lY76; 37:403-409.
5. Tefft M. Radiation related toxicities in National Wilms‘ Tumor
Study-I. 1nt J Rirdirrt Oticol Biol Phyu 1977; 2:455-463.
6 . Bishop HC, Tefft M, Evans AE, D’Angio GJ. Survival in bilateral
Wilms’ tumor. Review of 30 National Wilms‘ Tumor Study cabes. J
Pc,tlitrtr .Yrtr,q 1977; 12:631-637.
7. Beckwith JB, Palmer NF . Histopathology and prognosis of
Wilms‘ tumor. Results from the First National Wilms‘ Tumor Study.
Crrric.cr 1978: 41: 1937- 1948.
8. Breslow N E , Palmer NF . Hill LR, Buring J , D’Angio GJ.
Wilms’ tumor: prognostic factors for patients without metastases at
diagnosis. Results of the National Wilms’ Tumor Study. Ctrncer
1978: 4 1 : 1577- 1589.
9. Leape L, Breslow N , Bishop H C . The surgical treatment of
Wilms’ tumor: results of the National Wilms’ Tumor Study.
Atiii Surg 1978: 187:351-356.
10. D’Angio GJ, Tefft M. Breslow N, Meyer J . Radiation therapy
of Wilms’ tumor: results according to dose, field, post-operative
timing and histology. I t i t J Radiut Oncol Biol Phys 1978; 4:769-780.
11 . Ehrlich R. Bloomberg S, Gyepes M , Levitt S , Goodwin W.
Wilms’ tumor, misdiagnosed preoperatively. A review of nineteen
National Wilms’ Tumor Study I cases. J . Urol 1979: 122:790-792.
12. Bonadonna G , Monfardini S , DeLena M , Fossati-Bellani F ,
Beretta G . Phase I and preliminary phase 11 evaluation of adriamy-
cin. Cnncer Res 1970: 30:2572-2582.
13. Tan C , Etcubanas E , Wollner N er r r l . Adriamycin-an
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17. Peto R, Pike MC, Armitage P et ul. Design and analysis of
randomized clinical trials requiring prolonged observation of each
patient. I . Introduction and Design. BrJ CrriiL.er 1976; 34:585-612.
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of the liver in children-Review of experience in the acute and chronic
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The Ontario Cancer Foundation Toronto-Bayview Clinic

Radiation Oncologists are required for this new cancer center which is associated
with Sunnybrook Medical Centre and the University of Toronto. Construction of the
out-patient and radiation treatment facility will be completed in September 1981.
There will be an a s o c i a t e d in-patient oncology unit of 85 beds in Sunny-brook
Hospital. An interim center is currently operational. The Centre will treat 2500 new
patients a year and will have a major research orientation. The initial staff will include six
Radiation Oncologists, six Medical Oncologists and three Physicists. The radiation
equipment will include two 25 MEV and one 6 MEV linear accelerator and a cobalt unit.

Radiation Oncologists will be responsible for the total care of patients treated
.with radiation, whether as in-patients or out-patients. Applicants should indicate
their research interests which will be an important consideration with these
appointments.

Interested individuals should send a curriculum vitae and the names of three referees
to: Dr. R . D. T. Jenkin, Director, The Ontario Cancer Foundation, ‘Toronto-
Bayview Clinic, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada