METHODS
This study includes 42 patients with a unilateral or bilateral WT with a local Stage III disease who
received a low-dose (10.8 Gy) or lower-dose (9 Gy) flank radiotherapy (RT) or whole abdominal irradiation
between 1998 and 2018. Patients had undergone either upfront surgery followed by adjuvant
chemotherapy (CXT) or neoadjuvant CXT followed by surgery. Patients with lung metastasis without a
complete response to CXT also received whole lung irradiation (WLI) of 9?12 Gy.
RESULTS
The disease was staged as III in 22, IV in 12, and V in nine patients, respectively. After a median follow-up
of 75 months, the 2-and 5-year overall survival, locoregional relapse-free survival, and distant metastasisfree
survival rate was 92% and 79%, 87% and 76%, and 75% and 69%, respectively. None of these survival
rates were significantly different among 9 Gy and 10.8 Gy doses. Among patients receiving WLI, the lung
relapse rate was also similar between <12 Gy and 12 Gy of irradiation. Late toxicity was observed in 4
(10%) patients as scoliosis, cardiac dysfunction, renal injury with hypertension, and short stature in each.
CONCLUSION
De-escalated RT of 9 Gy to the flank or abdomen does not compromise oncologic outcomes in patients
with a local Stage III WT.
Keywords: De-escalated treatment; radiotherapy; Wilms
The first national multi-centric WT program was
conducted by the Turkish Pediatric Oncology Group
(TPOG) in 1997.[
Treatment of all patients were decided by a multidisciplinary tumor board. Upfront surgery followed by adjuvant CXT was performed in patients eligible for surgery. If the tumor was not amenable for total resection or in case of a thrombus, neoadjuvant CXT was administered. CXT regimens consisted of vincristine (1.5 mg/m2 [2 mg maximum] once weekly for 4 weeks) and actinomycin-D (15 µg/kg/day for 5 days in the 1st week) (VA) every 6 weeks, or vincristine (same dose once weekly for the first 10 weeks, then every 3 weeks), actinomycin-D (same dose), and doxorubicin (20 mg/ m2/day for 3 days) (VAD) +/- etoposide (E) (100 mg/ m2/day for 3 days) every 6 weeks for 12 and 18 months for Stage III and IV disease, respectively.
All patients were treated with a 9-10.8 Gy in 1.8-Gy
fractions flank RT or 9?0.8 Gy in 1.5-Gy fractions WAI.
If RT started on Monday, 9 Gy was applied, if started on
another day of the week, 10.8 Gy was applied. Patients
were treated with 2-dimensional (2D)-external beam
RT (EBRT) before 2009 and 3-dimensional conformal
RT (3D CRT) or volumetric modulated arc therapy
(VMAT) after 2009. The clinical target volume (CTV)
was the tumor at diagnostic imaging plus a 1-cm margin
including the whole operative bed. Whole vertebral
bodies were included in the RT portals at the levels concerned.
Involved LN sites were irradiated in patients
with gross LNs at diagnosis or metastatic LNs found in
the pathology specimen. In case of a tumor thrombosis
in the renal vein or inferior vena cava, the thrombus bed
was also included. The planning target volume (PTV)
was formed with a 0.7-1 cm margin to the CTV for 3D
CRT and VMAT plans which were optimized according
to the requirement that ≥95% of the PTV and ?99% of
the CTV received 95% of the prescribed dose. Patients
with pre-operative tumor rupture, diffuse tumor spillage
during surgery or peritoneal seeding received WAI.
In case of compromised surgical margins, flank RT was
also added. WAI included the whole abdominal cavity
from the dome of the diaphragms superiorly to the
inferior aspect of the obturator foramina including the
lateral peritoneal reflections. All efforts were made to
decrease the dose to the contralateral kidney.[
Patients without a complete response in the lungs
after the first course of adjuvant CXT underwent 9-12
Gy whole lung irradiation (WLI) in 1.5-Gy fractions.
The RT field included both lungs from the apices superiorly
to the level of the posterior costophrenic angles
inferiorly, the lateral borders being bilateral thoracic
walls. Patients with residual macroscopic nodule(s) following
WLI also received a boost dose to the nodule(s).
All patients were evaluated weekly during the
course of RT and followed every 3 months for the first
2 years, every 6 months until the 5th year, and annually
thereafter following RT. The incidence of acute and late
toxicity was evaluated based on Common Terminology
Criteria for Adverse Events version 4.0.[
Statistical analyses were performed using Statistical
Package for the Social Sciences version 23.0 (SPSS
Inc., Chicago, IL, USA). The primary end points were
LRC and patterns of failure. Secondary end points included
OS, EFS, locoregional recurrence-free survival
(LRRFS), distant metastasis-free survival (DMFS), and
treatment toxicity. LRC was defined as no relapse in the
renal fossa, or relapsed or de novo LN(s) in the renal
and the para-aortic (PA) region, and DM as the relapse
in a distant localization, diffuse peritoneal disease, or
extra-abdominal LN(s). OS was defined as the time
from diagnosis to the last follow-up or death from any
cause; EFS as the time from diagnosis to the date of LRR or DM, whichever comes first, or death from any cause;
LRRFS as the time from diagnosis to the date of LRR
or death from any cause; and DMFS as the time from
diagnosis to the date of DM or death from any cause,
respectively. Survival analyses were carried out using
the Kaplan?Meier method and compared using the
log-rank test. The risk factors (RF) (e.g., ones making a
local Stage III disease according to the TPOG plus neoadjuvant
CXT) were also analyzed. Multivariate analysis
was performed using the Cox proportional hazards
model. P<0.05 was considered statistically significant.
A biopsy was performed in 12 (28%) patients.
Twenty-nine (69%) patients underwent neoadjuvant
CXT (VA: 8, VAD: 9, VAD-E: 2). The response to
neoadjuvant CXT was partial in 26 (87%), stable in one
(3%), and progression in three (10%) tumors. Median
time to surgery was 63 days (range: 4?407 days). Total
nephrectomy was performed for 38 tumors whereas
four patients underwent partial nephrectomy. The disease
was Stage III in 22 (52%), IV in 12 (29%), and V
in 8 (19%) patients, respectively. Detailed surgical and
histopathological findings are shown in Table
Median time from surgery to RT start was 20 days
(range: 3?152 days). RT was started in the first 14 days in 12 (28%), and later than day 14 in 31 (72%) patients,
respectively. The reason for late RT is the late
referral of patients from other clinics. However, all patients
that applied late to our department had received
CXT until RT start. Flank RT alone was applied for 30
(70%) tumors and WAI for seven (16%), respectively.
Six (14%) tumors with residual disease after surgery
were treated with WAI followed by a flank RT boost.
Fourteen (33%) patients received WLI, and a boost
dose (7.2-9 Gy) to residual nodules was applied in two
patients. RT details are given in Table
Median follow-up was 75 months (range: 8-278 months). The 2- and 5-year OS rate was 92% and 79%, respectively. The 2-and 5-year EFS rate was 75% and 69%, respectively. Four patients developed LRR. The 2-and 5-year LRRFS rate was 87% and 76%, respectively. Most relapses (92%) occurred within 2 years of diagnosis. In relapsed patients, median OS was 16.3 months with a 2-and 5-year OS rate of 33% and 33% after recurrence, and 75% and 33% after diagnosis, respectively. Total relapse rate was significantly higher in Stage IV patients (62%) compared to Stage III patients (14%) (p=0.002). Factors associated with a higher rate of LRR were renal vein invasion and a higher number of RF (p=0.049 and p=0.005, respectively). The 2- and 5-year LRC rate was similar between <10.5 Gy and ≥10.5 Gy (88% and 88% vs. 96% and 96%; p=0.4). Duration between surgery and RT had no impact on the LRC rate (p=0.55).
Eleven (26%) patients developed DM during the follow-up (64% in the lung). The 2-and 5-year DMFS rate was 75% and 69%, respectively. Factors associated with a higher rate of DM were capsular invasion and peritoneal invasion (p=0.02, and p=0.013, respectively). The lung relapse rate did not differ between <12 Gy and ≥12 Gy WLI (p=0.9), and neither did the survival rates (p=0.5 for OS, p=0.4 for EFS, p=0.3 for LRRFS, and p=0.4 for DMFS, respectively).
In univariate analysis, peritoneal invasion and
higher stage significantly decreased all survival rates.
Male gender also decreased the EFS, LRRFS and DMFS rates. Other prognostic factors are shown in Table
EFS: Event-free survival; RT: Radiotherapy; LRRFS: Locoregional recurrence-free survival; Gy: Gray.
No severe acute toxicity was observed during RT. Late toxicity was observed in four (10%) patients. One patient developed scoliosis after 9 Gy WAI followed by 9 Gy flank RT via 2D EBRT at 4 years old, and developed scoliosis 10 years after RT was completed. She has also been observed for suspicious diabetes and is now alive with lung metastases. One patient diagnosed at age 1 developed systolic cardiac dysfunction 13 years following adjuvant CXT and 10.5 Gy WAI and is still alive with no evidence of disease. One patient developed renal failure and hypertension 2 years after adjuvant CXT was completed. She was diagnosed at age 3 and underwent neoadjuvant CXT, total nephrectomy, and 10.8 Gy flank RT. She is alive with no evidence of disease but under anti-hypertensive drugs. Finally, one patient is observed with a short stature who was diagnosed at age 3, received 10.8 Gy flank RT, and is alive with no evidence of disease. No patients devel- oped a secondary malignancy. One patient succumbed to complications of a salvage stem cell transplantation for relapsed disease.
We follow the recommendations of TPOG WT protocol
in which the main difference of RT from NWTS is
the reduced dose to the flank/abdomen. With 9 Gy deescalated
RT, we found the 2-and 5-year OS rate 92%
and 79% for all, 96% and 88% for Stage III, and 83%
and 56% for Stage IV patients; and the 2-and 5-year
EFS was 78% and 69% for all, 85% and 85% for Stage
III, and 51% and 31% for Stage IV patients, respectively.
In the NWTS-2 with 18-40 Gy RT, the 2-year OS
and relapse-free survival (RFS) rate was 84% and 70%
for Stage III, and 54% and 49% for Stage IV disease,
respectively.[11] In the NWTS-3 with a lower RT dose,
the 2-year OS and RFS rate was 92% and 85% for all
patients, and the 4-year OS and RFS rate was 73% and
68% in Stage III and IV disease, respectively.[
Although TPOG recommends upfront surgery, the
majority of our patients had undergone neoadjuvant
CXT due to unresectable tumors at diagnosis. Neoadjuvant
CXT is recommended by recent The International
Society of Pediatric Oncology (SIOP) guidelines which
primarily aims to reduce the need for RT due to abdominal
spillage during surgery. Flank doses varied between
15 Gy and 30 Gy based on disease stage and risk
groups with an additional boost dose to positive LNs in
the older SIOP trials.[
The primary aim of this study was to compare the
oncologic outcomes with regard to the flank RT dose.
The rationale for our de-escalated RT dose comes from the radiobiologic phenomenon of tumor repopulation
between RT fractions. We found no significant difference
in terms of LRC with 9 Gy when compared to
10.8 Gy. The recurrence rate was 29% which was significantly
higher in Stage IV disease compared to Stage
III. This rate is similar to the NWTS-3 results with a
relapse rate of 14?23% for Stage III favorable histology
(FH), 21-28% for Stage IV FH, 32?34% for Stage I?III
unfavorable histology (UH), and 42?47% for Stage IV
UH, respectively.[
In the NWTS-3, 10 Gy and 20 Gy WAI were equally
effective in patients with diffuse tumor spillage.[2] We
also did not find a significant difference in oncological
outcomes between 9 Gy and 10.8 Gy WAI. Besides,
<12 Gy WLI yielded similar results to 12 Gy in our
study. The main pattern of failure was DM, in accordance
with the previous data.[
The rate of DM in our study was found 26%, mostly
being in the lungs. This rate might seem high for patients
treated with a curative intend. However, all patients in
our series are already high-risk and the vast majority of
them could start RT later than 14 days due to late referral
to our center. Therefore, the 26% of DM rate is not
higher than the outcomes reported in the literature.
The AREN0532 study including Stage III disease
with FH revealed male gender as an independent negative
factor for OS and EFS.[
The Childhood Cancer Survivor Study reported
increased congestive heart failure, renal failure, and
hypertension rates in children treated for WT compared
to their siblings with hazard ratios of 23.6, 50.7,
and 8.2, respectively.[
Deterioration of the linear growth caused by vertebral
irradiation which is unavoidably included in the
RT field is dose-dependent.[
Limitations of the Study
The present study has some limitations. It is retrospective
in nature and the number of patients is limited as
we aimed to report our results in a homogenous group.
Although the plot lines of survival analyses were broad
from each other, we could not find a statistical significance
for prognostic factors reported in the literature.
Importantly, we showed that 9 Gy local RT does not
compromise LRC or survival outcomes in patients with
a local Stage III WT. Besides, <12 Gy WLI seems adequate
in patients with lung metastasis.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved by the Hacettepe University Non-İnterventional Clinical Trials Ethics Committee (no: 16969557-1558, date: 03/11/2020). Financial Support: None declared.
Authorship contributions: Concept - C.A., T.K., F.Y.; Design - M.Gül., B.A., B.Y., S.E.; Supervision - C.A., M.Gül., B.Y., M.Gür., T.K., F.Y.; Funding - None; Materials - A.E., S.Y.S., B.A., A.V., S.E.; Data collection and/or processing - A.E., S.Y.S., B.A., A.V., S.E.; Data analysis and/or interpretation - A.E., S.Y.S., M.Gül., M.Gür., F.Y.; Literature search - A.E., S.Y.S., F.Y.; Writing - A.E., S.Y.S.; Critical review - C.A., M.Gül., T.K., F.Y.
