Pediatr Blood Cancer 2014;61:1394–1397

Evaluation of Radiation Dose to Cardiac and Pulmonary Tissue Among Patients WithStage IV Wilms Tumor and Pulmonary Metastases

Ahsan Farooqi, PhD,1* Arsalan Siddiqi, PhD,2 Mohammad K. Khan, MD, PhD,2 and Natia Esiashvili, MD2

INTRODUCTION

Lungs are the most common site of hematogenous metastasis in

Wilms tumor (WT), with approximately 10% of all WT cases, and

80% of stage IVWT patients showing some evidence of pulmonary

involvement at initial diagnosis [1,2]. In these patients, whole-lung

irradiation (WLI) is frequently given at diagnosis, usually within

2 weeks from resection of a primary tumor, along with abdominal

radiotherapy (RT) and chemotherapy to control the metastatic and

primary sites of disease. However, the International Society of

Pediatric Oncology (SIOP) demonstrated that 75% of patients with

stage IV WT and pulmonary metastases responded to pre-

nephrectomy chemotherapy consisting of vincristine, dactinomy-

cin, and doxorubicin [3]. Overall survival in this group was

approximately 83% using this treatment strategy [3].

Drawing from SIOP experience, the Children’s OncologyGroup

(COG) initiated a clinical trial (AREN 0533) which limits

pulmonary RT to only those patients with stage IV WT and

pulmonary metastases who fail to respond to 6 weeks of treatment

with chemotherapy. Currently, around 60% of patients enrolled in

AREN 0533 are still requiring pulmonary RT due to persistence of

pulmonary metastases following chemotherapy [4]. Thus, in these

patients, RT is given sequentially leading to overlap of the

abdominal fields with the pulmonary radiation fields. The exact

doses and objective radiation dose limits are not well quantified in

the current AREN 0533 protocol.

Late complications secondary to chemotherapy and radiothera-

py are observed in approximately 25% of patients with Wilms

tumor and are a significant cause of mortality among the

survivors [5–8]. The cumulative frequency of congestive heart

failure (CHF) is 4.4% at 20 years with the relative risk of CHF

increasing with doxorubicin dosage (3.3/100mg/m2), lung irradia-

tion (1.6/10Gy), and left abdominal irradiation (1.8/10Gy) [9].

Pulmonary complications are seen in approximately 4% of patients

at 15 years from diagnosis, with substantially higher risk in patients

that received whole-lung irradiation (WLI) due to pulmonary

metastases (PM) [10]. We suspect that the radiation doses to the

heart and lungs in the sequential approach may be significantly

greater than the historical concurrent radiation approach, and may

increase the incidence of long-term cardiopulmonary toxicities.

METHODS

Patient Selection

For this study, we retrospectively identified 16 patients with

stage IV favorable histology (FH) Wilms tumor and pulmonary

metastases who received radiotherapy at our institution between

2006 and 2012 (Table I). Of the 16 patients, 12 received concurrent

radiotherapy (RT) to their flank/whole abdomen and lungs at the

time of diagnosis, and the remaining 4 received sequential treatment

in that they were first treated for their flank/abdomen for local

disease, and later received WLI to eradicate pulmonary metastases

that were unresponsive to chemotherapy. The CT simulation scans

for each patient were used to simulate either a sequential or

concurrent treatment. This resulted in a total of 32 treatment plans

that were evaluated for heart and lung dosimetric endpoints.

Patient Simulation and Planning

Patients were positioned supine and computerized tomography

(CT) simulation scans were generated. CT slice thickness was 2–

3mm. The lung planning treatment volume (PTV) was determined

by contouring of the three-dimensional clinical target volume

(CTV) representing whole-lung volume (generated from CT

Background. Most patients with stage IV Wilms tumor (WT) andpulmonary metastases are treated with surgery, local radiotherapy(RT), and whole-lung irradiation (WLI). The Children’s OncologyGroup is studying whether WLI should only be given if metastaticlung lesions persist following induction chemotherapy. We hypoth-esized that radiation dose to cardiac and pulmonary organs areincreased when WLI and abdominal RT fields are administeredsequentially. Procedure. We retrospectively identified 16 patientswith stage IV WT and pulmonary metastases to model dosimetryplans for concurrent and sequential flank or whole abdomen andwhole-lung fields. Results. Treatment plans were evaluated fordosimetric endpoints to the heart and the lungs. The mean dose (Gy)was significantly higher to the heart (15.8 vs. 12.1, P<0.0001) and

lungs (14.1 vs. 12.2, P<0.0002) when patients with stage IVWT andpulmonary metastases were treated with sequential RT. The percenttissue organ volumes (V) receiving highRT doses of 15 and 20Gy (V15

and V20) were negligible in concurrent treatment plans. Compara-tively, mean V15 and V20 values for sequential treatment plans were35% and 27%, respectively, for the heart, and 15% and 12%, for thelungs. Conclusions. The dose to the heart and lung tissue issignificantly increased when WLI and abdominal RT fields areadministered sequentially. While omission of WLI may be beneficialfor patients achieving good response to induction chemotherapy, theless favorable response group may be subjected to increased risk ofcardiac and pulmonary toxicities from sequential WLI. Pediatr BloodCancer 2014;61:1394–1397. # 2014 Wiley Periodicals, Inc.

Key words: late effects; radiation oncology; Wilms tumor

1Texas Tech University Health Sciences Center, School of Medicine

Cancer Center, Lubbock, Texas; 2Department of Radiation Oncology,

Winship Cancer Institute, Emory University School of Medicine,

Atlanta, Georgia

Conflict of interest: Nothing to declare.

�Correspondence to: Ahsan Farooqi, Texas Tech University Health

Sciences Center School of Medicine Cancer Center, 3601 4th Street

Mail Stop 9445 Lubbock, TX 79415-6450.

E-mail: ahsan.farooqi@ttuhsc.edu

Received 18 December 2013; Accepted 3 February 2014

�C 2014 Wiley Periodicals, Inc.DOI 10.1002/pbc.25007Published online 28 February 2014 in Wiley Online Library(wileyonlinelibrary.com).

images) with an additional margin of 1 cm for setup and respiratory

motion. For whole abdomen irradiation, the entire peritoneal cavity

was defined as the CTV that included the dome of the diaphragm as

the superior border with 1 cm PTV margin. Flank irradiation fields

encompassed target volume covering pre-operative gross tumor

volume based and involved kidney with at least 1 cm setup margin

and also with the medial border extended to cover the entire

vertebral body. In cases of lymph node involvement, the entire para-

aortic nodal chain was covered in clinical target volume. The CT

simulations were used to create 3D-CRT plans with standard

anterior/posterior (AP)-posterior/anterior (PA) field techniques

(Aria1 Oncology Planning System) using 6-MV photons (Varian

Trilogy Dual-Energy Linear Accelerator, Palo Alto, CA). Patients

who were treated concurrently at the time of diagnosis were

prescribed a total dose of 10.5Gy in 7 fractions to the flank or whole

abdomen (based on indication from pathological findings, i.e.,

presence or absence of peritoneal seeding with tumor cells). Lung

PTV received a total of 12Gy (10.5Gy as part of combined lung/

abdominal field plus additional 1.5Gy to lung PTV). Patients who

were treated sequentially were prescribed 10.8Gy to their flank

fields in 6 fractions or 10.5Gy to whole abdominal fields initially,

and then followed by 12Gy in 8 fractions to the whole-lung fields

(Fig. 1). In all cases, RTwas prescribed to the midplane of the AP/

PA fields and received 100% of the total dose.

Data Analysis

Normal tissue organ volumes (V) receiving high RT doses were

compared between patient treatment plans receiving either

sequential or concurrent RT. The percent tissue organ volumes

(V) receiving high RT doses of 15Gy (V15) and 20Gy (V20) were

calculated for each treatment plan and used for comparison. For the

purposes of this study, dose-volume comparisons were made for the

heart and lungs. The mean dose received by organs at risk (whole

heart and lungs) using either the concurrent or sequential treatment

plans were compared using the two-tailed paired samples t test.

Statistical significance was defined as a P-value of less than 0.05.

RESULTS

A total of 16 patients presenting with stage IV WT and

pulmonary metastases (PM) underwent radiation at our institution

Fig. 1. This image illustrates traditional radiotherapeutic fields used for whole-lung irradiation (WLI) and local radiotherapy (RT) to the primary

tumor site in the setting of a patient with stage IVWTand pulmonarymetastases. ImageA displays a single treatment field that encompasses disease

in both the left flank and the lungs, representing concurrent treatment. ImageB shows the significant overlap that occurs between the flank andWLI

treatment fields, were this patient to be treated sequentially. Note that the overlap occurs over areas which contain significant amounts of cardiac and

pulmonary tissue, resulting in increased radiation dosage to these organs.

TABLE I. Characteristics of Patients With Stage IVWilms Tumor

Patient Gender

Age of

diagnosis

(year)

Concurrent (C)

or sequential (S)

Local site

of radiation

1 Female 5 C Left

2 Female 9 C Right

3 Female 2 C Whole

abdomen

4 Female 7 C Left

5 Female 5 C Left

6 Male 2 C Right

7 Male 9 C Left

8 Female 4 C Left

9 Female 6 C Whole

abdomen

10 Male 5 C Left

11 Male 8 C Left

12 Female 7 C Left

13 Female 5 S Left

14 Male 6 S Left

15 Male 3 S Left

16 Female 5 S Left

Pediatr Blood Cancer DOI 10.1002/pbc

Evaluation of Radiation Dose in Wilms Tumor 1395

as part of this study (Table I). To produce a robust data set for dose-

volume comparison, we generated simulation plans for each of the

16 patients for both concurrent and sequential treatment. We

observed that due to overlap of treatment fields for abdominal/flank

irradiation and WLI (Fig. 1), patients who undergo sequential

treatment received a higher dose of radiation to critical organs such

as the heart and lungs. The mean dose received by the heart was

significantly (15.8 vs. 12.1, P< 0.0001) higher when patients were

treated sequentially (Fig. 2A, Table II). Similarly, the mean dose

received to the lungs was significantly increased (14.1 vs. 12.2,

P< 0.0002) when patients underwent sequential RT (Fig. 2B,

Table II). Patients 3 and 9, who required whole abdominal

irradiationþWLI, received the highest combined dose to the heart

and lungs when treated sequentially (Table II), due to a larger area

of overlap relative to patients receiving flank irradiation and WLI.

Note that there was no difference in combined dose to the heart and

lungs for concurrent treatment plans between the patients receiving

whole abdominal irradiation versus flank irradiation.

We also quantified the normal tissue organ volumes (V)

receiving high RT dosages of 15 and 20Gy (V15 and V20), in these

simulated treatment plans for both the heart and lungs. Because the

maximum dose to the heart and lungs in concurrent treatment plans

was less than 15Gy in all cases, the V15 and V20 values were

negligible. However, mean V15 and V20 values for sequential

treatment plans were 35% and 27%, respectively, for the heart, and

15% and 12%, for the lungs (Table II). These data support our

Fig. 2. Comparison of mean cardiac and lung doses between concurrent and sequential radiotherapy in the management of patients with stage IV

WTand pulmonary metastatic disease. A: The mean cardiac dose was found to be significantly (P< 0.0001) higher when patients were planned to

receive sequential irradiation to the flank/abdomen first, followed by whole-lung irradiation. B: Similarly, the mean lung dose was significantly

(P< 0.0002) increased among the sequential RT treatment plans as well.

TABLE II. Dosimetric Comparison of Mean Dose to Heart and Lungs, Among 16 Patients With Stage IVWTand Pulmonary Metastases

Patient

Heart Lungs

Mean dose

concurrent (Gray)

Mean dose

sequential (Gray)

Sequential

V15|V20 values

Mean dose

concurrent (Gray)

Mean dose

sequential (Gray)

Sequential

V15|V20 values

1 12.3 18.5 69%|55% 12.5 14.0 16%|11%

2 12.6 16.7 50%|30% 12.7 15.4 28%|20%

3 12.4 20.3 79%|68% 12.6 17.6 49%|40%

4 12.2 17.0 50%|42% 12.5 14.1 13%|9%

5 12.2 12.8 0%|0% 12.6 13.3 2%|1%

6 12.1 16.4 43%|35% 12.2 15.5 30%|25%

7 12.3 15.4 28%|21% 12.4 13.6 9%|6%

8 12.3 18.3 61%|50% 12.4 14.1 13%|9%

9 12.4 20.6 64%|58% 12.3 17.3 44%|38%

10 12.6 16.9 47%|34% 13.0 14.3 16%|11%

11 12.5 15.9 30%|21% 12.5 12.7 3%|2%

12 12.4 12.4 0%|0% 12.3 12.3 0%|0%

13 10.9 13.5 11%|4% 11.1 12.4 5%|3%

14 12.3 12.3 0%|0% 12.3 12.3 0%|0%

15 10.8 14.2 21%|10% 11.1 12.9 6%|1%

16 11.2 12.9 0%|0% 11.3 13.7 8%|6%

Mean 12.1 15.8 35%|27% 12.2 14.1 15%|12%

P< 0.0001 P< 0.0002

Pediatr Blood Cancer DOI 10.1002/pbc

1396 Farooqi et al.

hypothesis that dosage to the heart and lung tissue is increasedwhen

RT is administered sequentially, as opposed to concurrently at the

time of diagnosis in patients with stage IV disease and pulmonary

metastases.

DISCUSSION

Radiation therapy (RT) is one of the major contributors to side

effects seen among patients treated for Wilms tumor [5]. Prior

studies conducted by the National Wilms Tumor Study Group

(NWTS) attempted to limit the use of RT, and established that RT

can be omitted for patients with stages I and II disease and favorable

histology (FH), and lowered the treatment dose to 1,080 cGy (from

2,000 cGy) for patients with stages III and IV FH tumors [11–13].

However, controversy remains in regards to the use of RT to treat

lung metastases of patients with stage IV disease. The International

Society of Pediatric Oncology (SIOP) found that the majority of

patients with stage IV disease can achieve a long-term complete

response (CR) using only dose-intensive chemotherapy, and

reported a good event-free survival (EFS) and overall survival

(OS) with this strategy [14]. However, the number of patients who

ultimately received lung RT due to relapse was not reported in this

study. In another study conducted by the United Kingdom

Children’s Cancer Study Group (UKCCSG), EFS was severely

compromised in patients with stage IV disease when pulmonary RT

was withheld (79.2% vs. 53.3%, P¼ 0.009) [15]. Based on these

reports, it has been proposed that there exist two groups of patients

with stage IV WT and pulmonary metastases (PM): those that

respond to initial chemotherapy and show resolution of PM, and

those that require further therapy including whole-lung irradiation

(WLI) to eradicate chemorefractory disease.

The Children’s Oncology Group (COG) is studying whether it is

effective to limit pulmonary RT to only those patients who fail to

respond to 6 weeks of treatment with doxorubicin, dactinomycin,

and vincristine. Based on initial report, approximately 40% of

patients are showing complete response (CR) to pulmonary disease

following treatment with chemotherapy, whereas the remaining

60% are progressing to receiveWLI [4]. Unfortunately, there are no

good biomarkers to assess which patients are likely to respond to

chemotherapy, andwhichwill require chemotherapyþWLI to treat

pulmonary metastatic disease.

Our study introduces another variable that needs to be addressed

with regards to the role of RT in the management of patients with

stage IV WT and pulmonary metastases. Our data indicate that

patients not achieving complete response to initial chemotherapy

and undergoing sequential RT will inadvertently receive a

significantly higher dose of radiation to the heart and lungs. This

is largely due to the overlap that occurs in traditional treatment

fields for the flank/abdomen and the lungs. In these patients, the

increased dose received to the heart and lungs places them at an

increased risk of developing serious late-stage complications

frequently seen among WT survivors, such as pulmonary fibrosis,

and congestive heart failure [9,10].

Our data also highlight the importance of identifying novel

strategies based on more sophisticated methods for evaluating

tumor burden in the lungs or the use of tumor biomarkers that may

aid in discriminating between those patients whose metastases are

likely to respond to chemotherapy and those who will need more

intensive treatment such as WLI. Molecular studies have indicated

that elevated mRNA levels of telomerase components, hTERT,

encoding the telomerase catalytic component, and hTR, encoding

the telomerase RNA component, correlate with a negative

prognosis in Wilms tumor and an increased chance of recur-

rence [16,17]. Furthermore, loss of heterozygosity for chromo-

somes 16q and 1p in Wilms tumor predicts an adverse outcome

[18]. It is possible that these genetic changes, or other unknown

molecular events, confer resistance to chemoradiotherapy in the

setting of stage IV Wilms tumor. A recent report suggests that

survival of patients with stage IV WT and pulmonary metastases is

highly dependent upon primary tumor histology [19]. In this study,

patients were treated with pre-nephrectomy chemotherapy using

the SIOP strategy and then histologically graded following surgery

using the revised SIOP classification of renal tumors [20]. Overall

survival was found to be significantly poorer in children with high-

risk primary tumor histology (OS 44.4%) compared to intermediate

risk (OS 89.2%, P< 0.001) and low risk histology (OS 100.0%,

P< 0.001). These data indicate that high-risk histology may be

used as a marker to identify patients that require more aggressive

therapy at diagnosis.

In conclusion, our data show that patients with stage IVWTand

pulmonary metastases are exposed to increased radiation dose to

cardiac and pulmonary tissue if they undergo sequential RT as

opposed to concurrent RT. Additional studies are needed to identify

those patients with stage IV disease whowill require intensification

of therapy, and those in whom omission of WLI will be a safe

strategy for achieving good disease outcome and lower long-term

toxicities.

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