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\begin{document}

\title{Second Cancer Risk in Childhood Cancer Survivors Treated With
Intensity-Modulated Radiation Therapy (IMRT): An Updated Analysis of
More Than 10 Years of Follow-Up}



\author[1]{Kathryn Tringale}%
\author[2]{Dana Casey}%
\author[1]{Gregory Niyazov}%
\author[1]{Jessica Lavery}%
\author[1]{Chaya Moskowitz}%
\author[3]{Danielle Novetsky Friedman}%
\author[1]{Suzanne Wolden}%
\affil[1]{Memorial Sloan Kettering Cancer Center}%
\affil[2]{University of North Carolina System}%
\affil[3]{Memorial Sloan Kettering}%


\vspace{-1em}



  
  \date{May 28, 2024}


\begingroup
\let\center\flushleft
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\maketitle
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\selectlanguage{english}
\begin{abstract}
Background It is unclear how intensity-modulated radiation therapy
(IMRT) impacts long-term risk of second malignant neoplasms (SMNs) in
childhood cancer patients. Procedure Patients aged 10 years, many solid
SMNs after IMRT in childhood cancer survivors develop in the high dose
region. These data serve as a foundation for comparison with other
modalities of radiation treatment (e.g., proton therapy).%
\end{abstract}%



\sloppy


Second Cancer Risk in Childhood Cancer Survivors Treated With
Intensity-Modulated Radiation Therapy (IMRT): An Updated Analysis of
More Than 10 Years of Follow-Up

Kathryn R. Tringale\textsuperscript{1}, Dana L.
Casey\textsuperscript{2}, Gregory Niyazov\textsuperscript{3}, Jessica A.
Lavery\textsuperscript{4}, Chaya Moskowitz\textsuperscript{4}, Danielle
N. Friedman\textsuperscript{5}, Suzanne L. Wolden\textsuperscript{1}

Department of Radiation Oncology\textsuperscript{1}, Department of
Medical Physics\textsuperscript{3}, Department of Epidemiology and
Biostatistics\textsuperscript{4}, Department of
Pediatrics\textsuperscript{5}, Memorial Sloan Kettering Cancer Center;
Department of Radiation Oncology, University of North
Carolina\textsuperscript{2}

Corresponding Author:

Kathryn R. Tringale, MD MAS

tringalk@mskcc.org

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center

1275 York Avenue, New York NY 10065

Word Count

Abstract: 250

Manuscript: 2547

Tables: 3

Figures: 3

Supporting Documents: None

Short Running Title: Second Cancer Risk After IMRT

Keywords: Pediatrics, radiotherapy, second malignancies, survivorship,
IMRT

A version of this publication was presented at the annual American
Society of Radiation Oncology (ASTRO) meeting in Chicago, Illinois in
October 2021. The abstract is available online:
https://www.redjournal.org/article/S0360-3016(21)01523-6/fulltext.

Funding: Support for this work was provided to Memorial Sloan Kettering
Cancer Center by a core grant from the National Cancer Institute (P30
CA008748).\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Abbreviation & Phrase\tabularnewline
\midrule
\endhead
RT & Radiotherapy\tabularnewline
IMRT & Intensity-modulated radiotherapy\tabularnewline
IDL & Isodose level\tabularnewline
CSI & Craniospinal irradiation\tabularnewline
SIR & Standardized incidence ratio\tabularnewline
EAR & Excess absolute risk\tabularnewline
SMN & Second malignant neoplasm\tabularnewline
MDS & Myelodysplastic syndrome\tabularnewline
AML & Acute myeloid leukemia\tabularnewline
PA & Posteroanterior\tabularnewline
CNS & Central nervous system\tabularnewline
\bottomrule
\end{longtable}

ABSTRACT

Background

It is unclear how intensity-modulated radiation therapy (IMRT) impacts
long-term risk of second malignant neoplasms (SMNs) in childhood cancer
patients.

Procedure

Patients aged [?]21 years treated with IMRT between 1998-2009 and who
survived [?]5 years after IMRT were included. SMN site in relation to
isodose level (IDL) of IMRT was evaluated. Standardized incidence ratios
(SIR) and excess absolute risks (EAR) were calculated. Cumulative
incidences were estimated with death as a competing risk.

Results

Three hundred and twenty-five patients were included with median
follow-up of 11.2 years from IMRT (interquartile range, 9.4, 14.0) among
patients alive at the end of follow-up. Two hundred (62\%) patients had
[?]10 years of follow-up and 284 (87\%) patients were alive at the time of
analysis. Fifteen patients developed SMNs (11 solid, 4 hematologic).
Median time from IMRT to solid SMN was 11.0 years (range, 6.8-19.2) with
10- and 15-year cumulative incidences 1.8\% (95\% CI 0.7-3.9) and 3.5\%
(95\% CI 1.4-7.5), respectively; SIR was 13.7 (95\% CI 6.9-24.6) and EAR
was 2.8 per 1,000 person-years (95\% CI 1.0-4.6). Eight solid SMNs
developed within the IMRT field (100\% IDL {[}n=5{]}, 80\% IDL
{[}n=1{]}, 50\% IDL {[}n=1{]}, 40\% IDL {[}n=1{]}), one within the
70-80\% IDL of a conventional field, one was out-of-field, and one could
not be determined.

Conclusions

With median follow-up of \textgreater{}10 years, many solid SMNs after
IMRT in childhood cancer survivors develop in the high dose region.
These data serve as a foundation for comparison with other modalities of
radiation treatment (\emph{e.g.} , proton therapy).

INTRODUCTION

As treatments improve and the cohort of survivors from childhood cancer
increases, the risk of treatment-related toxicity becomes even more
relevant\textsuperscript{1}. It is known that radiotherapy is an
important risk factor in the development of second solid tumors in this
radiosensitive pediatric population\textsuperscript{2--4}.
Intensity-modulated radiotherapy (IMRT) is a highly conformal technique
that reduces the normal tissue volume exposed to a high radiation dose
yet can increase the volume of normal tissue exposed to lower doses, as
well as the total monitor units and integral dose to the
patient\textsuperscript{5,6}. Since radiation-induced carcinogenesis is
thought to follow a no-threshold, linear model, it has been theorized
that IMRT could increase the risk of SMN given the larger volume of
normal tissue exposed to some radiation. To investigate this, a
preliminary study of second malignancies in 242 childhood cancer
survivors after IMRT at our institution was published in
2015\textsuperscript{7}. At a median follow-up of 7.9 years, 4 patients
developed a second solid cancer with a 10-year cumulative incidence of
3.3\%. Here, we seek to expand upon this analysis with a larger cohort
and a median follow-up of more than 10 years.

METHODS

Patients

This study was a retrospective analysis of patients treated with IMRT at
[?]21 years of age at Memorial Sloan Kettering Cancer Center (MSKCC)
between December 1998 and February 2009. Patients were included if they
had survived and had follow-up data for at least 5 years after IMRT
initiation (n=325). The study was approved by the MSKCC Institutional
Review Board/Privacy Board. Data collected included age at diagnosis and
at IMRT initiation, sex, race, known hereditary cancer syndrome
(\emph{e.g.} , Li-Fraumeni, neurofibromatosis, or hereditary
retinoblastoma), primary tumor histology and location, chemotherapy
exposure, IMRT field, and IMRT dose. For patients exposed to
chemotherapy, the use of alkylating agents, anthracyclines, and/or
epipodophyllotoxins was specified.

Radiotherapy

IMRT field and dose were evaluated as previously
described\textsuperscript{7}. Specifically, the IMRT field was
categorized by site (e.g., central nervous system {[}CNS{]}), head and
neck, thorax, abdomen, pelvis, and extremities). If the patient was
exposed to IMRT on multiple occasions, the first exposure to IMRT was
used for the analysis. If the patient had multiple sites treated with
IMRT, the site with the highest dose was selected, and if the
prescription dose was the same, both fields were used. If the field
treated with IMRT was also exposed to conventional radiotherapy (18\% of
patients), the total dose was calculated and non-IMRT component was
noted, as previously described\textsuperscript{7}.

Determination of Second Malignant Neoplasm Development

Development of SMNs was captured by carefully reviewing the MSKCC
medical record, which includes outside correspondence with medical
professionals from other treating institutions. Of patients alive at the
time of analysis (n=284), 70\% and 75\% had follow-up within the last 2
and 3 years, respectively. Of all patients, 200 (61\%) had more than 10
years of follow-up from IMRT initiation. All SMNs were confirmed by
biopsy except for one patient whose family opted for comfort care, as
previously described\textsuperscript{7}. Imaging from the time of SMN
development was compared to the original IMRT plan to describe the
radiation dose delivered to and isodose level (IDL) at the site of SMN
development. Hematologic malignancies following IMRT were recorded
separately.

Statistical Analysis

Survivors were considered at risk of SMN starting 5 years after IMRT.
Cumulative incidence estimates of (1) all SMN and (2) second solid
malignancies occurring 5 or more years after the date of IMRT initiation
were calculated using the cumulative incidence method of competing
risks\textsuperscript{8}. Sensitivity analyses were also performed to
include patients who developed second cancers within 5 years (n=2).
Death was considered a competing event within both analyses, with
surviving SMN-free patients censored at the date of last follow-up.
Median time to SMN events is calculated descriptively among patients
that experienced an event. Standardized incidence ratios (SIR) were
assessed as the ratio of observed/expected cases of second cancer
development. Expected rates in the general population were obtained
using age-, gender-, and calendar-year specific cancer incidence rates
from the Surveillance, Epidemiology, and End Results (SEER)
Program\textsuperscript{9}. For calendar years after 2018, SEER rates
from 2018 were used, which are the most recently available. Excess
absolute risk (EAR) was computed by subtracting the expected number of
malignancies from the observed number of cases, dividing the difference
by the number of person-years of follow-up, and multiplying by 1,000.
For the SIR and EAR of second solid cancers, expected rates of solid
malignancies were obtained from the SEER Program by excluding
malignancies defined as leukemia, and calculations performed as above.
Statistical analysis was performed using R 4.1.0\textsuperscript{10}.

RESULTS

Patient Characteristics

Patient and treatment characteristics are described in Table 1. The
median age at IMRT initiation was 9.0 (range, 0.6-21.4) and 90 (28\%)
patients were [?]5 years of age. The most common primary cancer was
soft-tissue sarcoma (n=109, 34\%), followed by brain tumor (n=85, 26\%)
and neuroblastoma (n=64, 20\%). Most patients received chemotherapy
(n=282, 87\%), many of whom received alkylating agents (n=259, 80\%).
For all patients, the median follow-up was 11.0 years from IMRT (range,
5.1-20.5). Of the 284 patients alive at the time of analysis, median
follow-up was 12.0 years from diagnosis (5.4-34.2) and 11.2 years from
IMRT initiation (range, 5.1-20.1).

Second Solid Malignancies

Since the preliminary publication in 2015, 7 additional patients
developed a solid SMN for a total of 11 patients. Median time to solid
SMN from start of IMRT was 11.0 years (range, 6.8-19.2) among patients
with solid SMN, with 10- and 15-year cumulative incidences 1.8\% (95\%
CI 0.7-3.9) and 3.5\% (95\% CI 1.4-7.5), respectively (Figure 1). The
SIR was 13.7 (95\% CI 6.9-24.6) and EAR was 2.8 per 1,000 person-years
(95\% CI 1.0-4.6). Details of the patients who developed a solid SMN are
outlined in Table 2. The solid SMNs included high grade glioma (n=3),
osteosarcoma (n=3), colon adenocarcinoma (n=2), papillary thyroid cancer
(n=1), widely metastatic cancer of unknown primary (n=1), and presumed
sarcoma (n=1). Two patients had hereditary retinoblastoma, both of whom
developed secondary osteosarcoma. The mean dose to the IMRT field was
53.6 Gy (standard deviation, 24.3). On evaluation of site of SMN in
reference to the original IMRT plan as demonstrated in Figure 2, 5 solid
SMNs developed within the 100\% IDL of the IMRT field (3 osteosarcomas,
1 presumed sarcoma, 1 high grade glioma), 1 high grade glioma developed
within the 80\% IDL of the IMRT boost, 1 high grade glioma developed
within the 50\% IDL, and 1 colon adenocarcinoma developed within the
40\% IDL. A colon adenocarcinoma is estimated to have developed within
the 70-80\% IDL of the conventional posteroanterior (PA) field as part
of craniospinal irradiation at 20.5 years after RT (Figure 3). The
papillary thyroid carcinoma was out of the IMRT field. The metastatic
cancer of unknown primary could not be categorized in relation to IMRT.
The median adjusted prescription dose of IMRT was 54.0 Gy (range,
21.0-96.4) and the median dose to the site of SMN development (excluding
the unknown primary case, including the PA field case) was 36.9 Gy
(range, 0-96.4).

All Second Malignancies (Solid and Hematologic)

Since the preliminary publication, 4 additional patients developed a
second hematologic malignancy for a total of 6 patients with a second
hematologic malignancy. Details of patients who developed a second
hematologic malignancy are outlined in Table 3. The median age at IMRT
initiation among patients who developed a second hematologic malignancy
was 6.7 years (range, 2.9-9.1). Three patients developed myelodysplastic
syndrome (MDS), one developed acute myeloid leukemia (AML), and 2
developed MDS/AML. A total of 15 patients developed any SMN (11 solid, 4
hematologic) at a median time of 8.8 years from IMRT initiation (range,
5.9-19.2). Two of the patients who developed hematologic malignancies
did so within 5 years following IMRT (AML/MDS at 3.2 years and AML at
3.4 years). The 10- and 15-year cumulative incidences for any SMN 5
years after IMRT were 3.2\% (95\% CI 1.6-5.7) and 4.9\% (95\% CI
2.3-9.0), respectively (Figure 1). The SIR was 16.2 (95\% CI 9.1-26.8)
and EAR was 3.9 per 1000 person-years.

DISCUSSION

With a median follow-up of more than 10 years, we present the risk of
second malignancy after treatment of childhood cancer with IMRT. Since
the initial report in 2015, 7 additional patients developed a second
solid cancer, nearly all of which occurred more than 10 years after
IMRT. This updated analysis with a larger cohort and longer follow-up is
important to capture the long-term toxicity of SMN development after
IMRT.

The 10-year solid SMN cumulative incidence of 1.8\% reported here falls
within the range of risks previously reported following conventional RT
and does not suggest a relative increase in SMN from
IMRT\textsuperscript{3,11--15}. This comparable risk is encouraging
given the dose redistribution in IMRT leads to a larger volume of
low-dose exposure, which may present a risk for carcinogenesis as a
prior report found malignancies developing in tissue receiving less than
2.5Gy\textsuperscript{16}. Interestingly, in our cohort, second solid
malignancies developed most often within the high-dose region, with 5 of
11 subsequent tumors occurring within the 100\% IDL. The lowest doses in
our cohort were 15Gy (40\% IDL) and 18Gy (50\% IDL) at the sites where a
subsequent colon adenocarcinoma and high-grade glioma developed,
respectively. One patient developed a papillary thyroid cancer
completely out of the IMRT field. Although thyroid carcinogenesis can
occur after exposure of just 0.05Gy, with papillary comprising the most
common subtype, the pattern of development here suggests the
contribution of other risk factors, such as non-IMRT radiation exposure
(\emph{e.g.} , frequently diagnostic, on-treatment, and/or surveillance
imaging) and exposure to alkylating agents, which are known to increase
the risk of thyroid cancer more than 2-fold\textsuperscript{17,18}.

In the era of increasing availability of other radiation modalities,
such as proton beam RT, it is critical to understand how the risk of
second cancers compares between these approaches. While proton beam RT
introduces multiple potential advantages, such as sparing ``exit'' dose
and reducing the volume exposed to low- and intermediate dose, it is
unclear whether this dosimetric advantage leads to clinically meaningful
reduction in development of SMN. On the contrary, it has been theorized
that the passive modulation proton technique can potentially expose the
patient to an even higher dose of radiation distant from the target
compared to IMRT as a function of neutron production from the scattering
foil\textsuperscript{19}. To address this question, a recent study
published reported second cancer risks among 1713 children treated with
double-scattered proton therapy with a median of 3.3 years of
follow-up\textsuperscript{20}. While their study differed from our
report by including both benign and malignant tumors, as well as
including patients with less than 5 years of follow-up, they do report
results on a subset of 549 patients with at least 5 years of follow-up.
Among this subset, with a median of 7.1 years of follow-up, the 10-year
cumulative incidence of any second solid neoplasm (benign or malignant)
was 2.3\%, which is less than our preliminary report (3.3\%), leading to
their conclusion that proton beam RT does not seem to increase the risk
of second cancers and may in fact reduce the risk as seen in
adults\textsuperscript{21,22}. However, it is important to note that in
the current analysis of an expanded cohort with longer follow-up, the
10-year cumulative incidence of second solid malignancies after IMRT is
1.8\%. It is difficult to directly compare cumulative risk measurements
between studies with different methods and follow-ups as it is possible
that the 10-year cumulative incidence of second solid tumors reported by
Indelicato et al. may decrease with longer follow-up. Similarly, while
the subset of patients with long-term follow-up after proton therapy had
a relatively reduced SIR (10 vs 16.2) and EAR (1.2 vs 3.9 per 1,000
person-years) compared to our cohort, these estimates can vary widely
with methodology\textsuperscript{3,13,23}. These nuances, in addition to
the fact that most of the additional subsequent solid tumors developed
after 10 years in our cohort, highlight the importance of prolonged
follow-up to fully assess risk.

Additional factors beyond radiation therapy can contribute to secondary
malignancy risk, including initial tumor histology, genetic
predisposition, age, and systemic chemotherapy. In our cohort, all but
one patient who developed a second solid tumor had IMRT directed to the
head (including brain) and neck, which supports prior data demonstrating
an increased risk of second malignancy in patients with CNS
tumors\textsuperscript{3,13,24}. Five patients had a documented
hereditary predisposition syndrome: the 2 patients with hereditary
retinoblastoma both developed secondary solid cancers after IMRT, while
the 2 patients with Neurofibromatosis Type 1 and one patient with Li
Fraumeni Syndrome did not develop a second cancer. Of the 17 patients
who developed an SMN, all but one had been exposed to chemotherapy, and
of those, 94\% received an alkylating agent. Most chemotherapy-related
cases of AML/MDS occur within 5 years of treatment regardless of RT
exposure\textsuperscript{25}; therefore, the 2 hematologic malignancies
that developed \textless{}5 years after treatment in our cohort may be
explained by their exposure to epipodophyllotoxins. Younger age is a
known risk factor for radiation sensitivity and second cancer
development, which was supported by other analyses including the recent
study on subsequent neoplasm risk after proton beam
RT\textsuperscript{20}. This association was not clear in our data, as
9\% of the 90 patients aged [?] 5 years at IMRT developed a second cancer.
Interestingly, of the 6 hematologic malignancies, 2 patients were [?] 5
years of age at time of IMRT, one of whom developed AML/MDS \textless{}5
years after IMRT.

There are several limitations of this study. Like the preliminary
report, this study has a single-institution, retrospective design, but
does have a larger sample size of 325 patients and longer median
follow-up of 11 years. To ensure adequate follow-up, patients who were
lost-to follow-up or died within 5 years of IMRT were excluded. While
subsequent malignancies after radiation therapy are typically considered
a longer-term risk, reports have shown solid tumors even occurring
within 3 years of treatment\textsuperscript{13,16,20,24}, and it is
possible that these were not captured if the patient died within the
5-year period. Since our focus was on SMN, benign tumors were not
captured, but could also be a separate important treatment-related
outcome. Patients who had conventional RT were included and this dose
was incorporated into the total calculation of IMRT dose to the field of
interest; however, including these patients still provided valuable
insight as shown by the patient who developed a second solid cancer
within the 80\% IDL of the conventional PA field.

With a longer follow-up of median \textgreater{}10 years after IMRT, the
10-year cumulative incidence was reduced to 1.8\%; however, the
additional solid SMNs nearly all developed 10 years after IMRT,
resulting in a 15-year cumulative incidence of 3.5\%. While some solid
SMNs developed in the lower dose region, the most common site was within
the highest dose region, suggesting that the benefit of proton therapy
sparing the risk of SMN compared to IMRT may not be profound. Further
studies conducted with similar analyses are needed to better compare the
risk between these two modalities.

CONFLICTS OF INTEREST

The authors have no potential conflicts of interest to disclose.

ACKNOWLEDGEMENTS

None.

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LEGEND

Figure 1 Cumulative incidence curves for second cancers that developed
more than 5 years after IMRT (solid line: second solid cancers; dashed
line: any second cancer, including solid and hematologic malignancies).

Figure 2 Two examples of site of solid second malignant neoplasm (SMN)
development in reference to IMRT field. A) 11-year-old boy with
undifferentiated sarcoma, received 36Gy/20fx to the pelvis and
para-aortic lymph nodes, developed adenocarcinoma of the cecum 16 years
after IMRT at age 27. The site of SMN developed within the 40\% IDL and
had received \textasciitilde{}15Gy. B) 9-year-old boy with ALL involving
the CSF and arachnoid chloroma, received 18Gy/12fx to the whole brain
with IMRT boost to 24Gy/16fx, developed glioblastoma of the right
parietal lobe 16.5 years after IMRT at age 26. The site of SMN developed
within the conventional whole-brain radiotherapy field, within the 80\%
IDL of IMRT, and had received a total of \textasciitilde{}20Gy.

Figure 3 Site of solid second malignant neoplasm (SMN) development in
reference to posteroanterior field from craniospinal irradiation as part
of treatment for medulloblastoma. This SMN (colon adenocarcinoma)
developed 20.5 years after radiation therapy.

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