Abstract

Purpose

Hodgkin lymphoma (HL) survivors are susceptible to long-term side effects from definitive treatment with combination chemotherapy and radiation therapy (RT). Because late effects from RT correlate to radiation treatment volume, stage III/IV pediatric HL requiring large radiation fields are at greater risk for late complications. This study investigates the dosimetric impact of proton therapy (PT) to spare the organs at risk (OARs) in stage III and IV HL.

Patients and Methods

From October 2011 through January 2014, 7 pediatric patients with stage III or IV HL involving both supradiaphragmatic and infradiaphragmatic underwent treatment planning with 3-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), and PT to a dose of 21 Gy after ABVE-PC chemotherapy. Plans were normalized to meet treatment parameters including target coverage and dose to OARs.

Results

All 7 patients were treated with PT. PT had the lowest integral body dose (101 J; range, 55–139) compared with 3DCRT (180 J; range, 110–301) and IMRT (179 J; range, 96–298). PT led to a clinically significant absolute dose reduction compared with 3DCRT and IMRT in the heart (median, 8.8 Gy and 4.5 Gy), breasts (6.1 Gy and 5.2 Gy), lungs (3 Gy and 3.1 Gy), stomach (11.5 Gy and 7.6 Gy), liver (3.9 Gy and 6.4 Gy), and bowel (5 Gy and 4.7 Gy, respectively). A smaller reduction was seen in the thyroid (0.7 Gy and 0.2 Gy), pancreas (2.5 Gy and 1.2 Gy), left kidney (3.6 Gy and 1.2 Gy), and right kidney (0.9 Gy and 3.2 Gy, respectively). No benefit was seen for the esophagus (−0.2 Gy and −0.1 Gy).

Conclusion

Integral dose and dose to OARs were reduced with PT compared with 3DCRT and IMRT. Many of these absolute dose reductions are clinically meaningful and should lower the risk of late effects in this high-risk population.

Introduction

In the United States, there are currently approximately 175,000 Hodgkin lymphoma (HL) survivors. Although HL is rare in the general population, it is one of the most prevalent childhood cancers with over 1,000 cases diagnosed each year, of which approximately 50% are stage I or II and 50% are stage III or IV. Fortunately, even with advanced disease, 80% of patients survive at least 5 years and the 10-year survival rate approaches 76% [13].

Standard-of-care treatment for pediatric patients with stage III or IV HL in the United States is chemotherapy, with involved-field or involved-site radiation therapy reserved for patients receiving less-intensive chemotherapy regimens or those with incomplete or slow responses to chemotherapy [46]. Unfortunately, HL survivors are at a very high risk of long-term side effects from their definitive treatment [721]. In fact, Oeffinger et al [7] demonstrated that among more than 10,000 childhood cancer survivors, HL survivors endured some of the highest cumulative incidences of grade 3 to 5 severe, life-threatening, and fatal complications at a 28-year interval, including secondary malignant neoplasia (SMN) and cardiac toxicity. Because these sequelae are a function of exposure to both chemotherapy and radiation therapy, investigators have been seeking ways to reduce chemotherapy and radiation damage to normal tissue from HL treatment regimens [46, 18, 2225].

Studies have already shown the ability to reduce radiation exposure of nontargeted tissue by reducing the prescribed radiation dose and the target volume without sacrificing event-free survival rates; however, another way to achieve this goal is through the use of more conformal radiation techniques, including intensity-modulated radiation therapy (IMRT) and proton therapy (PT) [4, 6, 12, 26, 27]. Although researchers have demonstrated the dosimetric advantages of using IMRT and PT in patients with stage I or II HL [12, 26, 27], to our knowledge, no study has evaluated their use in patients with advanced-stage HL. Due to the challenges of delivering RT to large treatment fields in pediatric patients with stage III HL and stage IV HL with both supradiaphragmatic and infradiaphragmatic involvement (IVsi), conventional 3-dimensional conformal radiation therapy (3DCRT) using opposing anterior-posterior and posterior-anterior fields remain the standard treatment approach. The present study investigates dose reduction to the organs at risk (OAR) with IMRT and PT in 7 consecutive pediatric patients with stage III or IV HL treated at the University of Florida Proton Therapy Institute (Jacksonville, FL).

Patients and Methods

Under institutional review board approval, the pertinent medical records of 7 consecutive pediatric patients with stage III or IVsi HL previously treated with PT were reviewed. Eligible patients were younger than 18 years old, had an initial prechemotherapy staging computed tomography (CT) scan and either 18F-Flourodeoxyglucose positron emission tomography (PET)/CT or Gallium-67 citrate scans, and either complete or partial remission within 8 weeks of starting radiation therapy. Table 1 and Table 2 outline patient characteristics and prechemotherapy initial nodal sites as determined on staging work up. All patients had a complete response by PET/CT or Gallium scan by the end of treatment.

Table 1.

Patient, tumor, and treatment characteristics for patients A through D.

Patient, tumor, and treatment characteristics for patients A through D.
Patient, tumor, and treatment characteristics for patients A through D.
Table 2.

Patient, tumor, and treatment characteristics for patients E through G.

Patient, tumor, and treatment characteristics for patients E through G.
Patient, tumor, and treatment characteristics for patients E through G.

The methods for this investigation were based on a protocol established in a previous University of Florida study and with the goal of updating a prior case report [27]. Treatment set-up aimed to reproduce the positioning at the initial staging scans to facilitate the fusion of initial, response, and treatment planning CT images. Patients were positioned supine on the treatment couch and both a Vac-Lok bag (CIVCO Medical Solutions, Kalona, IA) and facemask were used for immobilization.

A 4-dimensional (4D) CT simulation was performed followed by a 3-dimensional (3D) CT scan with intravenous (IV) contrast (Philips Brilliance, Philips Medical Systems, Madison, WI). Patients were instructed to breathe normally and no attempt to restrict respiratory motion was made because no significant target movement due to respiratory motion was detected. All of the respiratory-phase scans and reconstructed average images were transferred with the IV 3D CT and the initial staging PET-CT scan (if available) to a MIMVista workstation (MIMVista Corp, Cleveland, OH). Patients were treated with either involved-site or involved-node radiation therapy to all the sites of initial involvement [28]. According to guidelines [28, 29], gross tumor volume (GTV) was contoured on the average 4D CT, and the clinical target volume (CTV) was defined as the prechemotherapy involved disease. The CTV was then uniformly expanded by 5 to 10 millimeters to create the planning target volume (PTV).

Using the averaged 4D CT for optimization and dose calculation, dosimetric plans for 3DCRT, IMRT, and PT treatment for each patient were prepared, totaling 21 plans. For PT, target and OAR volumes were imported into an Eclipse proton treatment planning system (Varian Medical Systems, Palo Alto, CA) and a 3D conformal proton therapy plan was created. Six of the patients with mediastinal disease for whom breathing motion was a concern had double-scatter plans developed and 1 patient with neck, bilateral axilla, and pelvic disease without breathing motion issues had a uniform-scanning plan developed. Although setup errors along the beam direction have no effect on dose distribution, a smearing factor was included in the proton range compensator design to account for intrafraction and interfraction motion perpendicular to the beam direction. Distal and proximal margins were calculated for each proton beam (proximal/distal-CTV-depth [mm] x 1.025 + 1.5 mm) to account for CT-number-to-proton-stopping-power conversion uncertainties and daily beam-delivery variations. Field apertures were calculated with a block margin to account for the proton beam penumbra at the target depth, and range compensators were calculated using an 8- to 10-mm smearing margin and up to 10-mm border smoothing values. The 3DCRT and IMRT treatment plans were calculated by exporting the scans and contours of the target and OARs used in the PT plans from MIMVista to a Pinnacle treatment planning system (Philips Healthcare, Andover, MA). For each plan, optimization objectives were selected to ensure that the required target coverage received high relative weights and were adjusted during an interactive modeling process to maximize OAR sparing. For 3DCRT, we utilized a combination of 6-, 10-, and 15-MV photon beams in opposing anterior-posterior and posterior-anterior beams. For IMRT, plans followed direct machine parameter optimization with approximately 10 segments per beam and a minimum segment area of 6 cm2. Several of the patients required matching fields with a match-line change performed halfway through treatment due to the length of the treatment area for the 3DCPT, 3DCRT, and IMRT plans.

All patients received a total radiation dose of 21 Gy (relative biological effectiveness [RBE]) in 1.5-Gy (RBE) daily fractionations for a total course of 14 days. Treatment plans were normalized and target coverage aimed to meet strict requirements for prescription dose (CTV D99% = 100% and PTV D95% ≥ 95%) and for OAR protection, including lung V20 <30%, mean lung dose <14 Gy (RBE), and mean heart dose <20 Gy (RBE). OARs were prioritized as follows: women, heart > breast > lung > thyroid > esophagus > body; men, heart > lung > thyroid > esophagus > body. Nontargeted tissues were defined as (body – PTV), and integral body dose was reported in joules and derived from multiplying the mean dose to the nontargeted body and multiplying the product by the volume of the non-targeted body.

No testing was done for statistical significance owing to the limited number of patients involved in the study.

Results

The relative reduction and absolute reduction (AR) in the integral body dose with PT was 46% and 83 J compared with 3DCRT, while the relative reduction and absolute reduction in the integral body dose with PT was 44% and 78 J compared with IMRT. Figure 1 depicts a 3DCRT, IMRT, and PT color wash dose distribution for a patient within the cohort. The OAR dose-volume histogram (DVH) is depicted in Figure 2A and B. The DVH demonstrates substantial reductions in the volume of the OARs receiving low doses of radiation when PT is used, while the 3DCRT and IMRT plans deliver low-dose radiation to a much larger volume. On the other hand, PT irradiates more of the body than IMRT in the region receiving 20 Gy and higher for most OARs.

Figure 1.

Comparison of the dose distribution of (A) 3-dimensional conformal radiation therapy (3DCRT), (B) proton therapy (PT), and (C) intensity-modulated radiation therapy (IMRT) plans. The clinical target volume (CTV; red), heart (brown), and breasts (pink) are outlined.

Figure 1.

Comparison of the dose distribution of (A) 3-dimensional conformal radiation therapy (3DCRT), (B) proton therapy (PT), and (C) intensity-modulated radiation therapy (IMRT) plans. The clinical target volume (CTV; red), heart (brown), and breasts (pink) are outlined.

Figure 2.

Median OAR dose-volume histogram comparing 3-dimensional conformal radiation therapy (3DCRT; blue), intensity-modulated radiotherapy (IMRT; red), and proton therapy (PT; green) for all patients included in this analysis. The y axis is the percentage of the organ and the x axis is in Gy.

Figure 2.

Median OAR dose-volume histogram comparing 3-dimensional conformal radiation therapy (3DCRT; blue), intensity-modulated radiotherapy (IMRT; red), and proton therapy (PT; green) for all patients included in this analysis. The y axis is the percentage of the organ and the x axis is in Gy.

Figure 2.

Median OAR dose-volume histogram comparing 3-dimensional conformal radiation therapy (3DCRT; blue) intensity-modulated radiotherapy (IMRT; red) and proton therapy (PT; green) for all patients included in this analysis. The y axis is the percentage of the organ and the x axis is in Gy.

Figure 2.

Median OAR dose-volume histogram comparing 3-dimensional conformal radiation therapy (3DCRT; blue) intensity-modulated radiotherapy (IMRT; red) and proton therapy (PT; green) for all patients included in this analysis. The y axis is the percentage of the organ and the x axis is in Gy.

Table 3 and Table 4 represent the mean OAR doses for 3DCRT, IMRT, and PT for the entire cohort along with the absolute dose reduction to the OARs when comparing PT to 3DCRT, PT to IMRT, or IMRT to 3DCRT. For all 7 patients, PT delivered the lowest dose to all of the OARs except the esophagus compared with 3DCRT. This included a large AR for the heart (median, 8.8 Gy), breast (6.1 Gy), lungs (3.0 Gy), stomach (11.5 Gy), bowel (5.0 Gy), liver (3.9 Gy), and left kidney (3.6 Gy), and a small AR for the thyroid (0.7 Gy), pancreas (2.5 Gy), and right kidney (0.9 Gy). When compared with IMRT, all 7 patients had the lowest dose to the heart, breast, lungs, stomach, liver, and right kidney with PT. In some cases IMRT offered lower doses to the esophagus, thyroid, pancreas, bowel, and left kidney compared with the PT plan. A large AR with PT versus IMRT was seen to the heart (median, 4.5 Gy), breast (5.2 Gy), lungs (3.1 Gy), stomach (7.6 Gy), liver (6.4 Gy), bowel (4.7 Gy), and right kidney (3.2 Gy), while smaller reductions were seen to the thyroid (0.2 Gy), pancreas (1.2 Gy), and left kidney (1.2 Gy).

Table 3.

Mean doses to organ at risk for the treatment plans generated with 3-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and proton therapy for the entire cohort.

Mean doses to organ at risk for the treatment plans generated with 3-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and proton therapy for the entire cohort.
Mean doses to organ at risk for the treatment plans generated with 3-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and proton therapy for the entire cohort.
Table 4.

Mean absolute dose reductions for the treatment plans generated with 3-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and proton therapy for the entire cohort.

Mean absolute dose reductions for the treatment plans generated with 3-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and proton therapy for the entire cohort.
Mean absolute dose reductions for the treatment plans generated with 3-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and proton therapy for the entire cohort.

Discussion

This study demonstrates important reductions to OAR doses and integral body doses with PT, while maintaining appropriate coverage of the target volume in patients requiring both supradiaphragmatic and infradiaphragmatic radiation. By reducing the dose to nontargeted tissue, PT appears to be the most appropriate technique to deliver consolidative radiation to pediatric and adolescent patients with stage III and stage IVsi HL because it is expected to cause fewer late effects among this high-risk patient cohort.

Pediatric and adolescent patients with stage III and IVsi receiving consolidative radiation therapy require some of the largest radiation fields in oncology, putting them at the highest risk of long-term side effects of radiation that may not develop for 20 to 40 years after completing radiation therapy. In a cohort of over 4,000 patients, Tukenova et al [9] found that death due to SMN was associated with increased integral doses of radiation. More specifically, patients exposed to greater than 150 joules had a statistically significant adjusted relative risk of 5.2 for developing carcinomas and a relative risk of 12.6 for developing sarcomas. In our study, PT reduced the integral dose by close to 50% compared with 3DCRT and IMRT and, furthermore, none of the PT plans delivered an integral dose greater than 150 joules. Consequently, we can deduce that PT should lower these patients' risk of secondary sarcomas and carcinomas based on the reduction in integral body dose.

Thoracic Radiation

Female survivors of HL are at a significantly higher risk of secondary cancers primarily due to an increased risk for developing secondary breast cancers. Bhatia et al [15] found that childhood survivors of HL have a seventy-five times greater risk of breast cancer and most of those breast cancers develop within the field of radiation. Although using smaller radiation therapy fields that omit the uninvolved axilla in female HL patients, such as involved-field treatment, has already shown a reduction in breast cancer development, it remains a problem in patients with axillary involvement [30]. In our investigation, PT reduced the volume of breast tissue treated to 5 Gy by 34% compared to 3DCRT and by 54% compared to IMRT. These volume reductions are important considering epidemiological studies have observed an increased risk of secondary breast cancers among Hodgkin lymphoma survivors with radiation doses as low as 4 Gy [19] to the breast. Consequently, the dose reduction to the breasts demonstrated with PT is expected to reduce the risk of secondary breast cancer among HL survivors. Although prior studies evaluating PT in patients with predominantly localized stage I/II HL have demonstrated less substantial reductions in breast dose, this is likely because fewer patients in that study had axillary involvement and, thus, the overall dose to the breasts was low for all three modalities [27]. Since the patients in this study included just stage III and IVsi patients, it is unsurprising that all 4 of the female patients would have a component of axillary/subpectoral disease at presentation, which would lead to substantially higher breast doses with either 3DCRT or IMRT that could be significantly decreased with PT. This is similar to the dose reduction seen by Andolino et al [31] in pediatric female patients.

HL often presents with mediastinal involvement, so lung irradiation poses an almost unavoidable dilemma. Lung radiation has been associated with an increased risk of pneumonitis, pulmonary fibrosis, pulmonary disease, and, most concerning, lung cancer after HL treatment [10, 11, 16, 18]. Salloum et al [11] showed that the relationship between radiation and SMNs in HL patients was highest for the development of lung cancer, for which the relative risk was 10.7. Within a population-based cohort of over 19,000 individuals treated for HL, another study found that lung SMN risks were elevated in all radiation categories starting at doses of 5 Gy or more, and the risks increased with increasing doses to the lung [18]. In the present study, proton therapy reduced the volume of lung receiving 5 Gy by 11% when compared with 3DCRT and 35% when compared with IMRT. Consequently, it is expected that the radiation dose reduction to the lungs is likely to reduce the risk of a secondary lung cancer among HL survivors. These findings are similar to prior studies demonstrating a reduction in radiation dose to the lungs in stage I/II HL patients with PT [27].

In addition to SMN, cardiotoxicity leads to a significant reduction in the survival of HL patients [10, 14, 25]. In a study that included over 14,000 5-year survivors of cancer diagnosed under the age of 21 years, Mulrooney et al [14] showed that the HL subgroup had the single highest hazard ratio for congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities. Moreover, average radiation doses above 15 Gy were associated with over a 2-fold increase in the hazard ratio of each of these cardiac sequelae. In this study, only PT sufficiently mitigated the dose to meet this target for OAR protection as the median for 3DCRT, IMRT, and PT were 20.5 Gy, 16.3 Gy, and 11.3 Gy. Furthermore, PT reduced the volume of heart receiving 5 Gy or more by 39% when compared with 3DCRT and 40% when compared with IMRT. PT reduced the volume of heart receiving 15Gy by 34% when compared with 3DCRT and 4% when compared with IMRT. Consistent with previous investigations in patients with stage I/II mediastinal HL [12], these results reaffirm PT's ability to attenuate radiation exposure to cardiac structures more effectively than either 3DCRT or IMRT for stage III and IVsi HL and, therefore, would be expected to reduce long-term complications [12, 27].

Despite prior studies demonstrating lower doses to the esophagus in patients with more limited involvement of HL [27], the same could not be said in patients with stage III/IVsi involvement. In these patients, the need to match PT fields within the mediastinum may raise the esophagus dose higher than that seen in the stage I/II patients where matching fields weren't required as often. Nevertheless, the higher dose seen in some of the PT plans to the esophagus was no greater than 1.2 Gy in any patient and on average was only 0.2 Gy higher than the 3DCRT esophagus dose and 0.1 Gy higher than the IMRT esophagus dose. Consequently, the dose reductions to the other OARs compensates for this concern.

Because patients with advanced-stage disease can present with involvement on both sides of the diaphragm, nontargeted abdominal structures risk irradiation. In a cohort of over 5,500 HL patients, there was an increased risk of gastrointestinal cancers, including stomach (relative risk, 28.9) and colon (relative risk, 13.8) cancers [13]. Of note, we observed that in our investigation patients with splenic involvement and/or paraaortic involvement appreciated a substantial margin of OAR dose reduction to abdominal structures. As illustrated in a cohort of over 5,100 patients that included survivors of testicular cancer or HL, van den Belt-Dusebout et al [8] found a linear dose-response relationship for stomach cancer with radiation doses up to 40 Gy. Additionally, they observed that mean stomach doses greater than 20 Gy were associated with a relative risk of 9.9 for SMN compared with doses below 11 Gy. In the present study, the mean stomach dose was 21.5 Gy (median) with 3DCRT, demonstrating a considerable increased risk of a stomach cancer with this treatment approach. Although all of the IMRT and PT plans had mean stomach doses below 20 Gy, the IMRT plan had a much higher stomach dose (14.6 Gy, median) compared with the PT dose (7.0 Gy). Thus, while both may decrease the incidence of stomach cancer, PT could lead to even further reductions. Additionally, it is likely that the lower stomach dose would decrease the risk of acute side effects, including nausea, vomiting, and fatigue, seen with radiation to the stomach.

Unintentional radiation to other abdominal OARS, including the liver, kidneys, pancreas, and bowel, is also likely to contribute to late effects among long-term survivors, such as kidney disease [32], liver disease [33], bowel obstruction [34], and diabetes [35]. A direct dose response is still unclear and data is still emerging. Yet despite the limited data, PT still resulted in overall lower mean doses to the kidneys, pancreas, liver, and bowel compared with 3DCRT and IMRT.

While PT appears to reduce OAR doses and integral doses in pediatric patients with stage III HL, as with any new burgeoning technology, diligent scrutiny must accompany this treatment option. As Hall et al [36] notes, to increase radiation fields to clinically practical sizes, some institutions currently use passive double-scattering delivery techniques, which entails passing the initial proton beam through a scattering foil, potentially introducing uncharged particles called neutrons into the field [36, 37]. Despite the initial apprehension caused by introducing neutrons, studies have shown only small differences in the amount of secondary neutrons generated with PT techniques as compared to photon treatments, suggesting that double-scattering techniques contribute a marginal influence if any on the dose distribution [38, 39]. Furthermore, no clinical study has supported these concerns [40]. As proton centers transition to active scanning techniques that do not require foil scattering, the production of secondary neutrons will become less of a concern.

Because of its small sample size, the present analysis may not have considered all of the potential disease sites in patients with stage III HL. Nevertheless, we included patients with involved head and neck, thoracic, abdominal, pelvic, and inguinal nodes, thereby representing a wide range of classic locations typically seen at presentation.

Conclusion

As this investigation supports, PT reduces radiation to nontargeted tissues in stage III HL pediatric patients without compromising target coverage. This improvement in OAR sparing and reduction in integral dose suggests an increased margin of safety against the long-term side effects of radiation therapy, and establishes the foundation for the clinical use of PT in this patient population.

ADDITIONAL INFORMATION AND DECLARATIONS

Conflict of Interest Statement: The authors have no conflicts of interest to disclose.

Acknowledgments: We would like to thank Jessica Kirwan and the editorial staff of the University of Florida Department of Radiation Oncology for editing and preparing the manuscript for publication, and Natalie Getman and Debbie Louis for dosimetric assistance on the study.

References

References
1
National Cancer Institute, Surveillance, Epidemiology, and End Results Program. Fast Stats: An interactive tool for access to SEER cancer statistics
.
Surveillance Research Program
. .
2
Howlader
N
,
Noone
AM
,
Krapcho
M
,
Neyman
N
,
Aminou
R
,
Altekruse
SF
,
Kosary
CL
,
Ruhl
J
,
Tatalovich
Z
,
Cho
H
,
Mariotto
A
,
Eisner
MP
,
Lewis
DR
,
Chen
HS
,
Feuer
EJ
,
Cronin
KA. SEER
Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations)
. .
Last updated: 20 Aug 2012
.
3
Ries
LAG
,
Young
JL
,
Keel
GE
,
Eisner
MP
,
Lin
YD
,
Horner
M-J
.
National Cancer Institute, SEER Program
.
SEER Survival Monograph: Cancer Survival Among Adults: U.S. SEER Program, 1988–2001, Patient and Tumor Characteristics
,
2007
.
Bethesda, MD
:
NIH Pub. No. 07-6215
.
4
Schwartz
CL
,
Constine
LS
,
Villaluna
D
,
London
WB
,
Hutchison
RE
,
Sposto
R
,
Lipshultz
SE
,
Turner
CS
,
deAlarcon
PA
,
Chauvenet
A
.
A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425
.
Blood
.
2009
;
114
:
2051
9
.
5
Wolden
SL
,
Chen
L
,
Kelly
KM
,
Herzog
P
,
Gilchrist
GS
,
Thomson
J
,
Sposto
R
,
Kadin
ME
,
Hutchinson
RJ
,
Nachman
J
.
Long-Term Results of CCG 5942: A Randomized Comparison of Chemotherapy With and Without Radiotherapy for Children With Hodgkin's Lymphoma–A Report From the Children's Oncology Group
.
J Clin Oncol
.
2012
.
6
Metzger
ML
,
Weinstein
HJ
,
Hudson
MM
,
Billett
AL
,
Larsen
EC
,
Friedmann
A
,
Howard
SC
,
Donaldson
SS
,
Krasin
MJ
,
Kun
LE
,
Marcus
KJ
,
Yock
TI
,
Tarbell
N
,
Billups
CA
,
Wu
J
,
Link
MP
.
Association between radiotherapy vs no radiotherapy based on early response to VAMP chemotherapy and survival among children with favorable-risk Hodgkin lymphoma
.
JAMA
.
2012
;
307
:
2609
16
.
7
Oeffinger
KC
,
Mertens
AC
,
Sklar
CA
,
Kawashima
T
,
Hudson
MM
,
Meadows
AT
,
Friedman
DL
,
Marina
N
,
Hobbie
W
,
Kadan-Lottick
NS
,
Schwartz
CL
,
Leisenring
W
,
Robison
LL
.
Chronic health conditions in adult survivors of childhood cancer
.
N Engl J Med
.
2006
;
355
:
1572
82
.
8
van den Belt-Dusebout
AW
,
Aleman
BM
,
Besseling
G
,
de Bruin
ML
,
Hauptmann
M
,
van 't Veer MB, de Wit R, Ribot JG, Noordijk EM, Kerst JM, Gietema JA, van Leeuwen FE. Roles of radiation dose and chemotherapy in the etiology of stomach cancer as a second malignancy
.
Int J Radiat Oncol Biol Phys
.
2009
;
75
:
1420
9
.
9
Tukenova
M
,
Guibout
C
,
Hawkins
M
,
Quiniou
E
,
Mousannif
A
,
Pacquement
H
,
Winter
D
,
Bridier
A
,
Lefkopoulos
D
,
Oberlin
O
,
Diallo
I
,
de Vathaire
F
.
Radiation therapy and late mortality from second sarcoma, carcinoma, and hematological malignancies after a solid cancer in childhood
.
Int J Radiat Oncol Biol Phys
.
2011
;
80
:
339
46
.
10
Mertens
AC
,
Yasui
Y
,
Neglia
JP
,
Potter
JD
,
Nesbit
ME
, Jr.,
Ruccione
K
,
Smithson
WA
,
Robison
LL
.
Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study
.
J Clin Oncol
.
2001
;
19
:
3163
72
.
11
Salloum
E
,
Doria
R
,
Schubert
W
,
Zelterman
D
,
Holford
T
,
Roberts
KB
,
Farber
LR
,
Kiehl
RK
,
Cardinale
J
,
Cooper
DL
.
Second solid tumors in patients with Hodgkin's disease cured after radiation or chemotherapy plus adjuvant low-dose radiation
.
J Clin Oncol
.
1996
;
14
:
2435
43
.
12
Hoppe
BS
,
Flampouri
S
,
Su
Z
,
Latif
N
,
Dang
NH
,
Lynch
J
,
Joyce
M
,
Sandler
E
,
Li
Z
,
Mendenhall
NP
.
Effective Dose Reduction to Cardiac Structures Using Protons Compared with 3DCRT and IMRT in Mediastinal Hodgkin Lymphoma
.
Int J Radiat Oncol Biol Phys
.
2012
;
84
:
449
55
.
13
Swerdlow
AJ
,
Barber
JA
,
Hudson
GV
,
Cunningham
D
,
Gupta
RK
,
Hancock
BW
,
Horwich
A
,
Lister
TA
,
Linch
DC
.
Risk of second malignancy after Hodgkin's disease in a collaborative British cohort: the relation to age at treatment
.
J Clin Oncol
.
2000
;
18
:
498
509
.
14
Mulrooney
DA
,
Yeazel
MW
,
Kawashima
T
,
Mertens
AC
,
Mitby
P
,
Stovall
M
,
Donaldson
SS
,
Green
DM
,
Sklar
CA
,
Robison
LL
,
Leisenring
WM
.
Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort
.
BMJ
.
2009
;
339
:
b4606
.
15
Bhatia
S
,
Robison
LL
,
Oberlin
O
,
Greenberg
M
,
Bunin
G
,
Fossati-Bellani
F
,
Meadows
AT
.
Breast cancer and other second neoplasms after childhood Hodgkin's disease
.
N Engl J Med
.
1996
;
334
:
745
51
.
16
Dores
GM
,
Metayer
C
,
Curtis
RE
,
Lynch
CF
,
Clarke
EA
,
Glimelius
B
,
Storm
H
,
Pukkala
E
,
van Leeuwen
FE
,
Holowaty
EJ
,
Andersson
M
,
Wiklund
T
,
Joensuu
T
,
van't Veer
MB
,
Stovall
M
,
Gospodarowicz
M
,
Travis
LB
.
Second malignant neoplasms among long-term survivors of Hodgkin's disease: a population-based evaluation over 25 years
.
J Clin Oncol
.
2002
;
20
:
3484
94
.
17
Ng
AK
,
Bernardo
MV
,
Weller
E
,
Backstrand
K
,
Silver
B
,
Marcus
KC
,
Tarbell
NJ
,
Stevenson
MA
,
Friedberg
JW
,
Mauch
PM
.
Second malignancy after Hodgkin disease treated with radiation therapy with or without chemotherapy: long-term risks and risk factors
.
Blood
.
2002
;
100
:
1989
96
.
18
Travis
LB
,
Gospodarowicz
M
,
Curtis
RE
,
Clarke
EA
,
Andersson
M
,
Glimelius
B
,
Joensuu
T
,
Lynch
CF
,
van Leeuwen
FE
,
Holowaty
E
,
Storm
H
,
Glimelius
I
,
Pukkala
E
,
Stovall
M
,
Fraumeni
JF
, Jr.,
Boice
JD
, Jr.,
Gilbert
E
.
Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease
.
J Natl Cancer Inst
.
2002
;
94
:
182
92
.
19
Travis
LB
,
Hill
DA
,
Dores
GM
,
Gospodarowicz
M
,
van Leeuwen
FE
,
Holowaty
E
,
Glimelius
B
,
Andersson
M
,
Wiklund
T
,
Lynch
CF
,
Van't Veer
MB
,
Glimelius
I
,
Storm
H
,
Pukkala
E
,
Stovall
M
,
Curtis
R
,
Boice
JD
, Jr.,
Gilbert
E
.
Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease
.
JAMA
.
2003
;
290
:
465
75
.
20
Hancock
SL
,
Tucker
MA
,
Hoppe
RT
.
Factors affecting late mortality from heart disease after treatment of Hodgkin's disease
.
JAMA
.
1993
;
270
:
1949
55
.
21
Galloway
TJ
,
Indelicato
DJ
,
Amdur
RJ
,
Swanson
EL
,
Morris
CG
,
Marcus
RB
.
Favorable outcomes of pediatric patients treated with radiotherapy to the central nervous system who develop radiation-induced meningiomas
.
Int J Radiat Oncol Biol Phys
.
2011
;
79
:
117
20
.
22
Constine
LS
,
Tarbell
N
,
Hudson
MM
,
Schwartz
C
,
Fisher
SG
,
Muhs
AG
,
Basu
SK
,
Kun
LE
,
Ng
A
,
Mauch
P
,
Sandhu
A
,
Culakova
E
,
Lyman
G
,
Mendenhall
N
.
Subsequent malignancies in children treated for Hodgkin's disease: associations with gender and radiation dose
.
Int J Radiat Oncol Biol Phys
.
2008
;
72
:
24
33
.
23
Guerin
S
,
Guibout
C
,
Shamsaldin
A
,
Dondon
MG
,
Diallo
I
,
Hawkins
M
,
Oberlin
O
,
Hartmann
O
,
Michon
J
,
Le Deley
MC
,
de Vathaire
F
.
Concomitant chemo-radiotherapy and local dose of radiation as risk factors for second malignant neoplasms after solid cancer in childhood: a case-control study
.
Int J Cancer
.
2007
;
120
:
96
102
.
24
De Bruin
ML
,
Sparidans
J
,
van't Veer
MB
,
Noordijk
EM
,
Louwman
MW
,
Zijlstra
JM
,
van den Berg
H
,
Russell
NS
,
Broeks
A
,
Baaijens
MH
,
Aleman
BM
,
van Leeuwen
FE
.
Breast cancer risk in female survivors of Hodgkin's lymphoma: lower risk after smaller radiation volumes
.
J Clin Oncol
.
2009
;
27
:
4239
46
.
25
Dorffel
W
,
Luders
H
,
Ruhl
U
,
Albrecht
M
,
Marciniak
H
,
Parwaresch
R
,
Potter
R
,
Schellong
G
,
Schwarze
EW
,
Wickmann
L
.
Preliminary results of the multicenter trial GPOH-HD 95 for the treatment of Hodgkin's disease in children and adolescents: analysis and outlook
.
Klin Padiatr
.
2003
;
215
:
139
45
.
26
Chera
BS
,
Rodriguez
C
,
Morris
CG
,
Louis
D
,
Yeung
D
,
Li
Z
,
Mendenhall
NP
.
Dosimetric comparison of three different involved nodal irradiation techniques for stage II Hodgkin's lymphoma patients: conventional radiotherapy, intensity-modulated radiotherapy, and three-dimensional proton radiotherapy
.
Int J Radiat Oncol Biol Phys
.
2009
;
75
:
1173
80
.
27
Hoppe
BS
,
Flampouri
S
,
Su
Z
,
Morris
CG
,
Latif
N
,
Dang
NH
,
Lynch
J
,
Li
Z
,
Mendenhall
NP
.
Consolidative involved-node proton therapy for Stage IA-IIIB mediastinal Hodgkin lymphoma: preliminary dosimetric outcomes from a Phase II study
.
Int J Radiat Oncol Biol Phys
.
2012
;
83
:
260
7
.
28
Specht
L
,
Yahalom
J
,
Illidge
T
,
Berthelsen
AK
,
Constine
LS
,
Eich
HT
,
Girinsky
T
,
Hoppe
RT
,
Mauch
P
,
Mikhaeel
NG
,
Ng
A
.
Modern Radiation Therapy for Hodgkin Lymphoma: Field and Dose Guidelines From the International Lymphoma Radiation Oncology Group (ILROG)
.
Int J Radiat Oncol Biol Phys
.
2013
.
29
Girinsky
T
,
van der Maazen
R
,
Specht
L
,
Aleman
B
,
Poortmans
P
,
Lievens
Y
,
Meijnders
P
,
Ghalibafian
M
,
Meerwaldt
J
,
Noordijk
E
.
Involved-node radiotherapy (INRT) in patients with early Hodgkin lymphoma: concepts and guidelines
.
Radiother Oncol
.
2006
;
79
:
270
7
.
30
Behringer
K
,
Josting
A
,
Schiller
P
,
Eich
HT
,
Bredenfeld
H
,
Diehl
V
,
Engert
A
,
Group GHLS. Solid tumors in patients treated for Hodgkin's disease: a report from the German Hodgkin Lymphoma Study Group
.
Ann Oncol
.
2004
;
15
:
1079
85
.
31
Andolino
DL
,
Hoene
T
,
Xiao
L
,
Buchsbaum
J
,
Chang
AL
.
Dosimetric comparison of involved-field three-dimensional conformal photon radiotherapy and breast-sparing proton therapy for the treatment of Hodgkin's lymphoma in female pediatric patients
.
Int J Radiat Oncol Biol Phys
.
2011
;
81
:
e667
71
.
32
Knijnenburg
SL
,
Mulder
RL
,
Schouten-Van Meeteren
AY
,
Bokenkamp
A
,
Blufpand
H
,
van Dulmen-den Broeder
E
,
Veening
MA
,
Kremer
LC
,
Jaspers
MW
.
Early and late renal adverse effects after potentially nephrotoxic treatment for childhood cancer
.
Cochrane Database Syst Rev
.
2013
;
10
:
CD008944
.
33
Hudson
MM
,
Ness
KK
,
Gurney
JG
,
Mulrooney
DA
,
Chemaitilly
W
,
Krull
KR
,
Green
DM
,
Armstrong
GT
,
Nottage
KA
,
Jones
KE
,
Sklar
CA
,
Srivastava
DK
,
Robison
LL
.
Clinical ascertainment of health outcomes among adults treated for childhood cancer
.
JAMA
.
2013
;
309
:
2371
81
.
34
Kenney
LB
,
Nancarrow
CM
,
Najita
J
,
Vrooman
LM
,
Rothwell
M
,
Recklitis
C
,
Li
FP
,
Diller
L
.
Health status of the oldest adult survivors of cancer during childhood
.
Cancer
.
2010
;
116
:
497
505
.
35
de Vathaire
F
,
El-Fayech
C
,
Ben Ayed
FF
,
Haddy
N
,
Guibout
C
,
Winter
D
,
Thomas-Teinturier
C
,
Veres
C
,
Jackson
A
,
Pacquement
H
,
Schlumberger
M
,
Hawkins
M
,
Diallo
I
,
Oberlin
O
.
Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study
.
Lancet Oncol
.
2012
;
13
:
1002
10
.
36
Hall
EJ
.
Intensity-modulated radiation therapy, protons, and the risk of second cancers
.
Int J Radiat Oncol Biol Phys
.
2006
;
65
:
1
7
.
37
Schneider
U
,
Agosteo
S
,
Pedroni
E
,
Besserer
J
.
Secondary neutron dose during proton therapy using spot scanning
.
Int J Radiat Oncol Biol Phys
.
2002
;
53
:
244
51
.
38
Moravek
Z
,
Bogner
L
.
Analysis of the physical interactions of therapeutic proton beams in water with the use of Geant4 Monte Carlo calculations
.
Z Med Phys
.
2009
;
19
:
174
81
.
39
Shin
D
,
Yoon
M
,
Kwak
J
,
Shin
J
,
Lee
SB
,
Park
SY
,
Park
S
,
Kim
DY
,
Cho
KH
.
Secondary neutron doses for several beam configurations for proton therapy
.
Int J Radiat Oncol Biol Phys
.
2009
;
74
:
260
5
.
40
Chung
CS
,
Keating
N
,
Yock
T
,
Tarbell
NJ
.
Comparative analysis of second malignancy risk in patients with proton therapy versus conventional photon therapy
.
Int J Radiat Oncol Biol Phys
.
2008
;
72
:
S8
.