Four-Dimensional Computed Tomography–Based Treatment Planning for Intensity-Modulated Radiation Therapy and Proton Therapy for Distal Esophageal Cancer

doi:10.1016/j.ijrobp.2008.05.014

International Journal of Radiation OncologyBiologyPhysics

Volume 72, Issue 1, 1 September 2008, Pages 278-287

https://doi.org/10.1016/j.ijrobp.2008.05.014 Get rights and content

Purpose

To compare three-dimensional (3D) and four-dimensional (4D) computed tomography (CT)–based treatment plans for proton therapy or intensity-modulated radiation therapy (IMRT) for esophageal cancer in terms of doses to the lung, heart, and spinal cord and variations in target coverage and normal tissue sparing.

Methods and Materials

The IMRT and proton plans for 15 patients with distal esophageal cancer were designed from the 3D average CT scans and then recalculated on 10 4D CT data sets. Dosimetric data were compared for tumor coverage and normal tissue sparing.

Results

Compared with IMRT, median lung volumes exposed to 5, 10, and 20 Gy and mean lung dose were reduced by 35.6%, 20.5%, 5.8%, and 5.1 Gy for a two-beam proton plan and by 17.4%, 8.4%, 5%, and 2.9 Gy for a three-beam proton plan. The greater lung sparing in the two-beam proton plan was achieved at the expense of less conformity to the target (conformity index [CI], 1.99) and greater irradiation of the heart (heart-V40, 41.8%) compared with the IMRT plan(CI, 1.55, heart-V40, 35.7%) or the three-beam proton plan (CI, 1.46, heart-V40, 27.7%). Target coverage differed by more than 2% between the 3D and 4D plans for patients with substantial diaphragm motion in the three-beam proton and IMRT plans. The difference in spinal cord maximum dose between 3D and 4D plans could exceed 5 Gy for the proton plans partly owing to variations in stomach gas filling.

Conclusions

Proton therapy provided significantly better sparing of lung than did IMRT. Diaphragm motion and stomach gas-filling must be considered in evaluating target coverage and cord doses.

Introduction

Pulmonary complications are the most common serious morbidity after esophagectomy and are the leading cause of postoperative mortality among patients treated with surgery for esophageal cancer. The incidence of postoperative pulmonary complications is 30% (1) and pulmonary complications are responsible for 55% of in-hospital deaths (2). Recent studies indicate that radiation exposure to lung may have a greater impact on postoperative pulmonary complications than do other clinical factors (3). Wang et al.(4) found that the volume of the lung spared from doses of 5 Gy or greater was the only independent predictive factor associated with postoperative pulmonary complications for patients with esophageal cancer treated with concurrent chemoradiotherapy followed by surgery. These findings, in combination with a report from Guerrero et al.(5) that the uptake of fluorodeoxyglucose in normal lung after low-dose irradiation has a linear relationship with the dose received, underscore the importance of reducing the volume of lung that receives doses as low as 5 Gy.

The effects of radiation therapy on the heart have been well documented in patients with breast cancer and lymphoma 6, 7. For esophageal cancer patients, Gayed et al. found that radiaton was associated with a high prevalence inferior left ventricular ischemia detected by myocardial perfusion abnormalities on cardiac gated myocardial perfusion imaging (8). Importantly, most perfusion defects were encompassed within an isodose line greater than 45 Gy in RT plan. The objectives of the current treatment strategy at our institution are local control, balancing doses to the lung and the heart, and limiting the point spinal cord dose to less than 45 Gy. In addition to avoiding pulmonary complications, preserving heart function is seen as increasingly important. However it is often difficult to decrease the heart dose without jeopardizing the dose distribution in the tumor or increasing the doses to other structures such as lungs and spinal cord.

Recent advances in photon treatment planning and delivery techniques, such as three-dimensional conformal radiation therapy (3D CRT) and intensity-modulated radiation therapy (IMRT), have led to improved radiation dose distribution and reduced exposures to the lungs and other surrounding normal tissues. Chandra et al.(9) studied the feasibility of using IMRT to improve lung sparing in patients with distal esophageal cancer. They demonstrated with treatment planning comparisons that IMRT reduced the V10, the V20, and the mean lung dose. However, another study by Nutting et al.(10) indicated that using IMRT conferred only a small benefit in terms of lung sparing compared with 3D CRT.

Further improvements in normal tissue sparing can be accomplished with proton therapy, which has fundamental physical advantages over photon beams 11, 12, 13. In particular, proton beams have sharp lateral penumbrae, finite penetration ranges, and can be spread and shaped laterally and in depth (14). These characteristics allow proton beams to deliver large and uniform doses to the tumor while sparing nearby normal tissues. Several investigators have documented the clinical benefit of protons in the treatment of esophageal tumors. In one such study, Sugahara et al.(15) escalated doses to the primary tumor to 80 Gy by using proton beams. They reported that this approach led to 5-year survival rates of 55% for patients with T1 tumors and 13% for those with T2 to T4 tumors.

Proton beam therapy for distal esophageal cancers is challenging because of the respiratory motion of the tumor, esophagus, diaphragm, heart, stomach, and lungs. Traditionally treatment planning has been done with a single 3D CT scan, which can be either a free-breathing scan or a time-averaged result of a 4D CT scan. Respiratory motion during CT data acquisition can induce severe motion artifacts, resulting in inaccurate assessment of organ shape and location, and hence using a single CT scan to design and evaluate the treatment plan may provide inaccurate information on the dose actually delivered to the patient 16, 17 . Numerous studies have shown that using a free-breathing or averaged CT scan to evaluate treatment plans is misleading; several groups 16, 17 showed that although the target dose appeared to be covered in a 3D-CT–based proton plan, the same treatment fields applied to a 4D-CT–based plan revealed severe underdosage of the target. For these reasons, a more complete understanding of the effects of respiratory motion in treatment planning is needed to assess the role of proton beams in the treatment of distal esophageal cancer.

The aim of this study was to quantify the degree of lung volume sparing at different dose levels with proton therapy as compared with IMRT. We also sought to clarify the differences in these treatment techniques with regard to the doses to the lung, heart, and spinal cord. We investigated these effects by comparing treatment planning methods based on 3D CT vs. 4D CT images.

Section snippets

Methods and Materials

We retrospectively selected 15 cases from our institutional records to represent typical anatomies. All patients had tumors involving the distal esophagus and gastroesophageal junction. All patients had been treated with definitive intent using photon 3D CRT or IMRT with concurrent chemotherapy in our clinic, and all had provided both free-breathing CT images and 4D CT images.

End points of IMRT, two-beam, and three-beam proton plans calculated using 3D CT images

The dose distributions of the IMRT photon plan and the two proton plans for Patient 13 are presented in Fig. 1. Limitations incurred by the physical characteristics of the photons resulted in considerable spread in the low-dose isodose lines (e.g., 20 Gy and 10 Gy) in the IMRT plan. In contrast, the two-beam proton plan showed minimal spread of the 20 Gy and 10 Gy isodose lines in the lungs. However this lung sparing was achieved at the expense of reduced conformity of dose to the ICTV: the CI

Discussion

Clinical studies have shown that minimizing the lung volume irradiated even to very low doses can result in fewer pulmonary complications (4). When we compared our findings on the volume of lung spared from 5 Gy (VS5) with recent clinical data available for the patients studied here, the lung sparing in the two- and three-beam proton plans could potentially reduce the probability of pulmonary complications from 18.5% (8.6%, 40.9%) with IMRT to 5% (0%, 19.9%) and 11% (2.5%, 25.4%) with the

Conclusions

We demonstrated that two-beam proton plans consistently spared larger volumes of lung and reduced the mean dose to the lung. However, the gain in lung sparing achieved with the two-beam proton plan was offset somewhat by reduced conformity to the target and by higher radiation to the heart relative to the IMRT and three-beam proton plans. For the three-beam proton plans, target conformity was similar to that of the IMRT plans; lung sparing was better than that with IMRT but worse than that with

References (25)

F.C.F. Lin et al.
Induction therapy does not increase surgical morbidity after esophagectomy for cancer
Ann Thorac Surg
(2004)
H.K. Lee et al.
Postoperative pulmonary complications after preoperative chemoradiation for esophageal carcinoma: Correlation with pulmonary dose−volume histogram parameters
Int J Radiat Oncol Biol Phys
(2003)
S.L. Wang et al.
Investigation of clinical and dosimetric factors associated with postoperative pulmonary complications in esophageal cancer patients treated with concurrent chemoradiotherapy followed by surgery
Int J Radiat Oncol Biol Phys
(2006)
T. Guerrero et al.
Reduction of pulmonary compliance found with high-resolution computed tomography in irradiated mice
Int J Radiat Oncol Biol Phys
(2007)
T. Girinsky et al.
Is intensity-modulated radiotherapy better than conventional radiation treatment and three-dimensional conformal radiotherapy for mediastinal masses in patients with Hodgkin's disease, and is there a role for beam orientation optimization and dose constraints assigned to virtual volumes?
Int J Radiat Oncol Biol Phys
(2006)
A. Chandra et al.
Feasibility of using intensity-modulated radiotherapy to improve lung sparing in treatment planning for distal esophageal cancer
Radiother Oncol
(2005)
C.M. Nutting et al.
A comparison of conformal and intensity-modulated techniques for oesophageal radiotherapy
Radiother Oncol
(2001)
U. Isacsson et al.
Comparative treatment planning between proton and x-ray therapy in esophageal cancer
Int J Radiat Oncol Biol Phys
(1998)
S. Sugahara et al.
Clinical results of proton beam therapy for cancer of the esophagus
Int J Radiat Oncol Biol Phys
(2005)
M. Engelsman et al.
Four-dimensional proton treatment planning for lung tumors
Int J Radiat Oncol Biol Phys
(2006)

Y. Kang et al.

4D Proton treatment planning strategy for mobile lung tumors

Int J Radiat Oncol Biol Phys

(2007)

H. Wang et al.

Implementation and validation of a three-dimensional deformable registration algorithm for targeted prostate cancer radiotherapy

Int J Radiat Oncol Biol Phys

(2005)

Cited by (113)

The role of proton therapy in esophageal cancer
2022, Cancer/Radiotherapie
En raison des propriétés physiques de la radiothérapie par faisceau de protons (PT), qui permet de déposer l’énergie à une profondeur spécifique avec une chute rapide de la dose au-delà de cette profondeur, la protonthérapie présente plusieurs avantages théoriques par rapport à la radiothérapie par photons pour le cancer de l’œsophage. Les protons ont le potentiel de réduire la dose reçue par les tissus sains et de permettre, plus sûrement, le traitement des tumeurs proches d’organes critiques, l’augmentation de la dose, le traitement trimodal et la réirradiation. Au cours des dernières années, des études rétrospectives multicentriques de plus grande envergure ont été publiées, démontrant d’excellents taux de survie, de toxicité plus faibles que prévus et même de meilleurs résultats avec la protonthérapie qu’avec la radiothérapie par photons avec la RCMI ou l’arcthérapie volumétrique modulée (VMAT). Bien que la protonthérapie soit associée à une réduction des toxicités, des complications postopératoires et des durées d’hospitalisation par rapport à la radiothérapie par photons, ces études comportaient toutes des biais inhérents à la sélection des patients pour la protonthérapie. Ces observations ont été récemment confirmées par une étude randomisée de phase II qui a montré une diminution significative de la toxicité avec les protons par rapport à la RCMI chez des patients atteints de carcinome de l’œsophage. Actuellement, deux essais randomisés de phase III (NRG-GI006 aux États-Unis et PROTECT en Europe) sont menés pour confirmer l’intérêt des protons dans les cancers de l’œsophage localement évolués et résécables.
Because of the physical properties of proton beam radiation therapy (PT), which allows energy to be deposited at a specific depth with a rapid energy fall-off beyond that depth, PT has several theoretical advantages over photon radiation therapy for esophageal cancer (EC). Protons have the potential to reduce the dose to healthy tissue and to more safely allow treatment of tumors near critical organs, dose escalation, trimodal treatment, and re-irradiation. In recent years, larger multicenter retrospective studies have been published showing excellent survival rates, lower than expected toxicities and even better outcomes with PT than with photon radiotherapy even using IMRT or VMAT techniques. Although PT was associated with reduced toxicities, postoperative complications, and hospital stays compared to photon radiation therapy, these studies all had inherent biases in relation with patient selection for PT. These observations were recently confirmed by a randomized phase II study in locally advanced EC that showed significantly reduced toxicities with protons compared with IMRT. Currently, two randomized phase III trials (NRG-GI006 in the US and PROTECT in Europe) are being conducted to confirm whether protons could become the standard of care in locally advanced and resectable esophageal cancers.
Comparison of intensity modulated proton therapy beam configurations for treating thoracic esophageal cancer
2022, Physics and Imaging in Radiation Oncology
Specific proton-beam configurations are needed to spare organs at risk (OARs), including lungs, heart, and spinal cord, when treating esophageal squamous cell carcinoma (ESCC) in the thoracic region. This study aimed to propose new intensity-modulated proton therapy (IMPT) beam configurations and to demonstrate the benefit of IMPT compared with intensity-modulated x-ray therapy (IMXT) for treating ESCC.
IMPT plans with three different beam angle configurations were generated on CT datasets of 25 ESCC patients that were treated with IMXT. The IMPT beam designs were two commonly-used beam configurations (anteroposterior and posterior oblique) and a recently proposed beam configuration (anterosuperior with posteroinferior). The target doses were 50–54 Gy(RBE) and 60–64 Gy(RBE) to the low-risk and high-risk target volumes, respectively. Robust optimization was applied for the IMPT plans. The differences in the dose-volume parameters between the IMXT and IMPT plans were compared.
With target coverage comparable to standard IMXT, IMPT had significantly lower mean doses to the OARs. IMPT with an anteroposterior opposing beam generated the lowest lung dose (mean = 7.1 Gy(RBE), V₂₀ = 14.1%) and the anterosuperior with posteroinferior beam resulted in the lowest heart dose (mean = 12.8 Gy(RBE), V₃₀ = 15.7%) and liver dose (mean = 3.9 Gy(RBE), V₃₀ = 5.9%). For the subgroup of patients with an inferior tumor location (PTVs overlapping a part of the contoured heart), the novel beam demonstrated the optimal OARs sparing.
Compared with IMXT, the IMPT plans significantly reduced the radiation dose to the surrounding organs when treating ESCC. IMPT beam configuration selection depends on the tumor location relative to the heart.
Current status and application of proton therapy for esophageal cancer: Proton Therapy for Esophageal Cancer
2021, Radiotherapy and Oncology
Esophageal cancer remains one of the leading causes of death from cancer across the world despite advances in multimodality therapy. Although early-stage disease can often be treated surgically, the current state of the art for locally advanced disease is concurrent chemoradiation, followed by surgery whenever possible. The uniform midline tumor location puts a strong importance on the need for precise delivery of radiation that would minimize dose to the heart and lungs, and the biophysical properties of proton beam makes this modality potential ideal for esophageal cancer treatment. This review covers the current state of knowledge of proton therapy for esophageal cancer, focusing on published retrospective single- and multi-institutional clinical studies, and emerging data from prospective clinical trials, that support the benefit of protons vs photon-based radiation in reducing postoperative complications, cardiac toxicity, and severe radiation induced immune suppression, which may improve survival outcomes for patients. In addition, we discuss the incorporation of immunotherapy to the curative management of esophageal cancers in the not-too-distant future. However, there is still a lack of high-level evidence to support proton therapy in the treatment of esophageal cancer, and proton therapy has its limitations in clinical application. It is expected to see the results of future large-scale randomized clinical trials and the continuous improvement of proton radiotherapy technology.
Measuring breathing induced oesophageal motion and its dosimetric impact
2021, Physica Medica
Citation Excerpt :
With a rigid motion model for the whole patient, they found no clinically significant dose deviations but that gamma passing rates decrease with an increase in the motion amplitude and can be violated for certain lung patients. Zhang et al. [16] investigated the difference in dose parameters between 3DCT and 4DCT based treatment plans for oesophageal cancer patients. Their volume based analyses showed that plans based on a 3DCT scan could overestimate the target coverage.
Purpose: Stereotactic body radiation therapy allows for a precise dose delivery. Organ motion bears the risk of undetected high dose healthy tissue exposure. An organ very susceptible to high dose is the oesophagus. Its low contrast on CT and the oblong shape render motion estimation difficult. We tackle this issue by modern algorithms to measure oesophageal motion voxel-wise and estimate motion related dosimetric impacts.
Methods: Oesophageal motion was measured using deformable image registration and 4DCT of 11 internal and 5 public datasets. Current clinical practice of contouring the organ on 3DCT was compared to timely resolved 4DCT contours. Dosimetric impacts of the motion were estimated by analysing the trajectory of each voxel in the 4D dose distribution. Finally an organ motion model for patient-wise comparisons was built.
Results: Motion analysis showed mean absolute maximal motion amplitudes of 4.55 $\pm$ 1.81 mm left-right, 5.29 $\pm$ 2.67 mm anterior-posterior and 10.78 $\pm$ 5.30 mm superior-inferior. Motion between cohorts differed significantly. In around 50% of the cases the dosimetric passing criteria was violated. Contours created on 3DCT did not cover 14% of the organ for 50% of the respiratory cycle and were around 38% smaller than the union of all 4D contours. The motion model revealed that the maximal motion is not limited to the lower part of the organ. Our results showed motion amplitudes higher than most reported values in the literature and that motion is very heterogeneous across patients.
Conclusions: Individual motion information should be considered in contouring and planning.
The use of tumour markers in oesophageal cancer to quantify setup errors and baseline shifts during treatment
2021, Clinical and Translational Radiation Oncology
Citation Excerpt :
The CBCT scans were verified for breathing motion related artefacts to exclude irregular breathing motion during CBCT acquisition. Additionally, in oesophageal cancer, respiratory motion can be mitigated through the use of an iCTV based on the motion observed on the planning 4D CT [36–38]. The inter-fractional variability of respiratory motion was investigated by Jin et al. by comparing a reconstructed 4D CBCT with the planning 4D CT [29].
To prospectively evaluate the feasibility of solid gold marker placement in oesophageal cancer patients and to quantify inter-fractional and intra-fractional (baseline shift) marker motion during radiation treatment. Radiotherapy target margins and matching strategies were investigated.
Thirty-four markers were implanted by echo-endoscopy in 10 patients. Patients received a planning 4D CT, daily pre-treatment cone-beam CT (CBCT) and a post-treatment CBCT for at least five fractions. For fractions with both pre- and post-treatment CBCT, marker displacement between planning CT and pre-treatment CBCT (inter-fractional) and between pre-treatment and post-treatment CBCT (intra-fractional; only for fractions without rotational treatment couch correction) were calculated in left–right (LR), cranio-caudal (CC) and anterior-posterior (AP) direction after bony-anatomy and soft-tissue matching. Systematic/random setup errors were estimated; treatment margins were calculated.
No serious adverse events occurred. Twenty-three (67.6%) markers were visible during radiotherapy (n = 3 middle oesophagus, n = 16 distal oesophagus, n = 4 proximal stomach). Margins for inter-fractional displacement after bony-anatomy match depended on the localisation of the primary tumour and were 11.2 mm (LR), 16.4 mm (CC) and 8.2 mm (AP) for distal markers. Soft-tissue matching reduced the CC margin for these markers (16.4 mm to 10.5 mm). The mean intra-fractional shift of 12 distal markers was 0.4 mm (LR), 2.3 mm (CC) and 0.7 mm (AP). Inclusion of this shift resulted in treatment margins for distal markers of 12.8 mm (LR), 17.3 mm (CC) and 10.4 mm (AP) after bony-anatomy matching and 12.4 mm (LR), 11.4 mm (CC) and 9.7 mm (AP) after soft-tissue matching.
This study demonstrated that the implantation of gold markers was safe, albeit less stable compared to other marker types. Inter-fractional motion was largest cranio-caudally for markers in the distal oesophagus, which was reduced after soft-tissue compared to bony-anatomy matching. The impact of intra-fractional baseline shifts on margin calculation was rather small.
Weekly robustness evaluation of intensity-modulated proton therapy for oesophageal cancer
2020, Radiotherapy and Oncology
Intensity-modulated proton therapy (IMPT) is expected to result in clinical benefits by lowering radiation dose to organs-at-risk (OARs). However, there are concerns about plan robustness due to motion. To address this uncertainty we evaluated the robustness of IMPT compared to the widely clinically used volumetric modulated arc therapy (VMAT) on weekly repeated computed tomographies (CT).
19 patients with oesophageal cancer were evaluated. IMPT and VMAT plans were created on a planning 4-Dimensional CT (p4DCT) and evaluated on weekly repeated 4DCTs (r4DCT). In case of inadequate target coverage or unacceptable high dose to normal tissue, re-planning was performed. Dose distributions of the r4DCTs were warped to p4DCT, resulting in an estimated actual given dose (EAGD).
Compared to VMAT, IMPT resulted in significantly lowered dose to heart, lungs, spleen, liver and kidneys. For IMPT, target coverage was adequate (after max 1 replanning) in 17/19 cases. In two cases target coverage remained insufficient. However, in one of these patients the summed dose was insufficient (due to tumor shrinkage) while weekly coverage was adequate. For the other patient the target coverage was also insufficient by VMAT, due to large anatomical changes during treatment. For VMAT, adequate target coverage was achieved in 18/19 cases without re-planning. However, for reasons of high OAR dose re-planning was required in two cases.
IMPT reduces the dose to OARs significantly, while achieving adequate target coverage in the majority of patients. Re-planning was necessary for both IMPT and VMAT due to anatomical changes.

View all citing articles on Scopus

: Supported in part by Grant No. (CA74043) from the National Cancer Institute and by the Research and Education Foundation Program of the Radiological Society of North America.

: Conflict of interest: none.

View full text

Physics ContributionFour-Dimensional Computed Tomography–Based Treatment Planning for Intensity-Modulated Radiation Therapy and Proton Therapy for Distal Esophageal Cancer

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Methods and Materials

End points of IMRT, two-beam, and three-beam proton plans calculated using 3D CT images

Discussion

Conclusions

Ann Thorac Surg

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Physics Contribution
Four-Dimensional Computed Tomography–Based Treatment Planning for Intensity-Modulated Radiation Therapy and Proton Therapy for Distal Esophageal Cancer