|Ahead of print publication
Dosimetric effects of repeat computed tomography scan during radiotherapy planning in esophagus carcinoma
Aafreen Khan1, Shashank N Singh2, Tauseef Ali1, Sahaj Palod1, Ridhima Ojha1, C Mahendran1, Virendra Bhandari1
1 Department of Radiation Oncology, Sri Aurobindo Medical College and PG Institute, Indore, Madhya Pradesh, India
2 Department of Radiation Oncology, AIIMS, Bhopal, Madhya Pradesh, India
|Date of Submission||12-Feb-2020|
|Date of Decision||05-Apr-2020|
|Date of Acceptance||22-Jun-2020|
|Date of Web Publication||28-Oct-2020|
Department of Radiation Oncology, Sri Aurobindo Medical College and PG Institute, Indore, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
Aim of Study: The aim was to assess the potential reduction in the doses to organs at risk (OARs) and target organ volume by doing replanning on repeat computed tomography (CT) scan during the 4th week of radiation therapy (RT).
Materials and Methods: Twenty-four histologically proven patients of inoperable esophagus carcinoma were studied. All patients received induction chemotherapy followed by concurrent chemotherapy and radiotherapy. CT simulation with proper immobilization was done, and images were transferred to the treatment planning system. Delineation of target volumes and OARs was done, and two plans were generated for 60 Gy in 30 fractions and 40 Gy in 20 fractions with intensity-modulated RT keeping the doses to OARs within the tolerance limits. Replanning for 20 Gy in 10 fractions was done on repeat CT scan during the 4th week of radiotherapy treatment, and potential reduction in doses to OARs and target organ volume was assessed.
Results: A total of 24 cases were analyzed for the adaptive plan with the coverage of the 95% prescription isodose for planning target volume. Statistical analysis was done by t-test. The difference in the doses received by the OARs was analyzed and was seen that due to re CT scan, the doses were reduced to the left lung V20 (mean 19.23 Gy vs. 17.35 Gy) and Dmean (mean 16.03 Gy vs. 14.25 Gy), right lung V20 (mean 18.38 Gy vs. 16.66 Gy) and Dmean (mean 15.70 Gy vs. 13.97 Gy), heart V25 (mean 38.72 Gy vs. 35.32 Gy) and Dmean (mean 26.40 Gy vs. 22.74 Gy), and spine 1% volume (mean 36.54 Gy vs. 33.39 Gy) and Dmax (mean 39.81 Gy vs. 34.34 Gy), gross tumor volume (GTV) (mean 67.37 cm 3 vs. 24.58 cm 3) and were all significantly smaller for the adaptive plan.
Conclusion: By doing adaptive radiotherapy in the 4th week of treatment using repeat CT scan, along with the response evaluation, there is a significant reduction in the volume of GTV, and replanning of treatment on repeat CT scan also helps us in reducing doses to the OARs resulting in reduced toxicity.
Keywords: Adaptive radiotherapy, esophagus, reduced normal tissue dose
|How to cite this URL:|
Khan A, Singh SN, Ali T, Palod S, Ojha R, Mahendran C, Bhandari V. Dosimetric effects of repeat computed tomography scan during radiotherapy planning in esophagus carcinoma. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 6]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=299458
| > Introduction|| |
A substantial number of cancers with numerous histology occur in the gastrointestinal (GI) tract, of which, colorectal, stomach, esophagus, liver, gallbladder, and pancreas are the six most common GI malignancies. Esophageal cancer ranks seventh in terms of incidence (572,000 new cases) and sixth in mortality (509,000 deaths). In India, esophageal carcinoma ranks sixth in terms of both incidence and mortality, with the incidence rate of 52,396 and mortality of 46,504 in year 2018. Histologically, the main tumor types are squamous cell carcinomas and adenocarcinomas. Sarcomas and small cell carcinoma account to <1%–2% of all esophageal cancers., Esophagus carcinoma presents with the symptoms of dysphagia (90%), odynophagia (50%), and weight loss (40%–70%).
As it presents at an advanced stage, it carries a poor prognosis, and all patients are not suitable for surgical resection. Hence, concurrent chemoradiation plays an important role in all inoperable diseases. Due to advanced disease, the area to be irradiated has large volumes, as it must cover submucosal spread and nodal disease as well, making it a great task to deliver radiation dose accurately with minimal toxicity. More than 75% of patients receiving radiation experience temporary esophagitis and dysphagia, sometimes requiring nutritional support.
Radiation pneumonitis and cardiac toxicity are relatively common complications in the treatment of esophageal cancer while delivering a large tumoricidal dose, causing a major concern for radiation planning. An increased risk of radiation myelopathy can be expected in connection with a dose escalation approach.
During the treatment, there can be interfractional variations of internal structures that can occur. Respiration-induced motion, along with setup errors, increases the total volume to be irradiated causing more irradiation to organs at risk (OARs). Using image guidance with daily cone-beam computed tomography (CBCT), we can minimize the random and systemic errors. Various other techniques, such as three-dimensional (3D) imaging systems (like CBCT), helical tomotherapy, and in-room CT on rails, improve the setup and increase the accuracy of radiation therapy (RT) delivery. The second strategy uses an evaluation of random setup errors, and based on the results, planning target volume (PTV) is corrected. This concept of adaptive radiotherapy was first described by Yan et al., and was executed in prostate cancer radiotherapy.
The goal of modern radiotherapy techniques is to minimize the posttreatment complications by improving the gross tumor volume (GTV) definition, reducing interfraction motion and intrafraction motion, and better dose delivery to the precisely defined PTV.
The aim of this study is to test the benefits of adaptive radiotherapy by doing repeat CT scan in the 4th week of treatment and generating a significant reduction in the volume of GTV which ultimately helps us in reducing doses to the OARs and thus resulting in reduced toxicity and improved results.
| > Materials and Methods|| |
A prospective observational study was carried out on 24 patients with histologically proven Stage II or more inoperable esophagus carcinoma patients registered from July 2017 to June 2019. Patients' parameters including age, sex, tumor site, histology, type and duration of induction chemotherapy, and concurrent chemotherapy were recorded. Patients with Karnofsky Performance Status (KPS) more than 70% were included in the study. An informed consent was obtained before undergoing further imaging during radiotherapy. Patients receiving radical radiotherapy for esophagus carcinoma were eligible. All patients received induction chemotherapy, followed by concurrent chemoradiotherapy.
Four-clamp thermoplastic mask (Orfit) was used to immobilize the patient. The patient was asked to breathe normally. CT simulation was done on Siemens SOMATOM Definition AS scanner (Germany), and the CT images of 3 mm slice thickness were obtained. These images were then transferred to Eclipse vs. 13.7 (Varian Medical Systems Pvt. Ltd., Palo Alto, CA, USA) treatment planning system. Delineation of the tumor on the planning CT scan was done. The GTV consists of the gross tumor and involved nodes as defined by diagnostic CT or positron-emission tomography (PET)-CT scan. The clinical target volume (CTV) was created by contouring the esophagus for 5 cm superiorly and inferiorly beyond the edge of apparent tumor along the length of the esophageal mucosa. The upper border of very distal tumors should not extend above the cricoid cartilage, unless there is gross disease. For radial margin, CTV should include the GTV with at least a 1–1.5 cm margin in all directions, also comprising periesophageal nodes, mediastinal and supraclavicular nodes in proximal tumors, and celiac nodes in distal/Gastroesophageal Junction (GEJ) tumors for microscopic spread. For the PTV, a 0.4 cm margin in all directions was added to the CTV [Figure 1]. OARs such as both lungs, heart, spine, both kidneys, and liver were also delineated on CT scan as per the Radiation Therapy Oncology Group (RTOG) guidelines. Intensity-modulated RT (IMRT) plan was generated to ensure PTV coverage by the 95% isodose while maintaining the OARs constraints. The dose distribution in the PTV and OAR was evaluated using dose–volume histograms (DVHs). A total dose of 60 Gy in 2 Gy/fraction for 30 fractions with IMRT were prescribed to the target volume, keeping the doses to OARs within tolerance limits. This plan was named as Plan A. Similarly, another plan was generated on the same CT scan for a dose of 40 Gy in 20 fractions at 2 Gy/fraction and was named as Plan-1.
|Figure 1: Clinical target volume of Plan-A (clinical plan). Green contour is clinical target volume, red contour is planning target volume|
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Adaptive radiotherapy planning
A repeat CT scan with same method was done during the 4th week of radiotherapy treatment. The tumor and involved nodes and the esophagus for the length of the PTV as defined in the clinical plan were contoured on repeat CT scan. There was no change in the superior and inferior length of the clinical PTV; this was so that the submucosal microscopic spread would always be covered by the prescribed dose. The contours on the repeat CT scan acquired in the 4th week of treatment were delineated keeping the margins same as per previous CT scan to create CTV1 [Figure 2]. Similarly, PTV margins were also delineated as per the previous scan with 0.4 cm circumferential margin around CTV1 to account for microscopic spread and contouring error and were labeled as PTV1. The goal was to achieve coverage of the PTV with the 95% isodose line for the PTV1 using similar field arrangement as per the clinical plan (Plan-A) [Figure 3]. A dose of 20 Gy at 2 Gy/fraction for 10 fractions was planned and was defined to be the adaptive plan and was named as Plan 2. A sum plan was generated using Plan 1 and Plan 2, which was labeled as Plan-B.
|Figure 2: Planning target volume on repeat computed tomography scan. Yellow contour denotes planning target volume 1 and pink contour denotes clinical target volume 1|
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|Figure 3: Planning target volume with the 95% isodose line using similar field arrangement|
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The following data were collected – GTV volume in Plan-A and Plan-B and the DVHs for the lung, heart, and spinal cord for clinical (Plan-A) and adaptive plan (Plan-B), as per the QUANTEC guidelines [Figure 4]. The potential reduction in doses to OARs and target organ volume was assessed. The difference of Plan-A and Plan-B was labeled as Plan-C [Figure 5].
|Figure 4: Dose–volume histogram of organs at risk (circle) for Plan-A; (square) for Plan-1; (triangle) for Plan-2. Blue spinal cord; pink heart; yellow left lung; cyan right lung|
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|Figure 5: Combination of both plans. Red contour denotes planning target volume of Plan A, yellow contour denotes planning target volume of repeat computed tomography. Difference can be noted in the volume of both planning target volume. Planning target volume length kept same in both plans|
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| > Observations and Results|| |
Twenty-four patients with histologically proven locally advanced esophagus carcinoma were analyzed between July 2017 and June 2019. Out of 24, 17 were male and 7 were female with a median age of 55 years (range of 26–80 years). All were having squamous cell histology. All patients received induction chemotherapy, followed by concurrent chemoradiotherapy with the prescribed dose of radiation, i.e., 40 Gy/20 fractions, followed by 20 Gy/10 fractions on repeat CT scan.
A total of 24 cases were analyzed for the adaptive plan with the coverage of the 95% prescription dose for PTV. Statistical analysis was done by t-test, which revealed a statistically significant difference in V20 of the left lung with P = 0.0001 (standard deviation [SD]: 3), V20 (mean) for Plan-A was 19.23 Gy, whereas for adaptive plan (Plan-B), it was 17.35 Gy. Similarly, Dmean for the left lung for Plan-A was 16.03 Gy and for Plan-B, it was 14.25 Gy and showed a significant difference in both the plans with P = 0.0001 (SD: 3.4). Likewise, V20 of the right lung also had a statistically significant difference in both the plans with P = 0.0001 (SD: 3.8), V20 (mean) for Plan-A was 18.38 Gy, and for Plan-B, it was 16.66 Gy. The Dmean for the right lung in Plan-A was 15.70 Gy, and for Plan-B, it was 13.97 Gy and was highly significant with P = 0.0001 (SD: 3.7).
The V25 dose for the heart for Plan-A was 38.72 Gy, whereas for Plan-B, it was 35.32 Gy again being statistically significant with P = 0.0001 (SD: 11.5). Dmean for the heart for Plan-A was 26.40 Gy and for Plan-B, it was 22.74 Gy and was highly significant with P = 0.0004 (SD: 11.2). The mean dose to the spine 1% volume for Plan-A was 36.54 Gy and for Plan-B, it was 33.39 Gy and is also highly significant with P = 0.0001 (SD: 2). Similarly, the spine Dmax dose for where Plan-A had value of 39.81 Gy, whereas Plan-B value was 34.34 Gy and has a significant difference in both the plans with a highly significant P = 0.0005 (SD: 3) [Table 1].
Finally, the difference of GTV in the initial CT scan and repeat CT scan was evidently significant with the mean of 67.37 cm 3 on the first CT scan and 24.58 cm 3 on the repeat CT scan indicating a substantial reduction in tumor volume.
Similarly, the mean volumes of CTV in both the plans showed a significant difference, with the mean of 217.03 cm 3 in initial CT scan and 83.8 cm 3 on repeat CT scan.
Likewise, the volume of PTV in both the plans also had a significant difference, with a mean of 356.6 cm 3 on the initial CT scan, whereas on repeat scan, it was 139.3 cm 3.
Thus, we saw a definite reduction in the doses to the OARs with no changes in the dose received by the PTV.
| > Discussion|| |
This study evaluates the benefits of adaptive radiotherapy acquired in the 4th week of treatment using repeat CT scan. There was a significant reduction in the volume of GTV which ultimately helps us in reducing doses to the OARs, which sequentially causes a significant reduction in treatment toxicity, in terms of both acute and late effects.
The concept of adaptive radiotherapy was described by Yan et al. and subsequently was refined and clinically implemented in prostate cancer radiotherapy delivery. The study involved a single plan modification within the 2nd week of treatment that improved the efficacy of dose delivery and dose escalation for radiotherapy for prostate cancer.
Adaptive radiotherapy has been introduced to manage an individual's treatment by doing targeted planning. The conventional method to compensate for variations in treatment position and internal organ motion sometimes requires addition of a large margin around the target, in this manner increasing the treatment volume and subsequently increasing normal organ toxicity while limiting the tumor dose. Adaptive radiotherapy has been initiated to either reduce or compensate for the effect of patient-specific treatment variation which occurs during radiotherapy.
A similar study was done by Hawkins et al. on CBCT-derived adaptive RT for radical treatment of esophagus carcinoma, which concluded that a reduced planning volume can be constructed within the 1st week of treatment using CBCT with a substantial reduction in OAR dose. The study demonstrated a significant reduction in the dose received by the heart, lungs, and spine because of lesser individualized CTV-PTV margins. We have applied a similar technique in the treatment of esophagus carcinoma, with remarkable reduction of the normal tissue irradiated using the IMRT technique.
Surrounded by bilateral lungs and mediastinal organs, esophageal cancer irradiation usually causes dose impacts on the lungs and heart, which may result in acute toxicities dominated by radiation pneumonitis and late toxicities such as cardiac events, pulmonary fibrosis, or deaths related to radiation exposure. Recent advances in radiation techniques (e.g., intensity-modulated radiotherapy, image-guided radiotherapy, PET, etc.) result in higher conformity, homogeneity, more normal tissue sparing, and less treatment time. Favorable prognosis and less toxicities were also seen in advanced techniques.
IMRT has justified advantages on dose constraint of the lungs and heart compared with 3D-conformal radiotherapy (3D-CRT).
The main aim of modern radiotherapy approaches in esophageal cancer is to minimize the posttreatment complications by the improvement of the GTV definition (PET-based planning), reduced interfraction motion (image-guided RT) and intrafraction motion (respiratory-gated RT), and better delivery of the dose to the precisely defined PTV (intensity-modulated RT and proton RT).
Modern radiotherapy approaches must evaluate the probability of organ-specific radiation toxicity. OARs for esophageal cancer radiotherapy include the lungs, heart, and spinal cord. Currently, we use QUANTEC as a reference for dose constraints.
In various studies, the increased risk of radiation pneumonitis correlated with heterogeneous parameters, such as mean lung dose (lung Dmean), the percentage of lung volume receiving at least 20 Gy (V20), 13 Gy (V13), 10 Gy (V10), or 5 Gy (V5). Multivariable analysis showed that V5 and V20 remained associated with this, with V5 of ≤65% and V20 of ≤25% optimal thresholds.
Other probable risk factors for radiation pneumonitis, besides the heterogenous dosimetric parameters, such as concurrent chemotherapy, age, pretreatment pulmonary functions, presence of chronic pulmonary disease, and others, have also been noticed.
Similarly, heart is another organ at risk during esophageal treatment. The most common manifestation of late radiation injury to the heart is pericardial disease. It may present as acute pericarditis, as chronic pericardial effusion, or can be asymptomatic. Radiation injury primarily consists of fibrosis and/or small-vessel injury.
In various other studies, cardiac toxicity in esophageal cancer patients treated with radiotherapy, with or without chemotherapy, the overall accrued incidence of symptomatic cardiac toxicity was as high as 10.8%, corresponding with several dose–volume parameters of the heart. The most frequent complications were pericardial effusion, ischemic heart disease, and heart failure.
Hence, to reduce the doses to OARs, we are using adaptive radiotherapy by doing re-CT scan during the 4th week of treatment without changing the margins of PTV which does not compromise to the doses.
| > Conclusion|| |
By doing adaptive radiotherapy using repeat CT scan in the 4th week of treatment, there was a significant reduction in the volume of GTV and which also helped us in reducing doses to the OARs resulting in reduced toxicity either acute or late, especially to the lung, heart, and spine and providing better patient compliance. The details of the response, survival, and late toxicity will be published when the results get matured.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Sharma A. Gastrointestinal cancers in India: Treatment perspective. South Asian J Cancer 2016;5:125-6.
] [Full text]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
Young JL, Percy CL, Asire AJ, Berg JW, Cusano MM, Gloeckler LA, et al
. Cancer incidence and mortality in the United States, 1973-77. Natl Cancer InstMonogr. 1981;(57):1-187.
Kwatra KS, Prabhakar BR, Jain S, Grewal JS. Sarcomatoid carcinoma (carcinosarcoma) of the esophagus with extensive areas of osseous differentiation: A case report. Indian J Pathol Microbiol 2003;46:49-51.
Schottenfeld D. Epidemiology of cancer of the esophagus. Semin Oncol 1984;11:92-100.
Wong R, Malthaner R. Combined chemotherapy and radiotherapy (without surgery) compared with radiotherapy alone in localized carcinoma of the esophagus. Cochrane Database Syst Rev 2006;(1):CD002092.
Hong TS, Crowley EM, Killoran J, Mamon HJ. Considerations in treatment planning for esophageal cancer. Semin Radiat Oncol 2007;17:53-61.
Rodrigues G, Lock M, D'Souza D, Yu E, Van Dyk J. Prediction of radiation pneumonitis by dose-volume histogram parameters in lung cancer – A systematic review. Radiother Oncol 2004;71:127-38.
Herman MG, Pisansky TM, Kruse JJ, Prisciandaro JI, Davis BJ, King BF. Technical aspects of daily online positioning of the prostate for three-dimensional conformal radiotherapy using an electronic portal imaging device. Int J Radiat Oncol Biol Phys 2003;57:1131-40.
Yan D, Vicini F, Wong J, Martinez A. Adaptive radiation therapy. Phys Med Biol 1997;42:123-32.
Yan D, Wong J, Vicini F, Michalski J, Pan C, Frazier A, et al
. Adaptive modification of treatment planning to minimize the deleterious effects of treatment setup errors. Int J Radiat Oncol Biol Phys 1997;38:197-206.
Vosmik M, Petera J, Sirak I, Hodek M, Paluska P, Dolezal J, et al
. Technological advances in radiotherapy for esophageal cancer. World J Gastroenterol 2010;16:5555-64.
Yan D, Lockman D, Brabbins D, Tyburski L, Martinez A. An off-line strategy for constructing a patient-specific planning target volume in adaptive treatment process for prostate cancer. Int J Radiat Oncol Biol Phys 2000;48:289-302.
Vargas C, Yan D, Kestin LL, Krauss D, Lockman DM, Brabbins DS, et al
. Phase II dose escalation study of image-guided adaptive radiotherapy for prostate cancer: Use of dose-volume constraints to achieve rectal isotoxicity. Int J Radiat Oncol Biol Phys 2005;63:141-9.
Brabbins D, Martinez A, Yan D, Lockman D, Wallace M, Gustafson G, et al
. A dose-escalation trial with the adaptive radiotherapy process as a delivery system in localized prostate cancer: Analysis of chronic toxicity. Int J Radiat Oncol Biol Phys 2005;61:400-8.
Wang D, Yang Y, Zhu J, Li B, Chen J, Yin Y. 3D-conformal RT, fixed-field IMRT and RapidArc, which one is better for esophageal carcinoma treated with elective nodal irradiation. Technol Cancer Res Treat 2011;10:487-94.
Hawkins MA, Brooks C, Hansen VN, Aitken A, Tait DM. Cone beam computed tomography-derived adaptive radiotherapy for radical treatment of esophageal cancer. Int J Radiat Oncol Biol Phys 2010;77:378-83.
Marks LB, Yorke ED, Jackson A, Ten Haken RK, Constine LS, Eisbruch A. Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys 2010;76:10-9.
Lee HK, Vaporciyan AA, Cox JD, Tucker SL, Putnam JB Jr, Ajani JA, 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;57:1317-22.
Shaikh T, Churilla TM, Monpara P, Scott WJ, Cohen SJ, Meyer JE. Risk of radiation pneumonitis in patients receiving taxane-based trimodality therapy for locally advanced esophageal cancer. Pract Radiat Oncol 2016;6:388-94.
Hsu FM, Lee YC, Lee JM, Hsu CH, Lin CC, Tsai YC, et al
. Association of clinical and dosimetric factors with postoperative pulmonary complications in esophageal cancer patients receiving intensity-modulated radiation therapy and concurrent chemotherapy followed by thoracic esophagectomy. Ann Surg Oncol 2009;16:1669-77.
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