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| ORIGINAL ARTICLE |
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| Year : 2020 | Volume
: 3
| Issue : 1 | Page : 17-24 |
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Dosimetric assessment of heart in cancer esophagus patients treated by chemoradiation: A retrospective analysis
Ankita Mehta, Piyush Kumar, Jitendra Nigam, NS Silambarasan, S Navitha, Arvind Kumar, Pavan Kumar
Department of Radiation Oncology, Shri Ram Murti Smarak Institute of Medical Sciences, Nainital Rd, Bhoji Pura, Bareilly, Uttar Pradesh, India
| Date of Submission | 30-Mar-2020 |
| Date of Acceptance | 28-May-2020 |
| Date of Web Publication | 08-Jul-2020 |
Correspondence Address:
Dr. Piyush Kumar
Shri Ram Murti Smarak Institute of Medical Sciences, Nainital Rd, Bhoji Pura, Bareilly, Uttar Pradesh,
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/jco.jco_6_20
Context: Radiation-induced cardiac events have not gained much concern in esophageal malignancies. There are several serious cardiac events, which may impact the overall survival rates. Aims: This study was designed to compare the dosimetric parameters of heart in patients with carcinoma esophagus planned by intensity-modulated radiotherapy (IMRT) and 3Dimensional conformal radiotherapy (3DCRT) technique. Materials and Methods: Twenty-two patients with carcinoma esophagus who were treated by the IMRT technique to a dose of 50.4 Gy were retrospectively selected for the study and corresponding virtual 3DCRT plans were generated for study purpose (total = 44 plans). The dosimetric parameters of the resulting plans were compared for planning target volume (PTV) and organs at risk: heart, left ventricle, left anterior descending artery, and lungs. Statistical Analysis Used: Paired t test. Results: The dosimetric parameters of PTV were comparable for D50, Dmean; however, a significant improvement was observed in D95 (P = 0.0005), D90 (P = 0.003), homogeneity index, and conformity index (P < 0.0001 each) with IMRT. A significant reduction in the various dose volumes of the heart (V20, V25, V30, V40, D33, D67, D100), left anterior descending artery (V30, V40), and left ventricle (V30, V40) along with mean dose was seen. The lung dose was nearly comparable in terms of Dmean and V20. Conclusion: IMRT has a better dose homogeneity and conformity compared to 3DCRT. Better cardiac sparing may translate into a decreased incidence of long-term radiation-induced cardiac complications. Keywords: 3Dimensional conformal radiotherapy (3DCRT), dosimetric parameters, heart, intensity-modulated radiotherapy (IMRT)
How to cite this article:
Mehta A, Kumar P, Nigam J, Silambarasan N S, Navitha S, Kumar A, Kumar P. Dosimetric assessment of heart in cancer esophagus patients treated by chemoradiation: A retrospective analysis. J Curr Oncol 2020;3:17-24 |
| Introduction | |  |
Chemoradiation is now the standard management of cancer esophagus.[1],[2] During radiotherapy planning, more stress is laid on the dosimetry of lungs and spinal cord, whereas heart has been of lesser concern due to poor survival rates and therefore lesser likelihood of developing long-term cardiac complications. There is accumulating evidence highlighting the significant impact of radiation-induced cardiac events on overall survival rates in patients with esophageal cancer independent of the presence of baseline cardiac risk factors.[3],[4],[5] These events have been causatively linked with microvascular and macrovascular damages manifesting as serious events such as ischemic heart diseases, pericardial effusion, atrial fibrillation, and sudden death with the probability increasing with the magnitude of radiation exposure.[6]
The robust implication of dosimetry of cardiac substructures has been well recognized in breast cancer with a growing practice of possible avoidance but this concept has not been embraced in esophageal cancer.[7],[8] The proven association of lethal cardiac events with decrease in ejection fraction and induction of atherosclerosis demands widespread adoption of sparing of the left ventricle and coronary artery in esophageal malignancies as well.[9],[10]
The clinical target volume (CTV) includes a large length of adjoining normal esophagus craniocaudally and a small volume of heart radially owing to the anatomical proximity with the tumors of distal and middle one-third esophagus. This leads to the inclusion of a major volume of heart in the radiation portal posing a major challenge in cardiac sparing. There is huge controversy among experts and in existing literature regarding the advantage of intensity-modulated radiotherapy (IMRT) over 3Dimensional conformal radiotherapy (3DCRT) technique in esophageal malignancies. However, the recent trends documented a huge upsurge in the use of IMRT technique that necessitates jurisdiction of the growing practice.[11]
This study compares the dosimetric parameters of the heart in patients with cancer esophagus planned by the IMRT and 3DCRT techniques.
| Materials and Methods | | |
A total of 22 patients with carcinoma esophagus of the middle and lower one-third who had been previously treated by chemoradiation between September 2017 and December 2019 with the IMRT technique to a dose of 50.4 Gy were retrospectively selected. The corresponding virtual 3DCRT plans (another 22 3DCRT plans) were generated for all patients. The IMRT and 3DCRT plans were compared in terms of dosimetric parameters of planning target volume (PTV) and organs at risk (OARs).
The patients treated with the IMRT technique were simulated in a supine position with arms overhead by using a thermoplastic cast. Intravenous and oral contrast-enhanced compuated tomorgrphy (CT) simulation imaging with a slice thickness of 3 mm was obtained.
Volume delineation
The delineation was carried out as per the consensus contouring guidelines for IMRT in esophageal and gastroesophageal (GE) junction cancer.[12]
- GTV (gross tumor volume): A minimum esophageal wall thickness of more than 5mm was delineated as GTV corresponding with tumoral length in endoscopy findings. The nodal GTV was identified with a shortest axis diameter of at least 1 cm.
- CTV: It included the adjoining normal esophageal mucosa 3-cm cranial and caudal to the GTV with a 1-cm radial margin inclusive of adjoining lymph node stations, but the expansion into heart and lungs was limited to 5mm. For tumors with extension to GE junction, the proximal 2 cm of the lesser curvature of stomach and celiac lymph nodes were included.
- PTV: It was taken as 1-cm isotropic expansion from CTV as per the institutional protocol.
The planning risk volume (PRV) margin for the spinal cord was 5mm. The heart was contoured along with the pericardial sac commencing from its base identified by the inferior aspect of the pulmonary artery passing across the midline and extended inferiorly up to the apex. The left ventricle and left anterior descending arteries were delineated as per the cardiac contouring atlas.[13]
IMRT planning
A total of 5 to 9 beam arrangement, usually seven beams of 6-MV photon energy were used [Figure 1]. Inverse planning was carried out and tissue inhomogeneities were considered in the beam optimization process using a progressive resolution optimizer (PRO) algorithm. The calculation was carried out by the analytical anisotropic algorithm (AAA). The maximum iteration limit was 1000 and the iteration time given was 1000s. The plans were calculated using dynamic Multileaf collimator (MLC) and jaw tracking tools.
Using the same volumetric contours of IMRT treatment plans, virtual 3DCRT plans were generated as described subsequently. The planning was carried out on Eclipse treatment planning system version 13.6.
3DCRT planning
The 3DCRT planning was carried out in two phases using 15-MV photons (as per department protocol) with prescription at the isocenter or the reference point. The first phase of treatment was delivered by parallel opposed anterior and posterior beams to a dose of 36 Gy in 18 fractions [Figure 2]. The second phase of treatment was delivered by three beams (one anterior and two parallel opposed lateral beams) with anterior tilt in the right lateral beam (gantry angle 280) and posterior tilt in the left lateral beam (gantry angle 100) to a dose of 14.4 Gy in 8 fractions [Figure 3]. The angles of oblique beams were so chosen to provide maximal exclusion of heart. The treatment plans were optimized by the field-in-field technique, varying beam weightage and enhanced dynamic wedges.,
Dosimetric assessment
The planning objectives were specified as dose to PTV ranging from 95% to 107% of the prescribed dose. The dose constraints to the OARs were prescribed as per recommended by Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC)[14],[15] and Radiation Therapy Oncology Group (RTOG).[16]
Dmax for the PRV spine: 50 Gy
Combined lungs: Dmean < 20 Gy and V20 < 30%
Heart dose: Dmean < 30 Gy,[15]D33 < 50 Gy, D67 < 45 Gy, and D100 < 40 Gy.[16]
The dose constraints were not defined for the left ventricle and left anterior descending artery due to lack of data in literature but were tabulated in results as seen in the treatment plans.
All plans were optimized so that 95% of volume receives a minimum of 95% of the prescribed dose. The D50 parameter was defined to be a minimum of prescription dose (50.4 Gy).
The dosimetric parameters assessed were D95, D90, D50, Dmean, V107, D2 (Dnear-minimum), D98 (Dnear-maximum), homogeneity index (HI), and conformity index (CI).
The HI and CI were calculated as per ICRU 83[17] and ICRU 62,[18] respectively.
Dose-volume parameters for OARs were assessed as follows:
Heart: Dmean, Dmax, D33, D67, D100, V5, V10, V20, V25, V30, V40, and V50
Left ventricle: Dmean, Dmax, V5, V10, V20, V30, V40, and V50
Left anterior descending artery: Dmean, Dmax, V5, V10, V20, V30, V40, and V50
Combined lungs: Dmean, V5, and V20.
Statistical significance
The statistical significance was calculated by using a paired t test of unequal variances. A value of P ≤ 0.05 was considered statistically significant.
Ethical considerations
The study was approved by the Institutional Ethical Review Committee before its inception.
| Results | | |
In this study, malignancies of lower one-third of the esophagus were more common than that of middle one-third (ratio 1.4:1.0) with squamous cell carcinoma being the most common histopathology. The tumor length in the majority of cases was less than 10 cm (mean 7.6 cm) [Table 1].
The PTV showed adequate coverage as per the prespecified objectives with both the techniques. The D50, the sole most important predictor of coverage,[17] showed comparable results in both techniques along with the Dmean. The D95% and D90% showed a small advantage of an average of 1 Gy in the IMRT technique, but this proved to be highly significant (P = 0.0005 and 0.003, respectively). The IMRT technique also provided to be significantly better (P < 0.0001) in terms of more homogenous distribution owing to a higher observed value of Dnear-min and lower value of Dnear-max. In all IMRT plans, the upper dose limit was not exceeded; however, in 3DCRT plans an average of 1% volume was exposed to a dose of more than 107% (V107%). There was also an appreciable improvement in CI with the IMRT technique (1.09 versus 1.45; P < 0.0001) [Table 2]. | Table 2: Comparison of dosimetric parameters of PTV between IMRT and 3DCRT technique
Click here to view |
The dosimetric parameters of the heart showed a significant reduction in terms of the mean dose, dose to partial and whole volumes (D33, D67, and D100), and high dose volumes (V20, V25, V30, V40, and V50) with the IMRT technique but this was accompanied by a huge and significant increase in the low dose volumes (V5 and V10) [Table 3]. | Table 3: Comparison of dosimetric parameters of heart between IMRT and 3DCRT technique. Dosimetric parameters of organs at risk (IMRT versus 3DCRT)
Click here to view |
The IMRT technique also proved to be advantageous in terms of sparing of the left ventricle with a significant reduction in the high dose volumes V30 and V40 and nearly comparable value of V20 and V50, but an indispensable rise in the low dose volumes V5 and V10 was observed. The impact of decrease in high dose volumes was counteracted by an increase in low dose volumes with the IMRT technique and the difference in mean dose among both the techniques was small and nonsignificant [Table 4]. | Table 4: Comparison of dosimetric parameters of left ventricle and left anterior descending coronary artery between IMRT and 3DCRT technique
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A similar trend was observed in terms of high dose volumes of the left anterior descending artery with an average reduction of 99.7% in V40 (P = 0.0004) and 93.4% (P < 0.0001) in V30 and a nonsignificant reduction of 6.4% in V20. In both the planning techniques, no part of the left anterior descending artery was exposed to a dose of 50 Gy (V50–0% in both the techniques). In terms of low dose volumes, the V5 was much higher in the IMRT technique (P = 0.007); however, the V10 was comparable. Overall the mean dose showed a significant reduction (P = 0.02) of approximately 36.17% with the IMRT technique [Table 4].
The dosimetric parameters of the combined lungs showed no significant difference in terms of mean dose, but the V20 showed a trend toward a significant reduction with the 3DCRT technique (P = 0.06). The V5 parameter highlighted the clear disadvantage of the IMRT technique in terms of low dose volumes with a huge and significant rise of approximately 20% over the 3DCRT technique (P = 0.003) [Table 5]. | Table 5: Comparison of dosimetric parameters of lungs between IMRT and 3DCRT technique
Click here to view |
| Discussion | | |
In esophageal malignancies, 3DCRT is still considered by some experts to be the standard technique.[19] The better conformity or sharp dose falloff beyond the PTV in the IMRT technique led to a cylindrical shape of 95% isodose line, but in 3DCRT plans a square-shaped distribution corresponding to the beam entry path was observed.
The dosimetry of heart along with its substructures showed a significant advantage with the IMRT technique in terms of reduction in the high dose volumes and the mean dose owing to better conformity. Despite deliberate cardiac sparing with optimal beam arrangement, collimation, and use of enhanced dynamic wedges, the exposure was beyond the recommended constraints in few of the 3DCRT plans. This is because of maximal indispensable contribution to high dose volumes from anterior beam especially in the first phase of treatment. This was complemented by a higher mean tumor length of 7.62 cm owing to delayed presentation with 22.7% of patients having a tumor length of more than 10 cm. The large length of radiation portals led to inclusion of nearly whole volume of heart making it tedious to achieve recommended dose constraints.
The better conformity with the IMRT technique did not translate into better lung sparing in terms of mean dose and V20 owing to a huge increase in the entry dose because of multibeam arrangement.
Xu et al.[5] in a study of 560 patients with carcinoma esophagus proved a significant correlation of 5-year survival rates with V20, V25, and V30 of heart on multivariate analysis, but no strong correlation established with the parameters V5, V10 and V40, V50. Henceforth, the reduction in the parameter V25, V30 of heart observed in our study with IMRT technique is expected to translate into a long-term decreased incidence of cardiac deaths providing a hope to improve the poor overall survival rates, whereas the increase in low dose volumes, that is, V5, V10 is not expected to have long-term clinical implications unlike breast malignancies.[8] The slightly better dosimetry of PTV may also reduce the high incidence of in-field locoregional failures, which might have an impact on the cause-specific survival rates. However, these assumptions are based on dosimetry require long-term clinical validation. In their study, the lung V20 and mean lung dose were found to be significantly independent predictors of overall survival but no robust correlation with the parameter V5. These findings also support the growing practice of IMRT as mean lung dose and V20 were not seen to differ significantly among the two planning techniques in our study. The V5 of lungs was seen to be significantly higher with the IMRT technique, but this technique has significant merits in terms of cardiac sparing and dosimetry of target region, justifying its increasing trend of use. The demerit in terms of a rise in low dose volumes of lung may be counteracted by attempting to minimize the number of beams.
Our findings were validated in a meta-analysis by Xu et al.,[20] where the irradiated volume of heart was observed to be much lesser in the IMRT technique (P = 0.02) in patients treated to a total dose of 50 Gy. Their study had a total of 80 patients for dosimetric analysis, whereas 871 patients were included in the analysis for overall survival that also highlighted the clear superiority of the IMRT technique (P = 0.007). There was no impact of technique on pneumonitis explained by no significant difference in V20 of the lungs among two planning techniques but the mean dose was proved to be significantly lesser in the IMRT technique contrary to our findings. However, the authors specified that there was a publication bias in terms of studies analyzing dosimetry of lungs
Ghosh et al.[21] also proved IMRT to be beneficial in terms of cardiac sparing with a reduction in the mean dose to an average of 22.4 Gy in IMRT from 29.2 Gy in the 3DCRT technique (P = 0.001). Their study showed a significant reduction in mean dose and V20 of the lung with a 3DCRT technique. However in our study, a trend toward a significant reduction (P = 0.06) was seen in V20 but the mean dose of the lung was nearly comparable. This may be due to posterior obliques beam arrangement used in their study compared to anterior and posterior oblique paired beams used in our plans.
Some of the studies have shown 3DCRT to have comparable results to that of the IMRT technique in terms of cardiac sparing and many experts still advocate against the growing practice of the IMRT technique. Taher et al.[22] in a recent prospective study of 20 carcinoma esophagus patients with tumors of middle or lower one-third showed efficient cardiac sparing in 3DCRT plans with no significant difference observed in comparison to IMRT plans in terms of mean dose and V30. A total of nine beams were used in their study for all IMRT plans compared to a usual 5 to 7 beam arrangement used across most of the studies, which might have led to an increase in the entry dose masking the effect of sharp dose gradient in IMRT plans. The methodology of 3DCRT plans was also quite different from 3 to 5 beams used in a single-phase manner, and gantry angles of 45° and 315° were also used along with the anterior and two paired lateral beams.
A similar study by Fawaz et al.[23] showed 3DCRT technique with three-fields in a single-phase manner (single anterior and paired left posterior oblique beams) to have better results in terms of cardiac sparing over volumetric modulated arc therapy (VMAT) technique; this was accompanied by a huge rise in the lung dose; however, the two-phase plans similar to our study showed inferior results in terms of dosimetry of heart compared to VMAT technique. These findings show that efficient cardiac sparing can be achieved by the 3DCRT technique but at the expense of rising lung dose.
Wu et al.[24] in a study of middle one-third patients with carcinoma esophagus treated up to a total dose of 60 Gy showed a reduction in the V25, V30, V50 and mean dose of heart with 5 beam IMRT plans compared to the standard two-phase 3DCRT plans but only the difference in V30 proved to be statistically significant. The IMRT technique had an impact on the high dose volumes of lung and heart but this was accompanied by an increase in the low dose volumes of lungs and normal tissues. The authors concluded that 3DCRT is a feasible option taking into consideration the cost-effectiveness and treatment delivery time.
Some other authors[21] have also recommended 3DCRT as the standard technique for esophageal malignancies despite the huge reduction in high dose volumes of heart observed with the IMRT technique attributed to the adequate and comparable coverage of PTV and nearly comparable or lesser lung doses with 3DCRT technique. The possible reason is that the robust implication of the high dose volumes of heart was not well realized until recently.
A meta-analysis by Steven et al.[11] showed no impact of IMRT on esophageal cancer-specific mortality or pulmonary mortality, but was significantly associated with lower all-cause mortality, cardiac mortality, and other-cause mortality that is consistent with the expectations from our dosimetric parameters of the heart showing better sparing.
Dosimetric analysis for substructures of heart–left ventricle and left anterior descending artery had been studied by Ling et al.[25] In their study of patients with postoperative esophageal cancer, no significant difference was observed in the mean dose of the left ventricle (30.3 Gy versus 27.3 Gy; P = 0.25) and left anterior descending artery (17.6 Gy versus 15.1 Gy; P = 0.441) among IMRT and 3DCRT plans. The proton beam treatment plans showed a significant reduction in the mean dose of these substructures. In this study also, the treatment plans using high energy photons showed no significant difference in the mean dose of the left ventricle (P = 0.47) as the reduction in high dose volumes with the IMRT technique was counteracted by an increase in the low dose volumes because of multibeam arrangement. However, the mean dose of the left anterior descending artery showed a statistically significant reduction with the IMRT technique (P = 0.02).
In this study, dose constraints to substructures were not predefined due to which its maximal avoidance potential of the IMRT technique may not be apparent. The 3DCRT plans revealed an indispensable increase in the high dose volumes of the left ventricle and left anterior descending artery with maximal contribution from anterior beams conferring an increased risk of cardiotoxicity. An optimal substructural sparing demands the precise and uniform validation of dose constraints and evolution of planning techniques in esophageal malignancies with maximal possible avoidance.
This study supports the growing institutional time trend of IMRT. The reduction in dose inhomogeneity and the better conformity offering cardiac avoidance with the IMRT technique provides a hope to improve the poor overall survival rates of esophageal malignancies. In most of the IMRT plans, the dose-volumes parameter of the heart were well below the recommended dose constraints offering the potential of dose escalation. Numerous studies[26],[27] have shown favorable results in dose-escalated settings. A study by Zhang et al.[28] showed that even for patients showing a complete clinical response after standard-dose radiotherapy, those receiving a dose of 59.4 Gy had significantly better local control, recurrence-free survival, and overall survival compared to patients treated to a dose of 50.4 Gy. Dose escalation may be considered when surgery is not being contemplated otherwise at the present the standard of care for middle and lower one third is preoperative radiotherapy.[29]
The increase in lung dose with the IMRT technique observed in this study was although nonsignificant but demands consideration as this may counteract the benefit of cardiac sparing on overall survival rates. It might be possible to reduce the lung dose by minimizing the number of beams.
| Conclusion | | |
The coverage of the PTV was optimal with both the techniques; however, the dose inhomogeneity was minimized and much better conformity was observed with IMRT plans. This technique also offers the scope of safe dose escalation that is still being practiced at many centers given the high incidence of locoregional failures. The clinical validation of the dosimetric advantage observed with the IMRT technique demands further research in large-scale studies with longer follow-up.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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