|Year : 2019 | Volume
| Issue : 1 | Page : 1-8
Sequential simulation computed tomography allows assessment of internal rectal movements during preoperative chemoradiotherapy in rectal cancer
Dae Sik Yang1, Jung Ae Lee1, Won Sup Yoon2, Nam Kwon Lee3, Young Je Park3, Suk Lee3, Chul Yong Kim3
1 Department of Radiation Oncology, Guro Hospital, Korea University College of Medicine, Ansan, Korea
2 Department of Radiation Oncology, Ansan Hospital, Korea University College of Medicine, Ansan, Korea
3 Department of Radiation Oncology, Anam Hospital, Korea University College of Medicine, Seoul, Korea
|Date of Web Publication||13-Mar-2019|
Dr. Won Sup Yoon
Department of Radiation Oncology, Ansan Hospital, Korea University College of Medicine, 123 Jeokgeum-Ro, Danwon-Gu, Ansan, GYG, 15355
Source of Support: None, Conflict of Interest: None
Purposes: The purpose of this study was to assess the internal rectal movement and to determine the factors related to extensive internal rectal movement using sequential simulation computed tomography (CT) images.
Materials and Methods: From 2010 to 2015, 96 patients receiving long-course preoperative chemoradiotherapy were included in our retrospective study. The initial simulation CT (Isim-CT) and follow-up simulation CT (Fsim-CT) for a boost were registered according to the isocenters and bony structure. The rectums on Isim-CT and Fsim-CT were compared on four different axial planes as follows: (1) lower pubis symphysis (AXVERYLOW), (2) upper pubis symphysis (AXLOW), (3) superior rectum (AXHIGH), and (4) middle of AXLOW and AXHIGH (AXMID). The involved rectum in the planning target volume was evaluated. The maximal radial distances (MRD), the necessary radius from the end of Isim-CT rectum to cover entire Fsim-CT rectum, and the common area rate (CAR) of the rectum (CAR, (Isim-CT∩Fsim-CT)/(Isim-CT)) were measured. Linear regression tests for the MRDs and logistic regression tests for the CARs were conducted.
Results: The mean ± standard deviation (mm) of MRDs and CAR <80% for AXVERYLOW, AXLOW, AXMID, and AXHIGH were 2.3 ± 2.5 and 8.9%, 3.0 ± 3.7 and 17.4%, 4.0 ± 5.2 and 27.1%, and 4.1 ± 5.2 and 25%, respectively. For MRDs and CARs, a higher axial level (AXVERYLOW/AXMID-HIGH, P = 0.018 and P = 0.034, respectively), larger bladder volume (P = 0.054 and P = 0.017, respectively), smaller bowel gas extent (small/marked, P = 0.014 and P = 0.001, respectively), and increased bowel gas change (decrease/increase, both P < 0.001) in rectum were associated with extensive internal rectal movement in multivariate analyses.
Conclusions: As a result of following internal rectal movement through sequential simulation CT, the rectum above the pubis symphysis needs a larger margin, and bladder volume and bowel gas should be closely observed.
Keywords: Organ movement, preoperative radiotherapy, rectal cancer
|How to cite this article:|
Yang DS, Lee JA, Yoon WS, Lee NK, Park YJ, Lee S, Kim CY. Sequential simulation computed tomography allows assessment of internal rectal movements during preoperative chemoradiotherapy in rectal cancer. J Can Res Ther 2019;15:1-8
|How to cite this URL:|
Yang DS, Lee JA, Yoon WS, Lee NK, Park YJ, Lee S, Kim CY. Sequential simulation computed tomography allows assessment of internal rectal movements during preoperative chemoradiotherapy in rectal cancer. J Can Res Ther [serial online] 2019 [cited 2019 Nov 22];15:1-8. Available from: http://www.cancerjournal.net/text.asp?2019/15/1/1/251620
| > Introduction|| |
Rectal cancer that is closely located to the anal verge can make anus-preserving surgery difficult, and hence, the quality of life of patients deteriorates. In addition, rectal cancer that has infiltrated the mesorectum can result in incomplete resection, which is one of the causes of local recurrence after definitive surgery. To reduce the possibility of an adverse outcome, preoperative radiotherapy or concurrent chemoradiotherapy (CCRT) has been performed for many years, and recent randomized clinical trial results of CAO/ARO/AIO-94, NSABP R-03, and MRC CR07/NCIC C016 studies have shown its positive effects on anal preservation and local recurrence in comparison with postoperative radiotherapy.,, Therefore, the recent guidelines recommend preoperative radiotherapy as the standard approach in locally advanced rectal cancer.,
To increase the tumor response after preoperative CCRT, preliminary studies for dose-escalation and intensity-modulated radiotherapy (IMRT) have been performed. To improve the efficacy of IMRT, the optimal margins must be decided based on several factors including the setup uncertainty, pelvic organ movement, and deformity during radiotherapy. Several previous studies of rectal cancer observed intrafraction or interfraction rectal movement using cone-beam computed tomography (CT) or helical tomotherapy. These studies were based on a small population of <30 patients, and it is hard to identify the related factors for extensive internal rectal movement.
For successful IMRT or precise radiotherapy for rectal cancer, our study aimed to comprehensively assess internal rectal movement and to identify factors related to extensive internal rectal movement using high-quality images from simulation CT in our relatively large cohort.
| > Materials and Methods|| |
Between January 2010 and December 2015, the patients diagnosed with rectal cancer at Ansan Hospital, Korea University Medical Center were included in this study. Eligibility criteria were patients with: (1) histologic confirmation of adenocarcinoma using endoscopic biopsy; (2) preoperative CCRT with a long-course schedule; (3) an Eastern cooperative oncology group performance scale score of 0–2; and (4) follow-up simulation CT (Fsim-CT) at approximately 40 Gy.
Exclusion criteria were patients who: (1) were aged 80 years over; (2) had poor image quality on simulation CT for registration; (3) had a treatment delay of over 10 days between interfractions; and (4) had a change of setup position during radiotherapy. Medical records and technical radiotherapy reports were reviewed after the Institutional Review Board approval of our study.
The intended three-dimensional conformal radiotherapy (3DCRT) schedule of 50.4 Gy/28 fractions, five times weekly was initially started in our hospital; however, it was changed to 50 Gy/25 fractions in November 2014. The concepts of bladder filling were explained to the patients on the 1st consultation day with two cups of water 2 h before the virtual simulation and each fraction. Specific bowel preparation was not recommended. Virtual simulation using a CT simulator (Brilliance Big Bore Oncology CT system, Philips Medical System, The Netherlands) was performed with a slice thickness of 5 mm during injection of iodine contrast dye. The image set was transferred to a radiotherapy planning system (Eclipse, Varian Medical System, CA) and after delineation of the target volume and organs at risk, three fields from posterior and both lateral directions were applied with 6 or 10 MV X-ray. All the target volumes were delineated by radiation oncologist. A minimum of 1-1.5-cm margin from the primary tumor superiorly and inferiorly was included in the clinical target volume (CTV). In addition, the CTV included the primary tumor, mesorectal compartment, elective regional lymph nodes, and other positive pelvic nodes in pelvis. The planning target volume (PTV) expanded at least 1 cm from the CTV.
After whole pelvic irradiation of 45 Gy/25 fractions and 44 Gy/22 fractions, and a boost to the tumor of 5.4 Gy/3 fractions and 6 Gy/3 fractions, respectively, were administered. To perform cone-down planning, Fsim-CT was done on 2 convenient days before a boost.
Two different regimens of a bolus infusion of 5-fluorouracil (5-FU) at 500 mg/m2/day for 5 days plus leucovorin during the 1st and last weeks and daily oral administration of capecitabine at 850 mg/m2/day during radiotherapy were used. Oral capecitabine has been favored since September 2014.
Two datasets of images from Isim-CT and Fsim-CT were registered with isocenter coordination, and a small mismatch was corrected according to the pelvic bony structure. It is similar to our daily therapeutic practice of online review and corrections applying orthogonal kilovoltage X-ray images.
According to a recommendation by the Radiation Therapy Oncology Group Consensus Panel Atlas More Details, normal pelvic tissue, such as the bladder, femoral heads, rectum (gastrointestinal definition: superiorly from the rectosigmoid flexure to an inferior border 3 cm from the anal verge), and bowel bag, was revised. In the same window of 0 HU and width 1000 HU, the air volume from the L4/L5 interspace to the end of the rectum was automatically calculated, and it was defined as the quantity of bowel gas. The extent of the bowel gas in the rectum on each axial plane was measured, and a value of <10%, 10%–50%, and >50% of the whole rectum area was graded as small, marked, and large extent of bowel gas, respectively. In addition, changes in the above grade were defined as decreasing, stable, or increasing according to the bowel gas on the Fsim-CT in comparison with the Isim-CT on the same axial plane.
The internal rectal movement was measured on four different axial planes. The lowest axial level (AXVERYLOW) was the lower margin of the pubic bone, the next axial level (AXLOW) was the upper margin of the pubic bone, and the highest axial level (AXHIGH) was before the rectum loses its round shape in the axial plane. The other axial level (AXMID) was midway between AXLOW and AXHIGH[Figure 1]a. If the rectum on the AXHIGH level was identified in a different axial plane in Fsim-CT, information on rectal movement was checked after the delineated rectum of Fsim-CT was craniocaudally moved to the same axial plane of Isim-CT.
|Figure 1: (a) Sagittal plane presenting the rectal contours of the initial and follow-up simulation computed tomography. (b) Examples of maximal radial distance and CAR in mid-axis. After the most different area between yellow (initial computed tomography) and green (follow-up computed tomography) contours was indicated, a necessary radius from the isocenter of the yellow to cover the green (blue line) was defined as maximal radial distance. The rate of red intersection area of the yellow and the green was defined as common area rate|
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The longest rectal diameters on above four axial planes were measured using Isim-CT. After the rectal boundary of Isim-CT was compared with Fsim-CT and the most different area of the rectum of Fsim-CT out of Isim-CT was searched, a necessary radius from the isocenter of the rectum of Isim-CT to cover the entire those areas over the rectum of Isim-CT was called as a maximum radial distance (MRD) in this study. If the rectum of Isim-CT included the entire rectal boundary of Fsim-CT, an unnecessary radius to cover the entire rectum of Fsim-CT was measured in the nearest area of the rectum of Fsim-CT within the rectum of Isim-CT and indicated as a negative sign [Figure 1]b.
In addition, the intersectional areas of the rectum between Isim-CT and Fsim-CT were measured on five different grades. The common area rate (CAR) was defined as the following formula: 100× (rectal area of Isim-CT∩Fsim-CT)/rectal area of Isim-CT. If the rectum of Isim-CT included the whole rectum of Fsim-CT, it was defined as Grade 0. According to the above calculation, a CAR of ≥90%, 80%≤90%, 60%≤80%, and <60% was categorized into Grade 1, 2, 3, and 4, respectively [Figure 1]b.
In cases of definitive surgery after preoperative CCRT, the pathologic findings were observed. Tumor response was measured using the suggested method by Chang et al. that is regarded as the Korean standard guideline. Age, sex (male/female), body mass index (≤25, >25 kg/m2), the tumor longitudinal size (≤5, >5 cm), tumor location from the anal verge (<5/5 ≤ 10, ≥10 cm), clinical T-stage (T2, T3, and T4), clinical N-stage (N0, N1, and N2), chemotherapy regimen (bolus 5-FU, capecitabine), and levels of the tumor marker carcinoembryonic antigen (CEA) (≤5, >5 ng/ml) were recorded as clinical factors. Bladder volume and bowel gas volume in Isim-CT, their volume difference between Isim-CT and Fsim-CT as an absolute value, bowel gas extent (small, marked, large), and bowel gas change (decrease, stable, and increase) in each axial plane were included as the information from planning CT.
The only AX where the PTV involved was assessed. The binary correlation test was checked for MRD and CAR between the pairs of AX from the same patient with the Pearson's coefficient. The distribution of the MRD regarding AX was evaluated using the one-way ANOVA test. Using the linear regression test, the MRD was compared according to the above-mentioned factors. For the CAR, the logistic regression test was conducted, and Grade 3–4 of the CAR was regarded as an effective value. The related factors with a P < 0.10 in univariate analyses in any AX entered into the multivariate analyses and backward selection methods were conducted. P <0.05 was statistically significant in two-sided analyses, and SPSS 20.0 (IBM SPSS, Chicago, IL, USA) was used for statistical analysis.
| > Results|| |
A total of 111 patients received preoperative CCRT and underwent both Isim-CT and Fsim-CT. Among them, eight were aged over 80 years, four had poor image qualities, two experienced treatment interruption, and one had a position change; all of these patients were excluded from the analysis. Finally, 96 patients with prone setup were included in our study. The median age was 62 years [Table 1]. Definitive surgery was performed, and the pathologic report was confirmed in 75 patients. Eight patients were transferred to another hospital for surgical resection, six patients had simultaneous metastases in other organs, two patients were lost to follow-up after CCRT, and five patients refused surgery due to old age, comorbidity, or their own choice. The complete or near complete regression of the primary tumor occurred in 19 cases (25.3%), but two cases among them had lymph node metastases (ypN1).
The extent of bowel gas on AXVERYLOW and AXLOW was small in most patients and was unchanged in Fsim-CT. However, AXMID of 27.1% and AXHIGH of 31.3% had the large extent of bowel gas and 42.3% and 36.7% of those cases experienced the decreased gas status in Fsim-CT, respectively [Figure 2].
|Figure 2: The relation of the extent and the change of bowel gas in rectum on each axial plane|
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The rectums in PTV included 56 cases for AXVERYLOW, 92 cases for AXLOW, and all cases for AXMID and AXHIGH. The mean longest diameter for AXVERYLOW, AXLOW, AXMID, and AXHIGH was 29 mm, 40 mm, 45 mm, and 40 mm, respectively. For 4, 8, 9, and 12 cases of AXVERYLOW, AXLOW, AXMID, and AXHIGH, the rectum of Isim-CT covered the whole rectal boundary of Fsim-CT. The mean ± standard deviation of the MRDs for AXVERYLOW, AXLOW, AXMID, and AXHIGH was 2.3 ± 2.5 mm, 3.0 ± 3.7 mm, 4.0 ± 5.2 mm, and 4.1 ± 5.2 mm, respectively [Table 2]. In one-way ANOVA, the distribution of MRD showed the significant difference between AXVERYLOW and AXMID or AXHIGH (P = 0.034). Therefore, a variable for axial planes was categorized as AXVERYLOW, AXLOW, and AXMID-HIGH.
|Table 2: Various measured and calculated values in different axial levels of the rectum|
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In univariate analyses, including all axial levels, axial level (AXVERYLOW vs. AXMID-HIGH) was associated with extensive MRD (P = 0.007). The other associated prognostic factors were lower CEA level (P < 0.001), initial bladder volume (P = 0.027), and bowel gas change (P < 0.001) [Table 3]. In multivariate analyses for the MRDs including all axial levels, lower CEA level (P = 0.005), higher axial level (AXVERYLOW vs. AXMID-HIGH, P = 0.018 and AXLOW vs. AXMID-HIGH, P = 0.035), larger initial bladder volume (P = 0.054), bowel gas extent (marked vs. small, P = 0.014), and bowel gas change (stable vs. decrease and increase vs. decrease, both P < 0.001) in the rectum were associated with higher MRD [Table 4].
|Table 3: Univariate analyses for the relations of maximal radial distance and various clinical and simulation factors|
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|Table 4: Multivariate analyses for the relations of maximal radial distance and various clinical and simulation factors|
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The CAR with Grade 3 and Grade 4 for AXVERYLOW, AXLOW, AXMID, and AXHIGH was 8.9%, 17.4%, 27.1%, and 25%, respectively. In univariate analyses, the initial bladder volume (P = 0.015) and the bladder volume difference (P = 0.025) were associated with lower CAR in AXVERYLOW. Bowel gas change (increase vs. decrease) was associated with lower CAR in AXMID (P = 0.001) and AXHIGH (P = 0.002). The lower CEA levels were statistically significant in AXMID (P = 0.014) and AXHIGH (P = 0.024). Tumor involvement in AXLOW (P = 0.007), the longest diameter in AXMID (P = 0.016), and initial bladder volume in AXHIGH (P = 0.003) were significant. In multivariate analyses including all axial levels, the poor CAR was associated with axial levels (AXVERYLOW vs. AXMID-HIGH, P = 0.034), bowel gas extent (stable vs. decrease, P = 0.0025 and increase vs. decrease, P < 0.001), initial larger bladder volume (P = 0.007), the small longest diameter (P < 0.001), and bowel gas change (marked vs. small, P = 0.001 and large vs. small, P = 0.002) [Table 5].
|Table 5: Multivariate analyses for the relations of common area between initial and following simulation computed tomography and various clinical and simulation factors|
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| > Discussion|| |
This study has assessed internal rectal movement using high-quality simulation CT images and has determined the related factors for extensive internal rectal movement. Through the MRD, we notice that the axial level and lower CEA level are important for this, in addition to the initial bladder volume and the extent and change of bowel gas in the axial rectum. Therefore, when expanding from the CTV to the PTV, generous margins would be needed in the axial rectum above the pubis symphysis. We presume that the 90th percentile value of MRDs might provide margins to cover all internal rectal movement in 90% of cases, and thought that the axial rectum above the pubis symphysis might need an additional margin of about 4-6 mm in comparison with the axial rectum below it. In a study based on cone-beam CT from 16 patients, similar results with our study were observed and the upper rectum required an additional margin of about 3 mm regarding anterior and left directions. CEA is one of the most important prognostic factors for rectal cancer. Although different clinical factors were not presented as prognostic factors of extensive rectal movement, we thought that the extent of tumor fixation to mesorectum might correlate with the CEA, and patients with a lower CEA level had relatively severe rectal movement during radiotherapy.
IMRT would be beneficial for two therapeutic aspects as follows: bowel toxicity and dose intensification. Due to the precision of beam delivery and the difficulty of changing radiotherapy plans, the target volume delineation for IMRT needs more consideration, particularly if simultaneous integrated boost (SIB) is planned for dose escalation. The SIB technique is an attractive option for preoperative CCRT for rectal cancer because it can deliver a higher dose to a local tumor; thus, it theoretically increases the likelihood of tumor regression after CCRT. Although it is anticipated that an ongoing randomized clinical trial (NCT02151019) enables to address the efficacy of IMRT to compare with 3DCRT in rectal cancer, there have been no randomized control trials or prospective studies. A retrospective study from a single institution compared toxicity and tumor regression grade between 3DCRT and volumetric-modulated arc therapy. Acute and late toxicity was reduced in volumetric-modulated arc therapy without improvement of tumor regression. However, a Phase-II study for IMRT combined with oxaliplatin and capecitabine chemotherapy did not show a positive effect on acute gastrointestinal toxicity in comparison with traditional CCRT studies.
An Italian group evaluated the margins for adaptive SIB in preoperative CCRT for rectal cancer. After 10 consecutive patients were assessed, the last six fractions of 20 patients were validated, and they recommended that an anterior margin of 7 mm and 5 mm elsewhere is adequate for 90% coverage of rectal maps in 90% of the population. A Japanese study observed that additional 7, 10, and 15-mm margins from the initial plans to each fraction of cone-beam CT uncovered the 2.1%, 0.7%, and 0.1% of each fraction of SIB volume for rectal cancer with IMRT, respectively. A Canadian group evaluated rectal motion using repeated simulation CT in 17 patients, and 8–9 and 4–7 mm of additional margins were needed for rectal and mesorectal motion, respectively. A Dutch group suggested nonuniform margins according to the directions to decrease the PTV by constructing population-based principle component analyses models.
Bowel gas in the rectum is one of the important factors for rectal movement in our study. For prostate cancer, the stool/gas volume of the rectum affected the prostate motion up to two-fold. Various preparation methods were assessed. To decrease rectal gas, a Japanese group recommended the Kampo formula, which is a traditional Japanese herbal remedy for patients with abdominal bloating or constipation. The UK group recommended a daily microenema as the best method in comparison with a leaflet education and a high-fiber diet for prostate cancer. An Indian group administered a mild laxative and decreased the variability of rectal volume by 25%, as well as the rectal dose.
Our study observed that the initial bladder volume was negatively related to internal rectal movement. However, bladder filling is important to spare small bowel irradiation. A Korean study showed that bladder filling decreased the irradiated bowel volume by 48%–82% in comparison with an empty bladder. Therefore, an empty bladder is not a good choice to just improve the internal rectal movement. It is difficult for patients to keep a large and constant bladder volume during daily repeated long-course radiotherapy. In 10 patients with uterine cervical cancer, another UK group observed that a bladder volume difference over 130 ml from planning CT to cone-beam CT affected the coverage of the PTV, and an initial bladder volume over 300 ml was unreproducible. Basic ultrasonography was used to measure bladder volume and to preserve uniformity.
This study has some limitations. First, only one image pair from each patient was used to evaluate internal rectal movement. Therefore, systematic and random errors could not be calculated and the personalized margins according to the clinical circumference could not be recommended in spite of the large cohort. In addition, simple education for bladder preparation was performed, and the patients' compliance was not monitored. Furthermore, because this study was introduced from 3DCRT, there might be minor differences in the IMRT circumference. Finally, because about one-quarter of patients had undergone definitive surgery at another hospital or had not undergone surgery for various reasons, our study was limited in its evaluation of the regression and extensive errors.
To sufficiently cover internal rectal movement during radiotherapy, the axial rectum above the pubis symphysis would need a larger margin, and patients with a large bladder volume and extensive bowel gas in simulation should be closely observed during radiotherapy. A repeated cone-beam CT at each fraction would be the option to observe these factors. Although the current standard therapy for preoperative CCRT for rectal cancer is 3DCRT, it is expected that IMRT would be more effective. Thus, our study was undertaken to understand the internal rectal movement according to various factors before IMRT becomes a more standard approach. A further study of bowel and bladder preparation and image-guided radiotherapy for rectal movement should be undertaken to improve the quality of precise radiotherapy.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]