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ORIGINAL ARTICLE
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A comparison of radiotherapy treatment planning techniques in patients with rectal cancers by analyzing testes doses


1 Department of Radiation Oncology, University of Health Sciences Antalya Education and Research Hospital, Antalya, Turkey
2 Department of Radiation Oncology, University of Health Sciences Adana City Training and Research Hospital, Adana, Turkey

Date of Submission12-May-2019
Date of Decision10-Aug-2019
Date of Acceptance23-Oct-2019
Date of Web Publication09-Oct-2020

Correspondence Address:
Evrim Duman,
Department of Radiation Oncology, University of Health Sciences Antalya Education and Research Hospital, Antalya
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_328_19

 > Abstract 


Purpose: To evaluate the target volume (TV) and critical organ doses with priority of testes with the comparison of conformal radiotherapy (CRT), dynamic intensity-modulated radiotherapy (DIMRT), and volumetric modulated arc therapy (VMAT) techniques.
Materials and Methods: CRT, DIMRT, and VMAT techniques were generated on computed tomography images in prone position of 10 male patients with distal rectal cancer. Conformity index (CI), heterogeneity index (HI), treatment time, and monitor units were examined; dose-volume-histograms (DVHs) for the TV and the organs at risk (OARs) were evaluated.
Results: Target dose coverage of all treatment plans was similar. HI and CI values for DIMRT and VMAT were closer to “1” compared to CRT. DVH parameters for OARs were decreased with DIMRT and VMAT compared to CRT. The percent volume (Vx) of 3 Gy dose of testes was 62.01% (±25.45%), 42.68% (±16.42%), and 35.89% (±14.97%) in the CRT, DIMRT, and VMAT techniques, respectively. V3 of testes decreased with VMAT compared to CRT and DIMRT (P = 0.008 and P = 0.051, respectively).
Conclusion: Modern radiotherapy techniques are superior to conformal techniques in planning quality parameters and sparing OARs. DIMRT and VMAT could be considered instead of CRT in the desire to preserve fertility of patients with rectal cancer.

Keywords: Intensity-modulated radiotherapy, rectal cancer, testes dose, volumetric modulated arc therapy



How to cite this URL:
Duman E, Bilek Y, Ceyran G. A comparison of radiotherapy treatment planning techniques in patients with rectal cancers by analyzing testes doses. J Can Res Ther [Epub ahead of print] [cited 2020 Oct 20]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=297619




 > Introduction Top


Colorectal cancer is the third most commonly diagnosed cancer, with a 10.9% worldwide incidence per year in males.[1] Rectal cancers constitute approximately one-third of all colorectal cancers, and the cumulative incidence risk of a male for rectal cancer is 1.2% from birth to 74 years.[1],[2]

The primary treatment for a potential curative disease is surgery, and the addition of radiotherapy and chemotherapy improves the local control rates in patients with a risk of local recurrence.[2] Neoadjuvant chemoradiotherapy before surgery has become the standard treatment in patients with locally advanced rectal cancer. Neoadjuvant chemoradiotherapy often reduces the local recurrence risk of resectable tumors, downstages the tumor, and improves resectability in most of the unresectable tumors.[3],[4]

Radiotherapy is currently recommended for many patients, and long-term survival after modern multimodal treatment is expected in at least 60% of patients with rectal cancer.[5] Although the most common side effect related to radiotherapy is intestinal toxicity, sexual dysfunction is one of the problems encountered, especially during prolonged survival.[4],[5],[6],[7],[8],[9] Lower serum testosterone and lower calculated free-testosterone values have been reported in patients who have been irradiated.[10]

Testicular function loss is especially prevalent in distal rectum tumors due to proximity of the testes to the radiotherapy treatment area.[10] The testes are outside the target radiation volume in most patients, but they can still be exposed to scattered radiation.[5] Although radiotherapy-induced testicular damage is related to the testicular dose of irradiation, the radiation dose limit for the testis has not been clearly defined.[11],[12] The germinal epithelium of the testis is very sensitive to radiation-induced damage, and the changes in spermatogonia occur after as little as 0.1 Gy. The number of spermatogonia reduces progressively over 21 weeks to their minimum levels after single radiation doses between 0.2 and 4 Gy. The recovery process depends on the dose of radiation. The ejaculated sperm count begins to increase at 7 months after irradiation with a single dose of 1 Gy, and it takes about 2 years to reach pre-irradiation levels.[13] Radiation-fractionated doses of ≥2 Gy to the testis can cause permanent azoospermia. Currently, sperm banking remains the only proven method in males treated with pelvic radiotherapy.[11]

Side effects related to radiotherapy can be reduced using advanced treatment methods and devices.[14] Intensity-modulated radiotherapy (IMRT) reduces acute and late toxicity compared to conformal radiotherapy (CRT), by limiting the radiation dose delivered to surrounding organs.[15],[16],[17] Volumetric modulated arc therapy (VMAT) with gantry rotation provides a more homogeneous dose distribution compared with IMRT at shorter treatment times.[18] VMAT treatment in patients with locally advanced rectal cancer has the potential to substantially reduce high-grade acute and late toxicity without impairing short-term oncological results.[19] In this study, we aimed to evaluate the target volume (TV) and critical organ doses with the testes by comparing 3-field CRT, 5-field dynamic intensity-modulated radiotherapy (DIMRT), and VMAT in patients with distal rectal cancers.


 > Materials and Methods Top


Patient selection

Ten men with rectum cancer who were treated with neoadjuvant chemoradiotherapy between March 2016 and August 2016 were included in this study. Inclusion criteria included patients with tumors located in the distal rectum (the first 10 cm from the anal verge) and patients with T3N1-2 disease. Large tumors invading the bladder, prostate, or pelvic lateral wall and tumors located in the proximal rectum extending to the sigmoid colon were excluded from the study. Treatment planning tomography images of the patients were re-evaluated retrospectively.

This study was approved by the Institutional Ethics Committee.

Simulation and contouring

Patients were immobilized in the prone position using a belly board. Computed tomography (simCT, Aquilion-LB; Toshiba, Tokyo, Japan) images were obtained using a 3-mm slice thickness without intravenous and oral contrast. The entire pelvis, from the upper abdomen to 2 cm below the scrotum, was included in the images.

In each patient, the primary tumor region was contoured as the gross tumor volume (GTV) with the help of positron emission tomography–computed tomography and pelvic magnetic resonance images. Clinical tumor volume-1 (CTV-1) was obtained by adding 20-mm margins in all directions to the GTV. CTV-2 contained regional lymph nodes (internal iliac, external iliac, and presacral lymph nodes) in addition to CTV-1. Five-millimeter margins were added in all directions to create planning target volume-1 (PTV-1) and PTV-2. Bladder, bilateral femoral heads, and small intestines surrounding the PTV-2 were outlined as organs at risk (OARs). There was a testis cavity on belly board and testes were contoured in the scrotum to assess the doses that were exposed.

Treatment planning

Three different techniques were used for each patient. In 3-field CRT plans, 0°, 90°, and 270° gantry angles were used with 18 MV photon energy. A total of 46 Gy of radiotherapy was planned for PTV-2 with 2 Gy fractional doses using 5-day weekly standard fractionation, and a 4 Gy boost was administered to PTV-1 to complete the total dose to 50 Gy. In 5-field DIMRT, 0°, 50°, 100°, 260°, and 310° gantry angles were used. VMAT was designed as a double partial arc starting at 270° and ending at 90°. A simultaneous integrated boost technique was used with 6 MV photon energy to perform both DIMRT and VMAT plans in 25 fractions for a total dose of 46 Gy for PTV-2 and 50 Gy for PTV-1.

The CMS Monaco 5.1 treatment planning system was used for all techniques. It was used for each plan, and 98% of the TV was used to cover 95% of the prescribed dose. OAR doses were kept below the QUANTEC tolerance limits.[20] It was aimed to be <50% of the volume of the testes in the 3 Gy isodose line recommended in the Radiation Therapy Oncology Group (RTOG)-0630 study[21] to evaluate the testes dose. In DIMRT and VMAT, the same dose constraints were used.

Treatment plan evaluation

Dose distributions in transverse, sagittal, and coronal slices for all plans were visually checked, and dose-volume-histograms (DVHs) were evaluated in terms of PTV and OARs. Since the major concern with IMRT and VMAT is low-dose volumes receiving higher doses than CRT, the percent volume (Vx) of the 2 Gy and 1 Gy doses for the testes was evaluated. In addition, the V0.1 for testes was evaluated because of its impact on changes in spermatogonia.

Conformity index (CI) and heterogeneity index (HI) were calculated. The CI and HI formulae are shown in Equation 1 and Equation 2, respectively. The monitor unit (MU) of each plan was examined. Beam-on times for VMAT and DIMRT were evaluated on the treatment planning system and were defined as the treatment times.

Equation 1

The CI calculation is shown where PIV was the reference iso-dose volume. The TV was equal to PTV-1. TVPIV was TV covered by the reference iso-dose. The CI value calculated as “1” was an ideal plan.



Equation 2

The HI calculation is shown. The high- and low-dose percentages in related structures were defined as X and Y, respectively. It was recommended in the International Commission of Radiation Unit-83 report to use 98% of the prescribed dose as the low-dose percentage and 2% of the prescribed dose as the high-dose percentage.[22] The HI value indicated as “1” was an ideal plan.



Statistical analyses

SPSS software, version 21 (IBM, Armonk, NY, USA) was used for the statistical analyses. The Friedman test and Wilcoxon signed-rank test were performed to analyze the variations between three different technique groups. A P < 0.05 was considered statistically significant.


 > Results Top


The mean PTV-1 and PTV-2 covered by the 95% isodose line are summarized in [Table 1]. There was no statistically significant difference between CRT, DIMRT, and VMAT for dose coverage of PTV, except for the dose distribution using VMAT, which was better than CRT for PTV-1 (P = 0.028).
Table 1: Mean planning target volume 1 and planning target volume 2 volumes covered by the 95% isodose line, conformity index, heterogeneity index, monitor unit, and treatment time values for 3-field conformal radiotherapy, 5-field dynamic intensity-modulated radiotherapy, and volumetric modulated arc therapy techniques

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The mean HI and CI values for all three plans are shown in [Table 1]. Although there was no statistically significant difference between HI values for DIMRT and VMAT (P = 0.65), they were significantly better than those of CRT (P = 0.011 and P = 0.007, respectively). The CI values were closer to “1” using DIMRT when compared with CRT and using VMAT when compared with DIMRT (P = 0.005 and P = 0.018, respectively).

The MU values for CRT, DIMRT, and VMAT are summarized in [Table 1]. The MU values were significantly higher for CRT than for DIMRT and VMAT (P = 0.005 and P = 0.005, respectively). The mean segment numbers for DIMRT and VMAT were 95 and 168 (±5), respectively. Treatment times for the DIMRT and VMAT plans are shown in [Table 1]. While the MU values for VMAT were higher than those for DIMRT, the treatment times were lower (P = 0.007 and P = 0.005, respectively).

The DVH evaluations for the bladder, small intestine, bilateral femoral heads, and testes are summarized in [Table 2].
Table 2: Dose-volume-histogram values of organs at risk in the 3-field conformal radiotherapy, 5-field dynamic intensity-modulated radiotherapy, and volumetric modulated arc therapy techniques

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The percent volume (Vx) of the 45 Gy dose for the bladder was decreased for DIMRT compared with CRT and decreased for VMAT compared with DIMRT (P = 0.007 and P = 0.028, respectively).

The V40 value for the small intestine was decreased for DIMRT and VMAT compared with CRT (P = 0.005 and P = 0.005, respectively). When comparing DIMRT and VMAT, a statistically significant difference was found in favor of VMAT (P = 0.022). Similar results were found for V45 values for the small intestine. VMAT provided the best protection for the small intestine when compared with CRT and DIMRT (P = 0.005 and P = 0.022, respectively). The maximum point dose (Dmax) for the small intestine was lower for DIMRT and VMAT when compared with CRT (P = 0.005 and P = 0.005, respectively).

With respect to the Dmax values for the right femoral heads, VMAT and DIMRT were superior to CRT (P = 0.013 and P = 0.022, respectively). In a similar manner, the decrease in Dmax values for the left femur observed for VMAT and DIMRT was statistically significant when compared with CRT (P = 0.007 and P = 0.017, respectively). For both femurs, there was no difference between DIMRT and VMAT (P = 0.87 and P = 0.33, respectively).

Similar results were found for V0.1 values for the testes. There was no statistically significant difference between V1 values for CRT, DIMRT, and VMAT (P = 0.097). The V2 value for the testes was decreased for DIMRT and VMAT compared with CRT (P = 0.009 and P = 0.007, respectively). When comparing DIMRT and VMAT, no statistically significant difference was found (P = 0.3). Comparison of V3 values for the testes revealed a statistically significantly decrease for DIMRT and VMAT when compared with CRT (P = 0.008 and P = 0.008, respectively) [Figure 1]. It was decreased by nearly 50% after VMAT compared with CRT. There was a 15.9% decrease in V3 values for the testes after VMAT compared to DIMRT, but it did not reach statistical significance (P = 0.051). Differences between the 3 Gy dose areas of the treatment techniques in the transverse sections of the tomography images of patients with rectal cancers are shown in [Figure 2].
Figure 1: The percent volumes of 3 Gy doses (V3) for testes in 10 patients. CRT = Conformal radiotherapy, DIMRT = Dynamic intensity-modulated radiotherapy, VMAT = Volumetric modulated arc therapy

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Figure 2: The 3-Gy dose volume differences obtained by subtracting treatment plans from each other (red line). CRT − VMAT: Conformal radiotherapy minus volumetric modulated arc therapy, CRT − DIMRT: Conformal radiotherapy minus dynamic intensity-modulated radiotherapy, DIMRT − VMAT: Dynamic intensity-modulated radiotherapy minus volumetric-modulated arc therapy. The highlighted green denotes the testes, and the highlighted orange line denotes the planning target volume-2

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 > Discussion Top


Three-dimensional CRT still remains the main modality of radiotherapy for patients with rectal cancers, in many institutions. Larger treatment volumes affect the acute and late toxicities of radiotherapy and the quality of life.[23] IMRT could be considered as the best choice of treatment planning to minimize toxicity.[24] VMAT is another radiation technique that has a shorter beam-on time and more homogenous dose distribution compared with IMRT.[18] A few studies have addressed the use of VMAT in rectal cancer with 360° arc rotation and compared it with CRT and IMRT.[18],[24],[25] A double arc technique was used in this study with a 270°-beginning and 90°-ending to minimize the dosimetry effect of the belly board and to prevent the small intestine from entering the treatment field.

Shi et al.[25] assessed the dosimetry difference between IMRT and VMAT in patients with rectal cancer undergoing radiotherapy after resection. They concluded that the dose distribution of VMAT was equal to or superior to IMRT. Although our results showed that PTV dose coverages were similar for PTV-2, a statistically significant change was only found between CRT and VMAT for PTV-1, with VMAT being more favorable. Target dose coverages of DIMRT and VMAT were found to be similar for both PTV-1 and PTV-2.

The CI formula, which is defined by the RTOG and suggested in the International Commission of Radiation Unit-83 report, is a useful adjunct for the evaluation of techniques.[22] The CI formula, which was used in this study, takes both the PTV and extra-PTV organs into consideration and currently has the widest range of utilization as a comparison index.[26] In a study reported by Wen et al.,[24] CRT, IMRT, and VMAT were compared, and dosimetry analyses demonstrated that IMRT was superior to CRT in the conformity and homogeneity of the dose distribution. According to CI results in our study, CRT was the poorest, and although DIMRT and VMAT showed similar results, VMAT was significantly better.

Dose homogeneity characterizes the uniformity of the absorbed dose distribution in the TV. The HI is defined as a tool for evaluating dose changes in the TV, such as HI.[27] Our results showed that the HI values were similar for both DIMRT and VMAT and closer to 1, when compared with CRT.

Shortening the treatment time reduces both the errors caused by the patient's movements during treatment and the errors caused by the internal organ movements.[28] Treatment time can be shorter with VMAT than with IMRT, because of more beam entry angles in VMAT.[29] In our study, the treatment time was shorter with VMAT than with DIMRT, as expected. Although MU values affect the treatment times during comparison of same treatment techniques, they do not directly affect the treatment times during comparison of different treatment techniques, such as CRT, DIMRT, and VMAT. In our study, MU values were high for CRT because wedges were used. The treatment time was shorter with VMAT than with IMRT, despite higher MU values.

Wen et al.[24] compared CRT, 5-field IMRT, and VMAT in patients with locally advanced rectal cancers undergoing preoperative radiotherapy and concluded that IMRT was superior to CRT in providing better OAR protection. Zhao et al.[14] compared CRT, IMRT, and VMAT, which were planned with a simultaneous integrated boost for locally advanced rectal cancers, and concluded that although IMRT and VMAT achieved comparable target coverages, IMRT was better for OARs and in sparing normal tissues. Shi et al.[25] reported that VMAT offers better small intestine protection with decreased treatment times, compared with IMRT. In our study, VMAT was better than DIMRT in protecting the small intestine and bladder, and DIMRT was better than CRT. Although there was no difference between VMAT and DIMRT, they were both superior to CRT for protection of left and right femurs.

There has been no dose range defined in the literature for the testes in patients treated with pelvic radiotherapy. The cumulative average radiation dose received by the testes was found to be 8.4 Gy in a study by Dueland et al.[30] and a decrease in testosterone hormone level was observed after a 3.3 Gy dose (10th fraction) in rectal cancer patients treated with radiotherapy in 2 Gy × 23–25 fractions. In the RTOG-0630 study,[21] it was recommended that a volume <50% of the testis should receive 3 Gy if there was a desire to preserve fertility. Bakkal et al. compared supine and prone treatment positions in patients with rectal cancer who were treated with CRT and concluded that the supine 4-field external beam radiotherapy allowed lower testicular doses than the prone 3-field and 4-field techniques. They reported that the reason was the greater distance between the lower edge of the field and the testes.[31] Another study by Banaee et al. concluded that a testicular shield was a suitable device for reducing peripheral doses to the testes in patients with bladder, prostate, and rectal cancers. It provided a 40%–70% reduction in absorbed testes doses of patients treated with 18 MV photon beams.[32] Our results showed that CRT in the prone position exceeded the dose constraint for testes defined by the RTOG-0630 study. In patients who are to be treated with CRT and desire to retain fertility, it is recommended to immobilize patients in the supine position with or without testicular shielding during radiotherapy or to recommend sperm banking before treatment.

Joye et al. reported that the prone position on a belly board was associated with reduced bowel doses during VMAT.[33] In our clinic, rectal cancer patients are routinely treated on a belly board in the prone position to reduce bowel toxicity. According to our results on planning computed tomography imaging in the prone position, VMAT provided the best testis protection compared with CRT and DIMRT. Although the mean V3 values of the testes for IMRT and VMAT were below the RTOG-0630 study constraint, it was decreased by nearly 50% and 15% after VMAT compared with CRT and DIMRT, respectively. Although our study was a dosimetry comparison study and did not include clinical findings, we were unable to determine if the volume reached with the VMAT technique was sufficient or insufficient for testicular protection. Future studies should be designed for this purpose.


 > Conclusion Top


Modern radiotherapy techniques were superior to conformal techniques in patients with rectal cancer. The best OAR protection was achieved with VMAT with the best target coverage, conformity, and heterogeneity using less treatment times. Testes, which are outside the target radiation volume, are exposed to radiation doses during radiotherapy. DIMRT and VMAT could be considered instead of conformal techniques in patients with rectal cancer, to preserve fertility.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Meistrich ML. Effects of chemotherapy and radiotherapy on spermatogenesis in humans. Fertil Steril 2013;100:1180-6.  Back to cited text no. 13
    
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Zhao J, Hu W, Cai G, Wang J, Xie J, Peng J, et al. Dosimetric comparisons of VMAT, IMRT and 3DCRT for locally advanced rectal cancer with simultaneous integrated boost. Oncotarget 2016;7:6345-51.  Back to cited text no. 14
    
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