Impact of VMAT-IMRT compared to 3D conformal radiotherapy on anal sphincter dose distribution in neoadjuvant chemoradiation of rectal cancer

Patient selection and radiation techniques

Between 2008 and 2016 a total of 154 rectal cancer patients were treated with neoadjuvant radiation therapy in our institution, 106 with IMRT (either RapidArc (88) or TOMO (28)) and 48 with 3D-RT. To compare IMRT with 3D-RT, we selected the subgroup which might has the greatest possible benefit of sphincter sparing. These are patients with rectal cancer of the middle third (5–12 cm) that were irradiated with a conventional regimen (total dose 45 Gy, single dose 1.8 Gy). In order to make the two groups as homogeneous as possible and thus comparable, we included only such patients in the study who had T3N+ disease.

Patients in the IMRT-group were treated on a Varian Clinac® DHX linear accelerator (Varian Medical Systems, Palo Alto, CA, USA) using IGRT (image-guided radiotherapy) with kilo-voltage cone-beam-CT scans (CBCT). Regularly 2 arcs were used (6 or 15 MV). Some patients received TOMO-therapy with the TomoTherapy Hi-ART-System (6 MV) (Accuray, Sunnyvale, USA). The dose was prescribed to the median of the PTV (ICRU83). Contouring and treatment planning for the intensity modulated radiation therapy was performed using the Eclipse 13.0 planning system (Varian Medical Systems, Palo Alto, CA, USA). Contouring was done on planning CT scans with 3 mm slice thickness. Patients in the 3D-group underwent chemoradiation between 2008 and 2012. All of those patients were treated with ONCOR – Digital Medical Linear Accelerator by Siemens and planned with Oncentra MasterPlan software Version 3.0 SP1, usually 4 fields were used. Daily image guidance was performed using 2D-MV imaging from 0° and 90°. The dose was prescribed to the reference point (ICRU50/62). Dose constraints for organs at risk (OAR) (femoral heads, small bowel, sigmoid colon, genitals and urinary bladder) orientated on Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) [31]. There were no constraints for the anal sphincter(s) in both groups.

In all patients, the clinical target volume (CTV) definition generally based upon the recommendations of the RTOG Consensus Panel Contouring [32]. In all patients, next to the primary tumor, the whole mesorectum, the peri-rectal-, pre-sacral- and internal iliac nodes were always included into the CTV. As recommended, the visible external iliac nodes were included in four patients in the IMRT group and three patients in the 3D-group. The lower border was at least 2 cm caudal of the gross disease. Further 0.7–1.0 cm were added to reach the PTV margin.

Contouring and definition of the anal sphincters

For dose-evaluation we defined the volume of the sphincters in two different ways: Most of the studies that analysed dose distribution to the anal sphincters used a unified approach (“sphincter region”) and combined the internal and external anal sphincters as one, mostly filled volume [28, 29, 33]. The cranial border was usually 1 cm below the ampulla recti. The entire anal canal including the anal mucosa/skin was contoured, (CT hyperdensity). For comparison, we defined the internal as well as the external sphincter as “anal sphincter” (AS) in the same way.

As a second, anatomically more detailed approach, we defined the internal anal sphincter (IAS), the external sphincter (EAS), and the levator ani muscle according to the following rules (Fig. 1):

• Internal anal sphincter: Thin muscle which encircles the anal canal. Inner demarcation: Anal mucosa. Outer demarcation: External anal sphincter.

• External anal sphincter: Encircles the internal anal sphincter and merges cranially (at the level of the cranial end of the internal muscle) into the levator ani muscle. Outer demarcation: Central perineal tendon.

• Levator ani muscle: Superior/lateral demarcation: Dorsal part of the pubic body/fascia of the obturator internus muscle. Caudal end: Transition to the external anal sphincter muscle at the level of the cranial internal sphincter muscle.

• Anal sphincter: Includes the internal and external anal sphincters described above.

For the delineation of the sphincters, a matched MRI-scan helped with most individuals, especially for the demarcation of the muscle to the mucosa or skin. For correct comparison, the final contouring was performed on the planning CT-scan in both groups.

Evaluation of dose and data

We examined the absolute max dose (D98%), absolute min dose (D2%) and the absolute mean and median dose to the entire volume of the different sphincters, respectively. Furthermore, we evaluated and compared the relative dose parameters (V10, V20, V30, V40, V45). In addition, we quantified the differences in dose distribution to the sphincters between the two groups by measuring the longitudinal distance between the 95 and 10% isodoses at the caudal level of the planar centre of the anal canal. For all dose parameters and the longitudinal distance between the isodoses, a Mann-Whitney U test was performed with SPSS 25.0 (SPSS Inc., Chicago, IL, USA) to identify significant differences between the IMRT- and the 3D-group (independent samples). With a p-value < 0.5, we assumed that there is a significant difference between the two groups.

Dose and sphincter function

Long-term functionality of the anal sphincters correlates with the dose to the sphincter complex. Most studies with large patient collectives, in which sphincter dose distribution was correlated with sphincter function, dealt with prostate cancer. The dose prescription in a treatment of prostate cancer is usually much higher (68–78 Gy) than of a long term nCRT concept of the rectum (45 Gy). In an analysis of 414 patients treated with 70 Gy to the prostate or postoperative region, Alsadius et al. could show that long-term fecal leakage largly increases with ≥40 Gy compared to a mean dose < 40 Gy [28]. Buettner et al. quantified dose distribution to the anal-sphincter region and sphincter control of 388 prostate cancer patients treated with 3D-technique [34]. Dose-surface maps were created to estimate the dose of the surface of the anal canal. Furthermore, DVHs and DSHs were determined. Subjective sphincter control correlated significantly with the dose of the sphincters. Optimal cut-points of 47 Gy to the anal sphincter and 45 Gy to the anal surface were found. The relative risk of unsatisfactory subjective sphincter control was also higher for patients receiving ≥30 Gy. One study was found dealing with sphincter function and the correlation of dose in nCRT treated rectal cancer patients. In this study, Arias et al. compared dose distribution and fecal incontinence in rectal cancer patients treated with chemoradiation. Patients with V20 > 0 had significantly more often poor sphincter function (Mean Wexner score of 5.5) compared to those with V20 = 0 (p = 0.008). In median the V20 was 34.9% (4.5–85.2%). The authors recommend a sphincter dose constraint of V20 = 0, if possible. In our study, the median V20 was 85.8% in the IMRT-group and 100% in the 3D radiation-group. The lowest V20 in the IMRT-group was 14.9% although we used the same method in contouring of the AS. We assume that the great difference in the V20 is related to the differences in the patient population. Arias et al. selected patients, who received sphincter-preserving surgery and who were more than 2 years free of overall relapse at the time of the study. In our study the majority of the patients had tumors starting from 5 to 6 cm from the anal margin, which resulted in an overlapping of the PTV with the cranial aspect of the AS in most of the cases. Nevertheless, a big difference between the two techniques occurred in V20 of the AS (IMRT: 80.1% vs. 3D: 96.5%; p = 0,004). Ultimately, V20, V30 and V40 of the AS, which were found to be relevant in prostate cancer studies, were significantly reduced in the IMRT group compared to 3D-technique.

Target volume definition and the effect on the anal sphincters

In rectal cancer, a high inter-observer variability in the definition of the clinical target volume in rectal cancer patients exist [35–37]. The caudal border and the ischioanal fossa are two of the structures which usually deviate most from contouring standards [37].

The fact, that loco-regional recurrences of rectal cancer usually occur posteriorly or laterally [38, 39] to the target volume, gives rise to the problem, that in rectal cancers, which are located near to the sphincter complex, an adequate CTV margin is needed. Subsequently, this results in a subtotal coverage of the anal sphincters by the PTV. On the other hand, especially if sphincter preservation is intended, a maximal protection of the sphincters has to be aimed. The common RTOG Consensus Panel recommendations define a caudal extension of the CTV of 2 cm to gross disease with an inclusion of the entire mesorectum to the pelvic floor, even in upper rectal cancers [32]. Roels et al. published recommendations for CTV delineation in advanced rectal cancer based on an analysis of local recurrences and lymph node involvement. They defined pelvic subsites for loco-regional recurrence. The inferior pelvic subsite, which includes the anal sphincter complex, was at risk of locoregional recurrence, when the tumor was within 6 cm from the anal margin or in those patients who were treated with abdominoperineal resection. For the reasons stated above the authors recommend an inclusion of this region in the CTV for patients with a tumor located ≤6 cm from the anal verge or in a situation where the tumor infiltrates the anal sphincter complex and an abdominoperineal resection has been planned. The current consensus guidelines (ESTRO35) differ for this caudal area. They recommend that the ischiorectal fossa should only be included in case of invasion of the external anal sphincter or the ischiorectal fossa [40].

The levator ani muscle is located more cranially to the caudal sphincter complex and is mostly completely covered by the PTV. This leads to a Dmean of about 45 Gy and a V40 of about 98% no matter which of the radiation techniques is used. Because of its cranio-caudal extension along the perirectal fat tissue, this structure is located in a high risk area for loco-regional recurrence. This means, that dose sparing is not desired or useful and more conformal radiation techniques couldn’t improve any protection of this structure.

In our study, the majority of the patients in both groups had cancers starting from 5 to 6 cm above the anal verge. Analogous to the recommendations of Roels et al., in these patients a caudal extension of 2 cm plus about 1 cm PTV margin results either in an overlap or a total coverage of the caudal sphincter muscles with the PTV (Fig. 3).

Regarding dose coverage of anal sphincters, two groups of middle third rectal patients can be identified. In patients, where the primary tumor is in close proximity to the anal sphincter complex, the sphincters should be included into the CTV. This was the case in exactly 8 of 16 patients in each group. The AS was completely covered by the previous PTV, which leads to a V40 of about 100% of the caudal anal sphincters. These patients do not benefit from sphincter protection by IMRT. In patients with a primary tumor starting 1 to 2 cm above the sphincter (also 8 of 16), the sphincter complex only partially overlaps with the PTV. These patients benefit greatly from a steep dose drop of IMRT compared to the 3D-irradiation (Fig. 3). The significant improvement of Dmin, Dmean as well as the V10–V40 in the IMRT-group compared to the 3D-group is supported by the fact that the 8 patients with total anal sphincter inclusion were part of the comparison. As it is known, that pathologic complete response is associated with higher radiation dose and finally improved outcomes, IMRT provides another advantage of local dose escalation (boost) without increased toxicity [41]. In rectal cancer patients of the middle third, this reduced target volume has often some distance to the sphincters and offers another opportunity of sphincter sparing.

Limitations

The main limitation of this study was the retrospective character. Furthermore, to make a comparison as accurate and meaningful as possible, many of the treated rectal cancer patients could not be included into the study. Unfortunately, this ultimately led to a relatively small number of patients for the final comparison. However, we were able to make the two groups very homogeneous, which ultimately led to a good comparability, in which significant differences in the dose at the sphincters could be shown.