Dosimetric comparison of organs at risk using different contouring guidelines for definition of the clinical target volume in anal cancer

Anal cancer (AC) is a relatively rare malignant tumor of the lower gastrointestinal tract. Chemoradiation (CRT) has been established as an organ-preserving standard approach in non-metastatic disease and is associated with good overall survival rates [1, 2]. So far, the most relevant prognostic factors correlating with survival endpoints are locoregional lymph node (LN) involvement, primary tumor size >5 cm, and pathological complete response [3]. Currently, three international recommendations for intensity-modulated radiation therapy (IMRT) exist for definition of the clinical target volume (CTV) of AC. These were published by the Radiation Therapy Oncology Group (RTOG), the Australasian Gastro-Intestinal Trial Group (AGITG), and the authors and collaborative groups of the British National Guidance (BNG) [4‐6]. The AGITG rightly pointed out that there is currently not sufficient evidence regarding the definition of the inguinal lymphatic drainage [6]. The inguinal region is affected primarily or metachronously in up to 40% of all AC patients [7‐9]. In a recent PET imaging-based analysis of patterns of LN involvement in primary AC, we (the lead institution) were able to demonstrate that the three guidelines differ in their hypothetical effectiveness to cover microscopic LN metastases. Based on these results, we worked out a recommendation for CTV delineation of the inguinal region [10]. Achieving the best possible locoregional control is an important objective in the treatment of AC. However, typical complications such as dermatological, genitourinary, and gastrointestinal side effects, and others like vaginal stenosis, hip osteoarthritis, or sexual dysfunction play a decisive role and should always be considered during treatment planning [11‐15].

In order to be able to estimate the efficiency regarding locoregional control rates and potential side effects of the different guidelines, we conducted a comparative study on the various CTVs and determined the dose to OARs.

We selected 12 patients with the primary diagnosis of squamous cell AC who were treated with CRT at our institution between 2012 and 2018. In all patients, we retrospectively generated the three different CTVs of the established guidelines and a fourth CTV using our own guidelines (LI) on the original planning CT scan with a slice thickness of 3 mm (all prone position). All guidelines are very similar regarding their recommendations for delineation of the elective LN regions in the pelvis (internal/external iliac, pre-sacral, internal obturatoric). There are, however, significant differences regarding the mesorectal and ischiorectal fossa and especially the inguinal region. For the essential contents of the guidelines, see Table 1. With regard to uncertainties leaving room for interpretation of the different definitions of the target volume, formulations such as “should be contoured as a compartment,” we tried to refer as much as possible to the respective atlases published. The planning target volume of the inguinal region (PTV^ing) was created by a 6-mm outer margin of the respective CTV. The planning target volume of the pelvic region which included the primary tumor region (PTV^pelvic) was conceived by increasing the CTV by 10 mm in all directions. The PTV was always limited to the surface of the body. Afterwards, mostly based on the pelvic normal tissue atlas of RTOG, the vulva, scrotum, femoral heads, small bowel, rectum, sigmoid colon, and the urinary bladder were defined [16]. The skin was determined as the volume that represents the first 3 mm of the body surface into the body. We also outlined the genitalia analogously to the genitalia contouring guidelines of Brooks et al. [17].

Subsequently, we created a main and a boost plan for the four different distinct PTVs in each individual for volumetric modulated arc therapy (VMAT) intended to be irradiated on a Varian Clinac® DHX linear accelerator (Varian Medical Systems, Palo Alto, CA, USA). The primary tumor region (PTR) and the pelvic LNs were supposed to receive a total dose of 50.4 Gy and the inguinal LNs were supposed to receive a total dose of 36 Gy (single dose 1.8 Gy). For the main plan, the dose prescription was 36 Gy (1.8 Gy single dose) to PTV1 (PTV^pelvic + PTV^ing), which included the PTR and the elective pelvic and inguinal LNs. 14.4 Gy (1.8 Gy single dose) was prescribed to PTV2 (PTV^pelvic) including the PTR and the elective pelvic LNs, disregarding the inguinal LNs for the sequential boost. The dose constraints for OARs based on Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) [21]. For VMAT, we regularly used three arcs in the main plan (PTV1) and two arcs for the boost plan (PTV2; 6 or 15 MV). The dose was prescribed to the median of the PTV (ICRU83) [18]. The software used for structure definition and dose comparison was Eclipse Treatment Planning System 13.0 (Varian Medical Systems, Palo Alto, CA, USA).

We retrospectively evaluated the dose to OAR in twelve patients by using three established international contouring guidelines and one guidance created by the LI for the definition of the elective target volume for IMRT of primary anal cancer. According to the guidelines of the National Comprehensive Cancer Network (NCCN, 2018), IMRT is preferred over 3D conformal RT. The anus and the perineum as well as the pelvic and inguinal LNs should be included in the target volume [19]. Although current contouring atlases refer to IMRT, the common constraints are often related to 3D conformal irradiation [20].

The fundamentally dreaded side effects of radiotherapy to the groin are lymphatic edema caused by inguinal fibrosis. The pronounced medial and caudal extensions of the target volume suggested by the BNG and LI groups lead in part to significantly higher dose rates to the genitals (Fig. 2; Tables 2, 3). Regarding RTOG 0630 (sarcoma), the median dose to the testis should not extend 3 Gy [23]. In each group, the median dose to the testis was higher than 5 Gy. Even if the absolute dose to the testicles is relatively low, we recommend considering special protection of the genitals. The D50% of the vulva was below 17 Gy in each group (RTOG 0529 constraints: 30 Gy). The risk of developing genital lymphedema is very low if a relatively low dose of 36 Gy is prescribed. The University of Florida presented long-term toxicity in 164 patients after elective radiation (>70% of the patients with ≥45 Gy) of the groin in pelvic cancers. Only three of them developed mild genital edema [24].

The greatest relative and absolute differences concerning the dose parameters between the different CTVs related to the skin. We authenticated a correlation between the skin dose and the inguinal PTV volumes. The caudal margin of the CTV is especially responsible for an increased volume. This is due to the fact that the inferior aspect of the minor tuberculum (BNG) and the level of the anal verge (LI) are usually situated lower than the ischial tuberosities (AGITG) or 2 cm below the femoral saphenous junction (RTOG; Fig. 1). The inguinal target volume was almost twice as high in the BNG and LI groups compared to RTOG (V30 Gy and V35 Gy, respectively). This aspect, however, seems to be of minor clinical relevance since the absolute dose radiation to the groin (36 Gy) is relatively low. Lee et al. identified 13 of 164 patients (8%) with inguinal fibrosis after elective radiation (>70% of the patients with ≥45 Gy) of the groin. None of these cases was severe or correlated with a decrease in quality of life [24].

To make clear recommendations for contouring of the inguinal region, results of studies dealing with the site of locoregional failure after IMRT of AC patients should be taken into consideration. Tomasoa et al. presented patterns of recurrence in 106 patients treated with simultaneously integrated boost (SIB) IMRT. After a median follow-up of 15 months, about 20% of the patients had locoregional relapse. Only two LN recurrences occurred at a pelvic site, while at least four patients had inguinal recurrences (4%, 6 LN) [25]. Furthermore, potential inguinal misses such the ones on superficial superomedial LNs could be identified in a PET imaging-based pattern of failure analysis in the context of established contouring guidelines ([26]; Fig. 3). Finally, the risk of relevant side effects due to slightly larger inguinal target volumes (BNG, LI) seems to be low, since both the absolute size differences and the prescribed dose are manageable, while inguinal recurrence is still relevant.

The four contouring guidelines differ significantly concerning the inguinal region. In order to avoid inguinal recurrence and to protect relevant OARs, further investigations are needed to generate uniform standards for the definition of the elective clinical target volume in the inguinal region.