Mapping of lateral pelvic lymph node recurrences in rectal cancer: a radiation oncologist’s perspective

Abstract

Purpose

Patterns of locoregional rectal cancer recurrences following total mesorectal excision (TME) were analyzed to define the irradiation volume, especially the lateral pelvic lymph node (LPLN).

Materials and methods

Of 1243 patients who underwent TME without pelvic radiotherapy between 2005 and 2012, the data of 826 patients with rectal adenocarcinoma without distant metastases were analyzed for relapse patterns, categorized as distant and locoregional (anastomosis, mesorectum, presacral area, and LPLNs) failure.

Results

The median follow-up was 61.8 months. The 5-year local recurrence-free, distant metastasis-free, overall survival rates were 88, 82, and 89%, respectively. Relapse occurred in 108 (13%) patients: 90 (11%) had distant and 28 (3%) had locoregional failure. Eight patients had LPLN recurrence: the 2 recurrences from upper rectal cancers occurred near the bifurcation of the common iliac artery into the external and internal iliac vessels; the 6 mid-lower rectal cancers had 16 recurrences near the internal iliac and obturator arteries—five occurred anterior to the obturator artery and posterior to the external iliac artery, superior to the femoral head. LPLN recurrence was associated with pN2 stage, perinodal extension, and lymphovascular invasion.

Conclusion

The LPLN component of pre- or postoperative irradiation volumes could potentially be optimized based on our mapping data. However, since patients in our institution at high risk for relapse received either preoperative or postoperative chemoradiation, further analyses are needed to confirm our findings.

Electronic supplementary material

The online version of this article (10.1007/s00432-018-2624-6) contains supplementary material, which is available to authorized users.

Introduction

Since the introduction of total mesorectal excision (TME) for rectal cancer, local failure rates have decreased dramatically, with further improvement in treatment success brought about by the addition of pelvic radiotherapy (Kusters et al. 2010; van Gijn et al. 2011), especially preoperative radiotherapy (Sauer et al. 2004). The preoperative radiation target volume (TV), determined by the frequency and distribution of local recurrence and lymph node positivity, includes the primary tumor site, mesorectum, presacral space, and lateral pelvic lymph nodes (LPLNs).

Delineating a clinical TV is the most challenging step when performing conformal radiotherapy; proper definition and delineation are required to avoid underdosing regions that could harbor cancer cells and to avoid exposing surrounding normal tissues to unnecessary toxicity. Several guidelines on contouring pelvic regions at risk have been published, aiming to decrease the inter- and intra-observer variability in clinical TV delineation (Fuller et al. 2011; Roels et al. 2006; Valentini et al. 2016). However, despite these efforts, variability persists, particularly in terms of how much of the LPLN chain—based on the level of the rectal tumor—should be contained in the radiation field. This question remains unanswered, even after the most recent report (Valentini et al. 2016).

The pattern of lymphatic drainage of the rectum differs significantly according to the level (Japanese Research Society for Cancer of the Colon and Rectum 1983; Steup et al. 2002). The lymphatic vessels of the upper half of the rectum ascend with the superior rectal vessels, passing into the inferior mesenteric nodes, whereas those of the lower half of the rectum travel laterally with the middle rectal blood vessels, reaching the internal iliac nodes. Therefore, LPLN recurrence is expected to occur more commonly with mid-lower rectal cancers. Given that patients with stage II or III lower rectal cancers occasionally develop LPLN metastases (~ 15%) (Sugihara et al. 2006), mesorectal excision with LPLN dissection is the standard procedure performed for patients with such cancers in Japan (Watanabe et al. 2015). Moreover, LPLN recurrence rates increase with specific risk factors (T3–4 tumors, tumor size > 4 cm, ypN + stage, LPLN size, or initial LPLN positivity) emphasizing the need for LPLN chain treatment (T. G. Kim et al. 2014, 2008; Sugihara et al. 2006). Because lateral pelvic nodal metastasis can significantly increase locoregional recurrence, it is important to pre-stratify patients according to relevant risk factors. Several studies investigating LPLN dissection or irradiation are underway (Fujita et al. 2012, 2017; Wei et al. 2016).

To optimize the radiotherapy TV, especially in terms of the LPLN area, we investigated patterns of failure by reviewing the data of patients who underwent TME only without pelvic radiotherapy for newly diagnosed rectal cancer. We evaluated the sites of locoregional recurrence stratified by the extent and location of the primary tumor, aiming to determine whether the radiation TV could be safely reduced in this era of TME and modern radiotherapy.

Materials and methods

Patient selection

Between January 2005 and December 2012, 1243 patients newly diagnosed with rectal cancer underwent surgery without any pelvic radiotherapy at our institution. On the other hand, 1348 patients received pelvic radiotherapy preoperatively (n = 710) or postoperatively (n = 647) during the same period. From the 1243 patients, patients with a follow-up duration < 2 years (n = 78), with distant metastases at the time of initial diagnosis (n = 136), whose surgery was not regarded as being a curative TME (n = 154), with tumor histology other than adenocarcinoma (n = 33), and with pathologic Tis stage tumors (n = 16) were excluded. The data of the remaining 826 patients were retrospectively analyzed. This study was approved by the institutional review board (IRB) of the Yonsei University Health System (4-2017-0896). The patient records/information was anonymized and de-identified prior to analysis, and informed consent was not obtained from each participant.

Treatment

Assessments and treatment approaches were determined by a multidisciplinary team at our institution’s Colorectal Cancer Center. Tumors were clinically staged using the American Joint Committee on Cancer (AJCC) classification, 7th edition. A specialized radiologist performed an magnetic resonance imaging (MRI)-based assessment to determine tumor location, as described previously (Chang et al. 2014). Tumors were staged based on a preoperative examination that included chest radiography and/or computed tomography (CT), abdominal and pelvic CT, and transrectal ultrasonography and/or pelvic MRI. Upper or mid-lower rectal tumors were divided using the peritoneal reflection on the sagittal T2-weighted images. Tumors with their lower edges located above the virtual line were defined as “upper rectal cancers,” whereas those with their upper edges lying below the line were denoted as “lower-middle rectal cancers” (Chang et al. 2014). In general, patients with clinically staged T3 or N+ disease were regarded to receive preoperative chemoradiotherapy. However, according to the location or exact extent of the tumor, some advanced stage tumors received upfront surgery. In most cases, TME was performed by three specialized colorectal surgeons at our institution. If highly suspicious LPLN metastases were seen on preoperative images, additional LPLN dissection was done during TME. The pathologic examination was reported in a standardized manner by qualified pathologists. Pathologic findings also described tumor differentiation, vascular invasion, lymphatic invasion, and resection margin in all specimens in addition to the T and N staging. Among patients with upfront surgery, physicians discuss the need for the postoperative treatment. If tumors are diagnosed with advanced pathologic stages or physicians think that there is a risk of residual tumors in the pelvis, patients receive postoperative pelvic radiotherapy and chemotherapy. All patients included in this study did not require preoperative or postoperative radiotherapy.

Follow-up and evaluation of relapse

Patients underwent standard follow-up at our institution’s Colorectal Cancer Center every 6 months for the first 3 years post-surgery and yearly thereafter. Colonoscopy was performed annually after surgery. All available imaging studies and colonoscopy reports were reviewed thoroughly. Details are provided in Supplementary Text 1. Patterns of recurrence were categorized as distant failure and locoregional failure (LRF). LRF included recurrence in the anastomotic site, mesorectum, presacral area, and LPLNs below the sacral promontory (common, internal, external iliac, and obturator lymph nodes). We primarily assessed the first failure event. All subsequent failures were referred to as “overall LRFs” or “overall distant failures.”

Mapping

One 47-year-old male patient (176 cm, 71 kg, body mass index 22.9 kg/m²) who did not develop recurrence post-TME for a stage T2N0M0 mid-rectal cancer was selected as the standard representative patient. His CT scans, conducted with a full bladder and in a prone position typical of a pelvic radiation treatment position, served as a template, because we wanted mapping data available for actual pelvic radiotherapy target delineation. All LRFs were marked on this template by hand, according to each patient’s diagnostic CT scan, using MIM software version 6.46 (MIM Software, Inc., Cleveland, OH, USA). To minimize interpersonal differences, several anatomic landmarks (main blood vessels, bones, muscles, and organs) were identified and used as anatomic references during registration, with manual adjustment. To reduce volume effects, each recurrent lesion/node was reduced to a 5-mm spot representing the epicenter. Each LRF lesion was also displayed as a schematic image on a coronal view of the major vessels (the common, external, and internal iliac artery and the obturator artery).

Statistical analysis

Local recurrence-free, distant metastasis-free, and overall survival rates were defined from the date of surgery to last follow-up or local recurrence, distant metastasis, and death from any cause, respectively. These rates were calculated using the Kaplan–Meier method, and prognostic impacts of clinical factors were analyzed using the log-rank test. Multivariate Cox regression analysis was used to identify independent prognostic factors. The Fisher’s exact or Chi square test was performed to identify any factors significantly associated with specific LRF events and to compare groups. IBM SPSS software, version 23 (IBM, Armonk, NY, USA) was used for statistical analyses. P values < 0.05 were considered statistically significant.

Results

Patient

Overall, 53 and 47% of tumors were located in the upper and mid-lower rectum, respectively. As seen in Table 1, with regard to final pathologic AJCC stage, 381 (46%) patients had advanced stage (≥ pT3 or pN+) tumors. Mid-lower rectal cancers were more advanced than upper rectal cancers (55 vs. 36%, p < 0.001). At initial diagnosis, all patients had no LPLN metastases (n = 820) or positive LPLNs which were dissected cleanly at the time of initial surgery (n = 6). The patients’ demographic and clinicopathologic tumor characteristics are listed in Supplementary Table 1.

Table 1.

Differences in patient characteristics when divided according to tumor location

Characteristics	Upper (N = 435)	Mid-lower (N = 391)	p value
	No. (%)
Age (years)			0.182
<60	177 (41%)	141 (36%)
≥60	258 (59%)	250 (94%)
Sex			0.341
Male	270 (62%)	230 (59%)
Female	165 (38%)	161 (41%)
Histology			0.409
WD	77 (18%)	86 (22%)
MD	339 (78%)	288 (74%)
PD	6 (1%)	6 (1%)
Mucinous	5 (1%)	7 (2%)
Unknown	8 (2%)	4 (1%)
pT/pN stage			< 0.001
T1N0	96 (2%)	110 (28%)
T1N1	4 (1%)	9 (2%)
T2N0	98 (23%)	141 (36%)
T2N1	14 (3%)	12 (3%)
T2N2	2 (0%)	1 (0%)
T3N0	125 (29%)	75 (19%)
T3N1	53 (12%)	25 (7%)
T3N2	31 (7%)	12 (3%)
T4N0	4 (1%)	2 (1%)
T4N1	4 (1%)	3 (1%)
T4N2	4 (1%)	1 (0%)
Advanced stage (≥ pT3 or pN+)			< 0.001
No	194 (45%)	251 (64%)
Yes	241 (55%)	140 (36%)
LVI			0.564
Negative	348 (80%)	319 (82%)
Positive	87 (20%)	72 (18%)
PNI			0.004
Negative	414 (95%)	386 (99%)
Positive	21 (5%)	5 (1%)
PNE			0.006
Negative	403 (93%)	379 (97%)
Positive	32 (7%)	12 (3%)
Proximal RM			0.999
Negative	435 (100%)	391 (100%)
Positive	0 (0%)	0 (0%)
Distal RM			0.067
Negative	435 (100%)	388 (99%)
Positive	0 (0%)	3 (1%)
CRM			0.931
Negative	428 (98%)	385 (98%)
Positive	7 (2%)	6 (2%)

WD well-differentiated, MD moderately differentiated, PD poorly differentiated, LVI lymphovascular invasion, PNI perineural invasion, PNE perinodal extension, RM resection margin, CRM circumferential resection margin

Treatment outcome

The median follow-up duration was 61.8 (range, 24.0–140.3) months. Relapses occurred in 108 (13%) patients and 113 (14%) patients died. The 5-year local recurrence-free, distant metastasis-free, overall survival rates were 88, 82, and 89%, respectively (Supplementary Fig. 1). Among 108 patients with relapse, LRF occurred as a first failure in 25 (3%) patients, while overall LRF events were noted in 28 (3%) patients. Distant failure occurred first in 90 patients (11%). The relapse rate for each risk group, as proposed by Gunderson (Gunderson et al. 2004), is shown in Table 2.

Table 2.

The difference in frequency of failures in each risk group divided by T/N stage

Risk group	Total no.	First LRF		Overall LRF		First DF
		No.	%	No.	%	No.	%
Low risk
T1-2/N0	445	9	2.0	9	2.0	13	2.9
Intermediate risk
T1-2/N1	39	0	0.0	0	0.0	9	23.1
T3/N0	200	8	4.0	8	4.0	31	15.5
Moderately high
T1-2/N2	3	0	0.0	0	0.0	0	0.0
T3/N1	78	1	1.3	2	2.6	20	25.6
T4/N0	6	0	0.0	0	0.0	0	0.0
High risk
T3/N2	43	6	14.0	6	14.0	12	27.9
T4/N1	7	0	0.0	1	14.3	2	28.6
T4/N2	5	1	20.0	2	40.0	3	60.0

We followed the Gunderson’s risk group classification (Gunderson et al. 2004)

LRF locoregional failure, DF distant failure

Of the first LRF events, 8 involved LPLNs, 9 involved the mesorectum, 9 involved the anastomosis, and 2 involved the presacral area. A greater proportion of first LRF events occurred in patients with mid-lower than with upper rectal cancers (4 vs. 2%)—other relapse rates were not significantly different (Table 3). Ten overall LRF events involved LPLNs, 9 involved the mesorectum, 10 involved the anastomosis, and 2 involved the presacral area.

Table 3.

Frequency of each failure according to tumor location

	Upper		Mid-lower		p value*
	No.	%*	No.	%*
Recurrence	60	13.8	48	12.3	0.519
First LRF	8	1.8	17	4.3	0.036
LPLN	2	0.5	6	1.5	0.115
Mesorectum	2	0.5	7	1.8	0.066
Anastomosis	5	1.1	5	1.3	0.865
Presacral area	1	0.2	1	0.3	0.940
Overall LRF	10	2.3	18	4.6	0.068
LPLN	3	0.7	7	1.8	0.288
Overall DF	54	12.4	36	9.2	0.140
Death	52	12.0	61	15.6	0.128

*We used Chi square test for this analysis, however, the small number of events limited statistical power

LRF locoregional failure, LPLN lateral pelvic lymph node, DF distant failure

Individual LPLN recurrences

Of the eight patients who had LPLN relapse as an initial LRF, two had upper rectal tumors and six had mid-lower rectal tumors; recurrence occurred at a median of 26.5 months and 12.2 months after TME, respectively (p = 0.115). The LPLN of only 1 patient were positive for metastasis at the time of initial surgery (Table 4).

Table 4.

Details of the characteristics of patients undergoing LRFs

	Age	Sex	Stage	Tumor laterality	Histology	LPLN metastasis	LPLN dissection	LVI	PNI	PNE	Proximal RM	Distal RM	CRM	Failure pattern	PFS (mo)	LRFS (mo)	DFS (mo)	Locations of failed lateral PLN	Current status	OS (mo)
Upper
1	75	M	T3N2	Bilateral	MD	–	–	–	+	+	–	–	–	LRF	12.6	12.6	17.1	Lt. internal iliac LN	DOD	40.6
2	75	M	T3N2	Bilateral	MD	–	–	+	–	+	–	–	–	LRF + DF	35.8	35.8	35.8	Rt. external iliac LN	AWD	45.9
Mid-lower
1	49	F	T1N0	Left	MD	–	–	+	–	–	Unknown	Unknown	Unknown	LRF only	23.8	23.8	94.2	Lt. obturator LN	AWD	94.2
2	37	M	T2N0	Right	MD	–	–	–	–	–	–	–	–	LRF + DF	13.9	13.9	13.9	Rt. internal iliac LN, Rt. obturator LNs (n = 2)	DOD	23.0
3	58	F	T2N0	Right	MD	–	–	–	–	–	–	–	–	LRF only	45.4	45.4	94.6	Rt. obturator LN	Died of unknown cause	94.6
4	63	F	T2N0	Left	MD	–	–	–	–	–	–	–	–	LRF only	12.2	12.2	40.5	Lt. obturator LN	AWD	66.6
5	74	M	T3N0	Bilateral	PD	–	–	–	–	–	–	–	–	LRF + DF	12.0	12.0	12.0	Lt. external iliac LNs (n = 2), Rt. obturator LNs (n = 2)	Died of other disease-unrelated cause	29.1
6	88	M	T3N2	Bilateral	MD	+	+	+	–	–	–	–	–	LRF + DF	6.9	6.9	6.9	Bilateral internal iliac LNs (n = 5), Rt. obturator LN	DOD	13.4

MD moderately differentiated, PD poorly differentiated, LPLN lateral pelvic lymph node, LN lymph node, LVI lymphovascular invasion, PNI perineural invasion, PNE perinodal extension, RM resection margin, CRM circumferential resection margin, LRF locoregional failure, DF distant failure, PFS progression-free survival, LRFS locoregional failure-free survival, DFS distant failure-free survival, DOD died of disease, AWD alive with disease, OS overall survival

Two patients with upper rectal tumors had LPLN recurrence: One involved the internal iliac lymph nodes just posterior to that artery, the other involved the external iliac lymph nodes just anterior to that artery. In both patients, these nodal relapses were located near the bifurcation of the common iliac artery into the external and internal iliac vessels. Both patients had locally advanced stage (pT3N2) tumors and one of them experienced concurrent distant failure. In all other locally advanced stage upper rectal tumors, no other LPLN recurrences were observed (Fig. 1a, Supplementary Fig. 2a).

Fig. 1.

Overview of locations of locoregional recurrences on the coronal view related to the major vessels. a In patients with upper rectal cancer (2 lesions of 2 patients). b In patients with mid-lower rectal cancer (16 lesions of 6 patients). In the each circular image, the direction and distance from the major vessel of each lesion are shown (IIA internal iliac artery, EIA external iliac artery, OA obturator artery). To determine the LPLN irradiation field, this area was divided into eight regions (‘a’ to ‘h’) based on the location of major vessels (the common iliac, external iliac, internal iliac, and obturator arteries). Each region was 1 cm anterior or posterior to the vessel or comprised the space between 2 major vessels

Sixteen recurrent LPLN lesions occurred in 6 patients with mid-lower tumors, 3 of whom had concurrent distant failure. Recurrent lesions involved the obturator (n = 8), internal iliac (n = 6), and external iliac (n = 2) lymph nodes, and all were in the vicinity of both the internal iliac and obturator arteries—even those associated with early stage tumors. Of the eight obturator lymph node lesions, six were located anterior to the obturator artery and posterior to the external iliac artery at the level of the superior border of the femoral head; three were located adjacent to and three were approximately 1 cm from the artery. The other two obturator lymph node lesions, located posterior to the obturator artery, were approximately 0.7 cm from the artery. All obturator lymph node recurrences were within a 1-cm radius of the obturator artery. Almost all the internal and external iliac lymph node relapses—except for 1 internal iliac lesion located approximately 0.7 cm from the artery—were in very close proximity to these arteries (Fig. 1b, Supplementary Fig. 2b).

Pathologic N2 stage, lymphovascular invasion, and perinodal extension occurred significantly more frequently in patients with subsequent LPLN recurrence. Other clinical factors including initial LPLN metastasis and circumferential resection margin status were also significant; however, the small number of events limited statistical power (Supplementary Table 2). The laterality of the initial rectal tumor affected the direction of LPLN recurrence, which occurred in the same direction as the primary tumor in all 4 patients with tumors showing a specific laterality (Table 4).

To determine the LPLN component of clinical TV, this area was divided into 8 regions (‘a’ to ‘h’) based on the location of major vessels. Each region was 1 cm anterior or posterior to the vessel or comprised the space between two major vessels (Fig. 1).

Nodal recurrences from upper rectal cancers developed only in the vicinity of the bifurcation of the common iliac artery (Fig. 1a); none occurred in LPLNs below the primary tumor’s caudal margin. Mid-lower rectal cancer recurrences occurred mostly at the lower levels (‘f’–‘h’) (Fig. 1b). Six of the eight obturator lymph node recurrences occurred between the obturator and external iliac arteries (region ‘h’), whereas almost all internal iliac lymph node recurrences occurred anterior to the internal iliac artery (region ‘g’); only 1 was located posteriorly (region ‘c’). There was 1 extraordinary recurrence of a mid-lower rectal cancer (Supplementary Fig. 2b, 2nd cut) within region ‘e’ (1 cm anterior to the external iliac artery). This 74-year-old man was diagnosed with a stage pT3N0 poorly differentiated lower rectal adenocarcinoma. Although the first pathologic examination suggested that this lesion may have been a distant gastric adenocarcinoma metastasis, because no other primary lesion was found on systemic evaluation, the lesion was diagnosed as a primary rectal cancer. This case was very unusual, (hence, it is unnecessary to include region ‘e’ in the lateral field in all cases of mid-lower rectal cancer).

Discussion

In this study, the LPLN recurrence rate was low in patients with upper rectal cancers: Only 2 lesions, located around the bifurcation of the common iliac artery into the external and internal iliac vessels, were noted; none were seen at the lower level. Therefore, in patients with upper rectal cancers, the LPLN component of clinical TV may be minimized to upper-level regions (‘a’–‘e’); inclusion of lower-level regions (‘f’–‘h’) could be considered for high-risk tumors (Fig. 2). For example, for T4 lesions with adherence to or invasion of organs or structures that drain to external iliac node, this recommendation would not be appropriate.

Fig. 2.

Example of lateral pelvic lymph node (LPLN) target volume delineation according to the location of tumors in the same cut of CT image. ‘Star’ indicates the location of obturator artery. In upper rectal cancer, the anterior area of the common iliac artery should be fully covered (~ 1 cm) (a), however, there is no need to give wide margin in front of the obturator artery (c) if there are no risk factors including T4 stage. In mid-lower rectal cancer, the anterior area of the obturator artery should be fully covered (~ 1 cm) (d), however, it is not necessary to include a wide area around the common iliac artery (b)

In patients with mid-lower rectal cancers, the incidence of LPLN recurrence was higher. Obturator lymph nodes were involved most commonly, followed by internal and external iliac lymph nodes. Therefore, in patients with mid-lower rectal cancers, it is important that the LPLN component of clinical TV be set wide, ensuring that the regions anterior and posterior to the obturator artery (regions ‘g’ and ‘h’) are included in the LPLN component of clinical TV. In addition, care must be taken to ensure that the entire LPLN chain (including regions ‘d’ and ‘e’) is covered sufficiently, especially when high-risk features are present. However, it is unnecessary to extend the clinical TV to include the area superior to the common iliac artery or anterior to the external iliac artery after the obturator artery comes out (Fig. 2).

Several pathologic and therapeutic factors affect the risk of LRF in the TME era. First, the location of the tumor within the rectum is critical, as high-seated tumors are covered by the peritoneum and a clear excision margin is more readily achievable. The local recurrence rate is reported to be 10−15% for tumors located in the lower third, which is higher than that for tumors located in either the middle (5−10%) or upper (2−5%) third of the rectum (Gunderson et al. 2004; Pahlman et al. 2007). Second, staging classifications such as the tumor node metastasis (TNM) and Duke’s (A, B, C) systems are useful for predicting prognosis. According to Gunderson’s pooled analysis (Gunderson et al. 2004), LRF rates for low (T1-2N0), intermediate (T1-2N1, T3N0), moderately high (T1-2N2, T4N0, T3N1), and high risk (T3N2, T4N1, T4N2) patients were ≤ 5, 8, 11, and 18%, respectively. In our study, LRF rates were similar to or somewhat lower than these. However, regardless of different LRF rates, TVs for early or locally advanced tumors have been very similar. The need for large TVs for early stage tumors is questionable. Volume reduction according to location or stage with different local recurrence rates should be considered, especially in the modern radiotherapy era.

Although radiotherapy delivers tumoricidal doses of radiation to the microscopic tumor cells in the pelvic cavity, normal tissues in the irradiated field are subject to injury. Fractionated doses of radiotherapy may induce an increase in the incidence of severe late complications in the small bowel (El-Malt et al. 2001). Patients receiving pelvic radiotherapy have higher rates of anastomotic complications other than strictures, including fecal incontinence, fistulas, abscesses, and bowel obstruction, than patients not receiving radiotherapy (Hassan et al. 2008). Although there have been some efforts to reduce radiation doses to the small bowel during pelvic radiotherapy in recent years (M. S. Kim et al. 2013; Nijkamp et al. 2011), further efforts are required. In our recent study, we investigated the feasibility of reducing the pelvic field for postoperative radiotherapy (Choi et al. 2017). Following on from that, this study aimed to optimize the pelvic field for preoperative radiotherapy.

Lateral recurrence is reportedly a leading cause of local recurrence, with 83% of patients with local recurrence developing lateral recurrence (Kim et al. 2008). If metastatic nodal metastases are not dissected, systemic recurrence can develop (Group et al. 2011; Kim et al. 2008). A Swedish report, however, found that lateral recurrence was not a major cause of local recurrence (6%) (Syk et al. 2006). Although the actual clinical importance of lateral recurrence remains unclear, recent studies on LPLN dissection suggest that if an accurate preoperative diagnosis of LPLN metastasis is obtained, nodal dissection is indicated as, compared with mesorectal excision alone, this reduces lateral recurrence (Akiyoshi et al. 2012). However, appropriate patient selection is important. Although the JCOG0212 trial (Fujita et al. 2012, 2017) showed that LPLN dissection significantly reduced local recurrence even in patients with no initial LPLN enlargement, this has yet to be confirmed by other studies. A strong argument against LPLN dissection is the very high rate of bladder and sexual dysfunction that occurs, compared with conventional resection; this is directly related to pelvic autonomic nerve damage (Fujita et al. 2012; Georgiou et al. 2009). Given the lack of consensus regarding LPLN dissection, it would be very helpful to understand LPLN failure patterns and to establish proper LPLN irradiation fields, rather than focusing on LPLN dissection considering the associated complications.

We wanted to optimize the LPLN component of clinical TV to avoid delivering unnecessary radiation. There were no differences between our definitions of the mesorectum, presacral space, sphincter complex, and ischio-rectal fossa and those used in other international guidelines (Fuller et al. 2011; Roels et al. 2006; Valentini et al. 2016). The superior, inferior, medial, and lateral borders used were not different to those recently proposed by Valentini et al. (Valentini et al. 2016). Regarding anterior and posterior borders, Valentini et al. (2016) suggest extending the anterior border in cases of T4 tumors, positive posterior LPLN, or numerous positive mesorectal lymph nodes. We propose extending the anterior border regardless of tumor stage in tumors involving the lower half of the rectum, emphasizing the importance of tumor level. From the level of the femoral head, the anterior border may be limited to the posterior wall of the obturator artery. Conversely, regardless of stage, it might be unnecessary to expand the anterior border for upper rectal tumors if no other risk factors, as presented by Valentini et al. (2016), are present—only the superior border should be noted. External iliac lymph nodes are generally not included in the preoperative radiotherapy field for rectal tumors, but it is advisable to include this for T4 tumors with anterior organ involvement or positive anterio-lateral lymph nodes (Roels et al. 2006). Although it was based on the small number of T4 patients in this analysis, none of our patients with T4 tumors had external iliac lymph node recurrences, regardless of tumor level, and no recurrences were located anterior to the external iliac artery after the origin of the obturator artery.

This study has some limitations. First of all, the number of events (recurrence and death) was lower than expected; this may be related to another limitation: possible selection bias. Patients judged to have a high risk of recurrence were excluded from our analysis, because they underwent preoperative or postoperative radiotherapy. Nevertheless, as 47% of tumors were locally advanced stage (≥ T3 or N+) and patients with perineural invasion, lymphovascular invasion, or perinodal extension (3, 19, and 5%, respectively) were included, our analysis seems to be notable. Although only four patients with locally advanced rectal cancer developed LRF, our optimized LPLN TV remains unchanged even if we limit the stage of patients. Second, our mapping data could certainly be used to support suggesting how to modify the TV. However, the limited numbers would be too small to support excluding subregions from clinical TV. As this recommendation is based on data from a single institution, these data should be accepted carefully and further research is required.

Despite these limitations, our mapping data, taking into consideration individual anatomic variation of the major vessels, provide visually useful data. In particular, we present a preoperative radiotherapy TV optimized for the level of the primary tumor. More specifically, we have demonstrated that the laterality of the primary tumor affects the laterality of LPLN recurrences. In the absence of a consensus on the preoperative radiotherapy TV, this study provides useful information to radiation oncologists.

In conclusion, the TV for LPLN irradiation could be optimized according to tumor location: For upper rectal cancers, the TV could be reduced, especially around the obturator artery; on the other hand, for mid-lower rectal cancers, a larger TV surrounding the obturator artery would be optimal. However, since patients in our institution at high risk for relapse received either preoperative or postoperative chemoradiation, further analyses are needed to confirm our findings.

Electronic supplementary material

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Funding

This work was supported by the National Research Foundation of Korea (NRF) Grant, funded by the Korean government (MSIP) (NRF-2015R1D1A1A01060710).

Compliance with ethical standards

Conflict of interest

The authors have stated that they have no conflicts of interest.

Research involving human participants and/or animals

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

For this type of study, informed consent is not required.