Clinical outcomes of neoadjuvant therapy followed by selective inguinal lymph node dissection and total mesorectal excision for metastasised rectal or anal canal adenocarcinoma

doi:10.21203/rs.3.rs-1997231/v1

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Clinical outcomes of neoadjuvant therapy followed by selective inguinal lymph node dissection and total mesorectal excision for metastasised rectal or anal canal adenocarcinoma

https://doi.org/10.21203/rs.3.rs-1997231/v1

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Journal Publication

published 28 Dec, 2022

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Purpose

Rectal or anal canal adenocarcinoma with inguinal lymph node metastasis (ILNM) is rare and is associated with poor prognostic outcomes. This study aimed to elucidate the clinical significance of neoadjuvant therapy followed by selective inguinal lymph node dissection and total mesorectal excision for rectal or anal canal adenocarcinoma with clinically suspected ILNM.

Methods

This study enrolled 15 consecutive patients who underwent neoadjuvant therapy and curative resection for rectal or anal canal adenocarcinoma with clinically suspected ILNM between 2005 and 2019 at a single institution. Inguinal lymph node dissection was selectively performed on the side of suspected metastasis before neoadjuvant therapy. Short- and long-term outcomes were retrospectively reviewed.

Results

Out of the15 patients, 11 were treated with neoadjuvant chemoradiation, three with chemotherapy, and one with chemoradiation followed by chemotherapy. Six patients had negative fluorodeoxyglucose (FDG) accumulation in inguinal lymph nodes on preoperative FDG-positron emission tomography (FDG-PET) scan, and their inguinal lymph nodes were also pathologically negative for metastasis. Of the nine patients who had positive FDG accumulation, four had pathologically positive inguinal lymph nodes. Seven patients (46.7%) had inguinal seroma postoperatively. Five-year-overall survival was 77.5%, and 5-year-relapse-free survival was 64.2%. No patient had a recurrence in the inguinal region.

Conclusion

In patients with rectal or anal canal adenocarcinoma associated with clinical ILNM, radical resection with neoadjuvant therapy provides a good long-term survival.

Rectal cancer

anal cancer

adenocarcinoma

inguinal lymph node dissection

neoadjuavnt therapy

metastasis

The frequency of metastasis to the inguinal lymph nodes in advanced rectal or anal canal adenocarcinoma is 0.3–6%, depending on the tumor depth and dentate line involvement [1–4]. However, the treatment strategy for rectal or anal canal adenocarcinoma with inguinal lymph node metastasis (ILNM) has not yet been established.

According to reports prior to 2000, rectal or anal adenocarcinoma with ILNM had an extremely poor prognosis, and palliative chemotherapy was recommended [5–7]. With the advancements in preoperative imaging [8, 9], perioperative treatments [10–14], chemotherapy after recurrence [15, 16], and the development of surgical techniques [17–19], the treatment outcomes of rectal adenocarcinoma have improved over the past two decades. Recent reports have shown an improved 5-year survival rate of 40–60% for primary rectal cancer patients with solitary ILNM [4, 20–22].

Preoperative treatment is important in terms of local control in the treatment of advanced rectal adenocarcinoma without ILNM; unfortunately, there are only limited reports on preoperative treatment in rectal or anal adenocarcinoma with ILNM. Furthermore, there is a lack of reports on surgical techniques for inguinal lymph node dissection, including the extent of dissection and how to perform it.

In this study, we demonstrated our standard surgical technique for inguinal lymph node dissection with en bloc resection of the superficial inguinal lymph nodes. Owing to the high frequency of lymphatic leakage after inguinal lymph node dissection, prophylactic bilateral dissection was not performed; instead it was performed only on the side where metastasis was suspected on preoperative imaging. We hope that our short- and long-term results will provide a better understanding of treatment strategies for rectal or anal adenocarcinoma with clinically suspected ILNM.

Patients

This was a single-center, retrospective study of 15 patients with rectal or anal adenocarcinoma associated with suspected ILNM on preoperative imaging. Since 2005, our institution has been performing chest and abdominal computed tomography (CT) scans for patients with advanced lower rectal or anal adenocarcinoma, and if there are no contraindications, abdominal contrast-enhanced CT and positron emission tomography (PET)-CT/ magnetic resonance imaging (MRI) examinations have been performed. Prior to treatment, two or more radiologists were consulted for ILNM diagnosis, and a conference consisting of gastrointestinal surgeons, gastroenterologists, and radiologists made the final determination of clinical metastasis.

ILNM has no strict definition; however, a short lymph node diameter of 1 cm or more, an abnormal shape, and an abnormal accumulation of fluorodeoxyglucose(FDG) were defined as clinically positive for metastasis. The definition of the anal canal and rectal adenocarcinoma was based on the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma. Briefly, those tumors with their center above the superior border of the puborectal sling were considered as rectal adenocarcinoma, and those below were considered as anal canal adenocarcinoma.

Patients with concurrent advanced cancer in other sites were excluded from this study. Patients who underwent curative resection for rectal or anal canal adenocarcinoma with clinical ILNM at Kobe University Hospital between 2005 and 2019 were included in this study. This retrospective study was approved by the Institutional Ethics Review Board of the Kobe University Hospital (IRB reference number: B210222).

Neoadjuvant treatment

Chemoradiotherapy was administered unless radiation was contraindicated or the patient requested chemotherapy. Patients received chemoradiotherapy before surgery with a combination of oral 5FU (capecitabine or tegafur-uracil (UFT)/leucovorin (LV)) and 45–50.4 Gy of radiation. Patients with contraindications to radiation therapy and those who requested chemotherapy were administered chemotherapy, and the regimen was based on the patient's age, general condition, and preference. One patient who was referred to our hospital after chemoradiation therapy at another institution received additional chemotherapy followed by radical surgery. Radical surgery was performed 5–8 weeks after chemoradiation therapy or 2–8 weeks after chemotherapy.

Surgical procedure

If the distance between the lower margin of the tumor and dentate line > 2 cm and a distal margin could be maintained, then a low anterior resection was performed. If the distance between the lower margin of the tumor and dentate line was < 2 cm, then an abdominoperineal resection was performed. Total pelvic exenteration was performed if there was vaginal, bladder, or prostate involvement. If metastasis was suspected in the lateral pelvic lymph nodes on preoperative imaging, subsequent lateral lymph node dissection was performed. Inguinal lymph node dissection was performed before total mesorectal excision (TME) and lateral lymph node dissection.

Inguinal Lymph Node Dissection

Due consideration was given to ensure resection of the suspected metastatic lymph nodes by resecting them together with the surrounding fatty tissue. Therefore, the extent of resection varied slightly depending on the degree of inguinal metastasis. The basic surgical technique is as follows: First, a 10–12 cm skin incision was made in the cephalocaudal direction, subcutaneous fat was incised with an electrocautery scalpel, and a skin flap was made in the medial and lateral directions after the incision of the superficial fascia. While ligating and dissecting the blood vessels and lymphatics, the external oblique aponeurosis was exposed to a cephalad, which was the cephalic end of the dissection (Online Resource 1). The fat was subsequently removed including the inguinal lymph nodes to expose the fascia lata laterally and the accessory saphenous vein caudally, followed by exposure of the fascia lata and fossa ovalis. The blood vessels and lymphatic vessels that pass between the fossa ovalis and the inguinal fat were ligated and dissected to prevent postoperative lymph leakage (Online Resource 2). Finally, the great saphenous vein was exposed, and the fat inside this vein was removed from the caudad to the cephalad to expose the fascia lata (Online Resource 3). We have presented a photograph and anatomical diagram of the post inguinal dissection (Fig. 1).

Follow-up after surgery

Follow-up was done every 3 months for the first 5 years and every 6 months thereafter. Serum CEA and CA19-9 were measured every 3 months as tumor markers. A thoracoabdominal CT scan was performed every 6 months. If anastomosis was performed, colonoscopy was performed at 1, 2, 3, and 5 years postoperatively. If metastasis was suspected by tumor markers or thoracoabdominal CT scan, then PET or MRI was performed. Local recurrence was defined as recurrence in the pelvis.

Statistical analysis

Statistical analysis was performed using JMP version 10 (SAS Institute Inc., Cary, NC, USA). Continuous variables were represented with median and range. Survival analysis was performed using the Kaplan-Meier method.

Patient characteristics

Out of the 15 cases, four had anal canal adenocarcinoma and the remaining patients had rectal adenocarcinoma. Demographic and clinical characteristics are shown in Table 1. The median age of patients was 66 years (range: 71–78). Ten patients (66.7%) had dentate line involvement, and the distance between the tumor and dentate line was within 5 cm in the other five patients. Eleven patients (73.3%) were treated with preoperative chemoradiotherapy as neoadjuvant therapy. Three patients were treated with preoperative chemotherapy, including one patient who received seven courses of FOLFOX plus bevacizumab at his request, one patient who received six courses of FOLFOXIRI plus bevacizumab at his request, and one patient who received six courses of FOLFOX because she had previously been treated with radiation therapy for uterine cancer and could not receive chemoradiation. One patient was referred after preoperative chemoradiotherapy at another hospital and was operated on after seven courses of FOLFOX plus cetuximab.

Table 1

Demographic and clinical characteristics
Characteristics	Case (%)
Gender
Male	8	(53.3)
Female	7	(46.7)
Age, y
Median (range)	66	(41–78)
ASA class
ASA 1–2	14	(93.3)
ASA > 2	1	(6.7)
Distance from the anal verge, cm
Median (range)	0	(0–5)
Clinical tumor stage^a
T2	1	(6.7)
T3	4	(26.7)
T4	10	(66.7)
Clinical nodal stage^a
N1	2	(13.3)
N2	13	(86.7)
Neoadjuvant therapy
CRT	11	(73.3)
CT	3	(20.0)
CRT followed by CT	1	(6.7)
^aTumor were classified according to the eighth edition of the Union for International Cancer Control tumor-node-metastasis cancer staging system.
Data are presented as n (%)
ASA, American Society of Anesthesiologists; CRT, chemoradiotherapy; CT, chemotherapy.

Operative outcomes and pathological findings

Operative outcomes and pathological findings are listed in Table 2. Unilateral inguinal dissection was performed in six patients and bilateral inguinal dissection in nine patients. Seven patients (43.8%) had inguinal seroma of Clavien-dindo classification Grade 2 or higher. Reoperation for inguinal seroma was necessary in three cases (20.0%); lymphatic ligation was performed in two cases, and drainage was performed in one case because of infection. Preoperative treatment resulted in a marked effect in three patients (20.0%). Two patients had positive circumferential resection margins.

Table 2

Operative and pathological outcomes
Characteristics	Case (%)
Approach
Open	6	(40.0)
Laparoscopic	9	(60.0)
Surgical procedure
Low anterior resection	3	(20.0)
Abdominoperineal resection	10	(66.7)
Total pelvic exenteration	2	(13.3)
Postoperative complications, Clavient-dindo classification grade≧Ⅱ
Inguinal seroma	7	(46.7)
Superficial wound infection	5	(33.3)
Intra-pelvic abscess	1	(6.7)
Small bowel obstruction	1	(6.7)
Histology
Well/moderately differentiated	13	(86.7)
Poorly differentiated/mucinous	2	(13.3)
Pathological tumor stage^a
T0	3	(20.0)
T1	0	(0)
T2	3	(20.0)
T3	4	(26.7)
T4	5	(33.3)
Pathological nodal stage^a
N0	8	(53.3)
N1	4	(26.7)
N2	3	(20.0)
Proximal resection margin positive	0	(0)
Distal resection margin positive	0	(0)
Circumferential resection margin positive	2	(13.3)
^a Tumor were classified according to the eighth edition of the Union for International Cancer Control tumor-node-metastasis cancer staging system

Fluorodeoxyglucose accumulation in the inguinal region

FDG-PET scans were performed after neoadjuvant therapy in 14 patients (93.3%). One patient who did not undergo an FDG-PET scan after preoperative treatment underwent an FDG-PET scan before neoadjuvant therapy, and no FDG accumulation was observed in that case. Six patients had negative FDG accumulation in the inguinal lymph nodes on preoperative FDG-PET scan, and their inguinal lymph nodes were also pathologically negative for metastasis. Of the nine patients who had positive FDG accumulation, four (44.4%) had pathologically positive ILNM (Table 3).

Table 3

Neoadjuvant treatment, preoperative fluorodeoxyglucose PET-CT/MRI findings, pathological findings, and long-term outcomes
Age	Sex	Neoadjuvant treatment	Before neoadjuvant therapy		After neoadjuvant therapy		ILN dissection	Pathological findings					Site of recurrence/ interval from treatment to recurrence	Outcome/ follow-up
Age	Sex	Neoadjuvant treatment	Maximum size of ILN (mm)	SUVmax/ clinical diagnosis	Maximum size of ILN (mm)	SUVmax/ clinical diagnosis	ILN dissection	Number of metastatic ILN	Number of ILN harvested	pT stage^a	pN stage^a	Response to chemotherapy or radiation^b	Site of recurrence/ interval from treatment to recurrence	Outcome/ follow-up
78	F	CRT	21	-	16	2.12/ P	B	4	13	2	2	Grade 1a	Local/6y0m	Alive/8y10m
66	M	CRT followed by CT	14	-	14	3.13/ P	U	1	4	4a	1	Grade 1b	Local /1y0m	Alive/3y4m
62	M	CRT	11	2.31/ P	11	3.58/ P	B	1	2	3	1	Grade 1b	No /7y1m	Alive/7y1m
71	F	CRT	20	2.49/ P	19	2.49/ P	U	1	2	3	1	Grade 2	Lung /1y1m	Died/3y10m
41	F	CRT	12	-	9	1.86/ N	B	0	6	2	0	Grade 1a	No/16y7m	Alive/16y7m
66	F	CRT	23	5.22/ P	10	1.71/ N	B	0	5	0	0	Grade 3	No/9y11m	Alive/9y11m
71	M	CRT	11	1.72/ N	9	-	B	0	9	0	0	Grade 3	No/8y7m	Alive/8y7m
64	F	CRT	15	2.72/ P	7	1.87/ N	U	0	2	2	0	Grade 2	No/5y6m	Alive/5y6m
78	F	CT	11	10.46/ P	8	1.52/ N	B	0	14	4b	0	Grade 1a	No/3y0m	Alive/3y0m
57	M	CT	21	14.60/ P	9	1.84/ N	U	0	2	0	0	Grade 3	No/2y4m	Alive/2y4m
71	M	CRT	12	3.60/ P	8	2.12/ P	U	0	2	4a	0	Grade 1b	No/8y6m	Alive/8y6m
54	F	CRT	7	1.95/ N	7	3.12/ P	U	0	7	3	1	Grade 2	No/4y1m	Alive/4y1m
67	M	CRT	12	1.97/ N	12	3.95/ P	B	0	18	3	2	Grade 1b	Local/4y6m	Alive/5y3m
62	M	CRT	13	7.04/ P	9	3.68/ P	B	0	11	4b	0	Grade 1b	Local/7m	Died/2y7m
62	M	CT	10	-	10	3.14/ P	B	0	11	4b	2	Grade 1a	Lung /1y0m	Died/1y6m
^aTumor were classified according to the eighth edition of the Union for International Cancer Control tumor-node-metastasis cancer staging system.
^b Histological criteria of primary rectal cancer for the assessment of response to chemotherapy or radiation were classified according to the 3rd English edition of the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma [26]: Grade 0 (No effect), Grade 1a (Minimal effect: Tumor cell change < 1/3), Grade 1b (Mild effect: Tumor cell change < 2/3), Grade 2 (Moderate effect: Tumor cell change > 2/3), Grade 3 (Marked effect: No viable tumor cells are observed)
M, male; F, female; ILN, inguinal lymph node; SUVmax, the maximum standardized uptake value; P, positive; N, negative; B, bilateral; U, unilateral; CRT, chemoradiotherapy; CT, chemotherapy; PET-CT/MRI, positron emission tomography/ magnetic resonance image

Adjuvant therapy

Nine patients (66.7%) received postoperative adjuvant chemotherapy. Three patients received 5FU/LV, two received FOLFOX therapy and four received CapeOX therapy.

Long-term outcomes

The median follow-up period was 63 months. The 3- and 5-year overall survival rates were 86.2% and 77.5%, respectively. The 3- and 5-year recurrence-free survival rates were 73.3% and 64.2%, respectively (Fig. 2).

Rectal or anal canal adenocarcinoma with ILNM is rare, and is often encountered clinically and the treatment strategy is challenging. Systemic chemotherapy is recommended for patients with unresectable distant metastasis; however, no clear treatment strategy has been established for patients with resectable distant metastasis or no metastasis other than ILNM. There are no prospective clinical studies in patients with rectal or anal canal adenocarcinoma with only ILMN; only retrospective studies in a small number of cases have been reported. While long-term survival of more than 5 years was extremely rare in reports prior to 2000 [5–7], recent reports have reported 5-year survival rates of 15.9–55.2% [4, 20–24]. This study had the highest number of cases of radical resection for simultaneous metastases and the most favorable outcomes among papers reporting 5-year overall survival rates of 50% or greater [20–22].

Lymph node metastasis of rectal or anal canal adenocarcinoma often occurs in the mesorectum, and total mesorectal excision is the foremost procedure in the treatment of rectal or anal canal adenocarcinoma. However, lymph node metastasis of rectal or anal canal adenocarcinoma can also extend beyond the mesorectum, with typical examples being para-aortic lymph node metastasis, lateral lymph node metastasis, and inguinal lymph node metastasis. The 5-year recurrence-free survival rate for lymph node dissection for para-aortic lymph node metastases is about 15%, with limited efficacy [25, 26]. Lateral lymph node dissection for lateral lymph node metastases is considered effective and has been reported to reduce local recurrence in a randomized controlled trial (RCT) [17]. Inguinal lymph node dissection for inguinal lymph node metastases has exhibited good results in some studies [20–22], including in this study, and may potentially be effective.

The common technique for dissecting the inguinal lymph nodes for rectal or anal canal adenocarcinoma is to dissect the shallow inguinal lymph nodes, but the extent of dissection has not been established. We considered it important to resect lymph nodes suspected of metastasis along with surrounding fat after neoadjuvant therapy. The fascia lata, fossa ovalis, accessory saphenous vein, and great saphenous vein are good anatomical landmarks for inguinal lymph node dissection.

Few reports mentioned inguinal seroma after inguinal dissection for rectal cancer, and one study reported it in four of 17 patients (23.5%) who underwent inguinal lymph node dissection [20]. In another study of 240 patients who underwent inguinal dissection for malignant melanoma, 51.2% had wound complications and 21.5% had seroma [27]. In this study, seven of 15 patients (43.8%) who underwent inguinal lymph node dissection had inguinal seroma, and three (20%) required reoperation, which was relatively a high complication rate. Although the frequency of inguinal seroma varies depending on the extent of lymph node dissection and the definition of the complication, postoperative inguinal seroma is an important complication after inguinal lymph node dissection and may be the cause of hesitation to dissect.

The indications for preoperative treatment of rectal cancer with ILMN may require further investigation. Results of several RCTs have indicated that chemoradiotherapy improved local control [11, 28] and total neoadjuvant therapy improved disease-free survival [10, 12]; however, there is no clear evidence of overall survival improvement. There is a report signifying a 55.2% 5-year survival rate after radical surgery without neoadjuvant treatment for rectal cancer with ILMN. In this study, all patients were treated preoperatively, and no pathologic inguinal lymph node metastasis was observed in patients with negative FDG uptake in the inguinal region after neoadjuvant therapy. Therefore, inguinal lymph node dissection may be omitted in cases in which FDG uptake is negative after neoadjuvant therapy.

There are several limitations in this study. First, this was a retrospective study that may include bias. Second, the inguinal lymph node metastasis may be over-estimated because it was determined clinically rather than pathologically. However, we felt that a clinical diagnosis was appropriate, as a preoperative needle biopsy was not easy to perform because of the proximity of important blood vessels in the inguinal region, and an exploratory biopsy could obscure the anatomy at the time of inguinal lymph node dissection. Third, this study did not include patients with resectable distant metastases in the liver or lungs other than the inguinal lymph nodes; hence, it was not possible to demonstrate what treatment would be best in these patients. Fourth, this was a single-center study with a small number of cases.

To conclude, radical surgery including inguinal lymph node dissection after adjuvant therapy has demonstrated a better long-term prognosis in patients with rectal or anal canal adenocarcinoma associated with ILNM, although a high rate of inguinal seroma was observed.

Funding:

This work was supported by Japan Society for the Promortion of Science KAKENHI (grant number 21K16446).

Competing Interests:

The authors have no competing interests to declare that are relevant to the content of this article.

Ethical approval:

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Ethics Review Board of the Kobe University Hospital (reference number: B210222; |Date of approval|).

Informed Consent:

Ethical approval was waived by the Institutional Ethics Review Board of the Kobe University Hospital in view of the retrospective nature of the study and all the procedures being performed were part of the routine care.

Data Availability statement:

The data that support the findings of this study can be made available from the corresponding author upon reasonable request.

Authors’ Contribution:

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Hiroshi Hasegawa, Takeru Matsuda, Kimihiro Yamashita and Ryuichiro Sawada. The first draft of the manuscript was written by Hiroshi Hasegawa and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Acknowledgments:

This work was supported by Japan Society for the Promortion of Science KAKENHI (grant number 21K16446).

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No competing interests reported.

OnlineResource1.mp4
Online Resource 1: Video from skin incision to exposure of the cephalic end of the dissection
OnlineResource2.mp4
Online Resource 2: Video of inguinal lymph node dissection around the fossa ovalis and outside the accessory saphenous vein
OnlineResource3.mp4
Online Resource 3: Video of inguinal lymph node dissection inside the great saphenous vein

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published 28 Dec, 2022

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Submission checks completed at journal
25 Aug, 2022
First submitted to journal
25 Aug, 2022

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Clinical outcomes of neoadjuvant therapy followed by selective inguinal lymph node dissection and total mesorectal excision for metastasised rectal or anal canal adenocarcinoma

Status:

Journal Publication

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

Introduction

Methods

Patients

Neoadjuvant treatment

Surgical procedure

Inguinal Lymph Node Dissection

Follow-up after surgery

Statistical analysis

Results

Patient characteristics

Operative outcomes and pathological findings

Fluorodeoxyglucose accumulation in the inguinal region

Adjuvant therapy

Long-term outcomes

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1