Oncologic outcomes after resection of para-aortic lymph node metastasis in left-sided colon and rectal cancer

Aim The optimal surgical management strategy for para-aortic lymph node (PALN) metastasis has not attracted as much attention as surgery for liver or lung metastasis. The purpose of this retrospective study was to evaluate the oncologic outcomes after synchronous resection of PALN metastasis in left-sided colon and rectal cancer. Methods Between January 1986 and August 2016, 29 patients with pathologically positive PALN metastases who underwent curative resection at our hospital were retrospectively reviewed. We examined clinicopathological characteristics, long-term oncologic outcomes, and factors related to favorable prognosis in these patients. Results The 3-year overall survival and recurrence-free survival (RFS) rates were 50.5% and 17.2%, respectively. In total, 6 (20.7%) patients experienced no recurrence in the 3 years after surgery, while postoperative complications were seen in 9 (31.0%) patients. The 3-year RFS rate was significantly better in the pM1a group than in the pM1b/pM1c group (26.3% and 0.0%, respectively, p = 0.032). Conclusion PALN dissection for patients without other organ metastases in left-sided colon or rectal cancer is a good indication as it is for liver and lung metastasis.


Background
Para-aortic lymph node (PALN) metastasis occurs in less than 1.3% of colorectal cancer (CRC) patients. 1 PALN is associated with poor prognosis. 2 While management of metastatic CRC has long been based on systemic chemotherapy, several studies have suggested that more aggressive surgical resection is a potentially curative treatment for liver and lung metastasis in selected patients with acceptable postoperative morbidity. [3][4][5] Recently, surgical resection has been established as the standard therapy for liver and lung metastasis.
However, the clinical significance of surgical management of synchronous PALN metastasis remains highly controversial because of the lack of definitive evidence regarding survival outcomes and the safety of surgical techniques. 6 There is insufficient data to guide the stratification of patients for aggressive treatment. 3 We aimed to clarify the oncologic outcomes after synchronous resection of PALN metastasis in leftsided colon and rectal cancer.

Patients
In this retrospective cohort study in a single institution, between January 1986 and August 2016, 574 patients with stage Ⅳ CRC underwent surgery, including noncurative surgery, at our cancer center. Of these, 43 underwent PALN dissection synchronously with primary CRC resection.
The selection criteria for PALN dissection were as follows: (1) pathological diagnosis of CRC; (2) suspected PALN metastasis on preoperative imaging, such as abdominal/pelvic computed tomography (CT) or positron emission tomography; and (3) judgment that curative resection was possible (i.e., no signs of upward PALN swelling extending above the renal vessels, or obvious invasion of PALN metastases to the great vessels). Curative resection was defined as complete tumor resection with all margins being negative. The indications for PALN dissection were thoroughly discussed and determined at our multidisciplinary team conferences with radiologists and hepatobiliary surgeons.
In total, 29 patients who were pathologically positive for PALN metastasis were included. We excluded patients with secondary malignancies and double cancer.
The study protocol was conducted in accordance with the Declaration of Helsinki. The need for written consent from study subjects was waived by the institutional review board. This retrospective study was approved by the Ethical Advisory Committee of Tochigi Cancer Center before study initiation.

Evaluation parameters
The classification system of the Union for International Cancer Control (8 th edition) was used to determine pathological tumor depth and distant metastasis. The extent of regional lymph node metastasis was classified into three categories according to their location: (1) pericolic/perirectal lymph nodes were defined as lymph nodes close to the bowel wall; (2) intermediate lymph nodes were defined as lymph nodes along the feeding arteries; and (3) main lymph nodes were defined as lymph nodes related to the origin of the feeding artery. In addition, lateral pelvic nodes were defined 4 as lymph nodes along the common internal and external iliac vessels and downward to the level of the obturator internus muscles. Postoperative complications were classified according to the Clavien and Dindo classification.

Surgery and follow-up
Curative surgery was performed following the standard principles of total mesorectal excision. After identification of the ureter and gonadal vessels, PALN dissection began from the aortic or bifurcation of the iliac artery. We removed all lymphovascular tissues in the area using the following boundaries: the lower border of the left renal vein, the right border of the inferior vena cava, and the right border of the left gonadal vessels (Fig. 1).
Patients underwent a standardized follow-up every three months for the first three years. At each follow-up, physical examination and laboratory test were performed. CT was performed every six months. Colonoscopy was performed one year after surgery, and repeated at least every two years.

Main outcome measures
The primary end points were three-year overall survival (OS) and recurrence-free survival (RFS) rates.

Statistical analysis
All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R Commander designed to add statistical functions frequently used in biostatistics.
Differences in categorical and continuous variables were analyzed using the chi-square test (or Fisher's exact test) and Student's t-test. The Kaplan-Meier method was used to compare OS and RFS rates. Univariate and multivariate analyses of factors associated with oncologic outcomes were evaluated using the Kaplan-Meier method, and the Cox proportional hazards model was used to estimate hazard ratios. Survival curves were created using the log-rank test. From the receiver operating characteristic (ROC) curves, the threshold of PALN metastasis was set to four (area under the ROC curve, 0.741; 95% CI, 0.531-0.951). A probability level of p<0.05 was considered to indicate a statistical difference.

Results
Clinicopathological characteristics are shown in Table  PALN, para-aortic lymph node Operative and postoperative results are shown in Table 2. Only one (3.4%) patient was operated on using a laparoscopic approach. The median operating time was 248 (110-645) minutes and the median estimated blood loss was 628 (20-4900) g. The median hospital stay was 40 (8-106) days.

Discussion
The present study demonstrated that PALN dissection for left-sided colon and rectal cancer with synchronous PALN metastasis without other organ metastases was associated with a favorable prognosis. This is one of a few characteristic studies that has shown the clinical significance of PALN dissection.
Similar to liver and lung metastasis, synchronous PALN metastasis from a CRC is categorized as Stage Ⅳ disease. Liver and lung metastasis resection are widely accepted as standard treatments and fiveyear survival rates are over 50% following surgery. 7 PALN dissection was first described in 1950 by Dr. Deddish as a modification of the Miles abdominoperineal resection to reduce local recurrence in rectal cancer. 8 However, routine PALN dissection has since been abandoned in view of the increased surgical morbidity, such as urinary and sexual dysfunction, without corresponding improvements in recurrence rates and overall survival. 9 On the other hand, recent studies have reported that prolonged survival can be obtained following resection of PALN metastasis. 10-14 Each of these studies was a retrospective cohort study, and so significance of the PALN dissection remains unconfirmed and highly controversial.
We think that curative resection, using PALN dissection, is a prerequisite for a favorable prognosis.
Past studies have shown that low curative resection rates lead to low survival rates. 12 Therefore, we did not perform PALN dissection on patients in whom it was established that curative resection was not possible based on preoperative imaging diagnosis.
Our PALN dissection area was similar to that of past studies. It is necessary to perform PALN dissection for right-sided colon cancer while maintaining the great vessels, such as the superior mesenteric artery or celiac artery. Because of this, in right-sided colon cancer, systematic PALN dissection is anatomically impossible and the dissection effect is not to be obtained as it is with leftsided colon and rectal cancers. For this reason, we limited the indication for PALN dissection to leftsided colon and rectal cancer.
The 3-year OS rate and the three-year RFS rate were significantly better in the pM1a group than in the pM1b/pM1c group, which was similar to the results of Yamada et al. 11 In our study, there were no significant differences in clinicopathological characteristics, such as tumor location and histology, the number of metastatic regional lymph nodes, and the number of metastatic PALNs in the pM1a group and pM1b/pM1c group (Table 3). These results suggest that other organ metastases without PALN are the most important prognosticators. In our study, there was no distant lymph node recurrence in the 8 pM1b/pM1c group, and all recurrences occurred in other organs. Consequently, patients with PALN metastasis with other organ metastases should be excluded from the indication for PALN dissection. Recently, several studies have reported an optimum cutoff for lymph node size to identify patients positive for lateral lymph node metastases of lower rectal cancer on preoperative imaging. 17,18 However, reports on preoperative diagnosis of PALN metastasis are rare. Further studies on accurate preoperative imaging diagnosis and patient selection for PALN dissection are therefore necessary.
The benefits associated with removing PALN metastasis should be weighed up against the risk of morbidity. In the present study, postoperative morbidity occurred in 31.0% of patients, which was comparable with that of other studies (7.8-38.9%). [10][11][12][13][14] The main morbidity was surgical site infection, and the rate of Clavien and Dindo classification grade Ⅲ or above was only 10.3%, with no perioperative death. These results suggest that the incidence of postoperative morbidities associated with PALN dissection is within acceptable limits.
There were several limitations to the present study, including the single institutional experience, the small sample size due to the rarity of this metastatic pattern, and the retrospective analysis. The study period was long, lasting over 30 years; and during this time, the optimal indication for PALN dissection and treatment strategy, e.g. chemotherapeutic regimens, would have changed.
Additionally, assessment of sexual dysfunction was not performed. A global assessment method, such 9 as the International Index of Erectile Function, should be used for all cases. However, our results clearly showed that favorable prognosis could be expected in select patients with left-sided colon and rectal cancer using isolated PALN metastasis. In light of our results supporting the role of PALN dissection, large and multi-institutional prospective studies are required to overcome these problems.

Conclusions
In conclusion, PALN dissection for patients without other organ metastases in left-sided colon or rectal cancer can be a feasible treatment option as it is for liver and lung metastasis.

Ethics approval and consent to participate
Institutional approval for this retrospective study was obtained from the Ethical Advisory Committee of Tochigi Cancer Center before initiating the study.

Consent for publication
Not applicable.

Availability of data and materials
The datasets analyzed during the current study available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
No funding was received for this research.

Authors' contributions
Conception or design of the research; or the acquisition, analysis, or interpretation of data for the