Research ArticleClinical Studies

Predictors of Lateral Pelvic Lymph Node Metastasis in Advanced Low Rectal Cancer Treated With Neoadjuvant Chemotherapy

TETSUO ISHIZAKI, KENJI KATSUMATA, MASANOBU ENOMOTO, JUNICHI MAZAKI, RYUTARO UDO, TOMOYA TAGO, KENTA KASAHARA, HIROSHI KUWABARA, YUICHI NAGAKAWA and AKIHIKO TSUCHIDA
Anticancer Research April 2022, 42 (4) 2113-2121; DOI: https://doi.org/10.21873/anticanres.15693

Abstract

Background/Aim: This retrospective study used magnetic resonance imaging to identify clinicopathological predictors of lateral pelvic lymph node metastasis in patients with advanced low rectal cancer treated with neoadjuvant chemotherapy; only few such studies have been reported. Patients and Methods: Sixty-one patients with advanced low rectal cancer who underwent total mesorectal excision and lateral pelvic lymph node dissection after neoadjuvant chemotherapy between April 2013 and December 2019 were included in this study. Univariate and multivariate analyses were used to analyze the relationship between lateral pelvic lymph node metastasis and clinicopathological factors, such as lateral pelvic lymph node size, measured before and after neoadjuvant chemotherapy using magnetic resonance imaging. Results: The short-axis diameter of lateral pelvic lymph nodes before neoadjuvant chemotherapy (p=0.003, odds ratio: 2.898, 95% confidence interval=1.534-9.143) was the only identified independent preoperative predictor. Based on the receiver operating characteristic curve analysis, the cut-off value of the short-axis diameter of lateral pelvic lymph nodes before neoadjuvant chemotherapy was 6.8 mm. The area under the curve was 0.761 (95% confidence interval=0.723-0.932). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 77.8%, 72.1%, 53.8%, 88.6%, and 73.8%, respectively. Conclusion: The preoperative predictor of lateral pelvic lymph node metastasis in advanced low rectal cancer treated with neoadjuvant chemotherapy was the short-axis diameter of lateral pelvic lymph nodes before neoadjuvant chemotherapy. When lateral pelvic lymph nodes with short-axis diameters above 6.8 mm are present, lateral pelvic lymph node dissection may be necessary.

Key Words:

Thirty years ago, the 5-year overall local recurrence rate after rectal resection for rectal cancer was >20% (1). However, rectal surgeons have improved this rate by using better surgical techniques and multimodal treatments. Total mesorectal excision (TME) for advanced low rectal cancer has become popular since the publication of a report by Heald et al. in 1982 (2). Western rectal surgeons have achieved a significant reduction in the local recurrence rate by using neoadjuvant chemoradiotherapy (CRT) (3–5) targeting the lateral pelvic lymph nodes (LPLNs) (6), making TME and CRT the gold standard for treating advanced lower rectal cancer in Western countries. However, although one of the aims of CRT is to control remnant cancer cells such as LPLNs, some patients who receive CRT still develop lateral local recurrence (7, 8). The importance of LPLN dissection has been gradually recognized since the recent publication of a multicenter study; the study reported that a combination of LPLN dissection and TME reduced 5-year lateral local recurrence rates from 19.5% to 5.7% in patients with low rectal cancer who had an LPLN short-axis (SA) diameter of ≥7 mm before CRT (9).

However, Eastern rectal surgeons (especially in Japan) use TME and LPLN dissection instead of CRT as the standard treatment (10). A multicenter randomized trial (JCOG0212 study) (11) reported that a combination of LPLN dissection and TME significantly reduced the local recurrence rates (13% to 7%, p=0.02). However, LPLN dissection has poor outcomes, such as surgical complications (12), sexual dysfunction, and voiding dysfunction (13). Accurate or correct preoperative diagnosis of pathological LPLN (pLPLN) metastasis in advanced low rectal cancer provides an appropriate indication for LPLN dissection. This, in turn, allows the appropriate selection of patients who may benefit from oncological therapy. Furthermore, excessive surgical stress can be prevented or avoided by omitting unnecessary LPLN dissection in pLPLN metastasis-negative patients. Therefore, there is an increased need for accurate preoperative prediction of the presence or absence of pLPLN metastasis in Western and Eastern countries.

Adequate local staging of advanced low rectal cancer (e.g., LPLN metastasis) is important for optimizing surgical procedures. Preoperative diagnostic studies of LPLNs using magnetic resonance imaging (MRI) are available (14, 15). However, no consensus has been reached regarding the diagnostic criteria. In particular, to avoid CRT adverse outcomes, such as anal dysfunction (16) and increased secondary cancer risk (17), TME and LPLN dissection after neoadjuvant chemotherapy (NAC) is recommended. Several MRI studies have reported predictors of LPLN metastasis in patients with advanced low rectal cancer who did not receive preoperative treatment (18, 19) and in those who received CRT (9). However, few studies have reported predictors of LPLN metastasis in patients with advanced low rectal cancer treated with NAC. Therefore, the aim of this study was to identify clinicopathological predictors of LPLN metastasis (e.g., criteria for LPLN size) in patients with advanced low rectal cancer treated with NAC.

Patients and Methods

Treatment strategies and inclusion criteria. The indication for treatment of low rectal cancer in our institution was TME without preoperative treatment for all clinical (c)T1 or cT2 and cN0. TME and LPLN dissection is performed after NAC for all cT3 or cT4 and cN1 or cN2 without distant metastasis. CRT was not performed as a preoperative treatment. Low rectal cancer was defined as located within 60 mm distance from the anal verge, histologically diagnosed as adenocarcinoma. Rectal cancer was classified according to the seventh edition of the American Joint Committee on Cancer classification guidelines (20). The NAC regimens that were administered were fluorouracil/folinic acid plus oxaliplatin (FOLFOX) (21), capecitabine plus oxaliplatin (XELOX) (22), or S-1 and oxaliplatin (SOX) (23) for 8 to 9 weeks. Surgery was performed 3-4 weeks after NAC. This was a single-center retrospective study. A total of 66 consecutive patients with cT3 or cT4 and cN1 or cN2 underwent TME and LPLN dissection after NAC at Tokyo Medical University Hospital between April 2013 and December 2019. After the exclusion of one patient who died from another disease, one patient who had multiorgan cancer, and three patients without preoperative MRI findings, 61 patients were included in the study (Figure 1). This study was approved by the Tokyo Medical University Ethics Committee (approval no. T2019-0054). All the study participants provided informed consent.

Figure 1.
Figure 1.

Patient selection flow diagram for this study. cT3: Clinical T3; cT4: clinical T4; cN1: clinical N1; cN2: clinical N2; NAC: neoadjuvant chemotherapy; TME: total mesorectal excision; LPLN: lateral pelvic lymph node.

Surgical procedures. Surgery for rectal cancer was performed with the patient in the lithotomy position and under general anesthesia. The surgical procedures included open surgery, laparoscopic surgery, and robotic surgery. After TME, lymph nodes with high frequency of metastasis in the internal iliac region between the two membranes, prehypogastric nerve fascia, and vesicohypogastric fascia, were accurately dissected using the standard LPLN dissection procedure. Next, important dissection of lymph nodes in the obturator region between the vesicohypogastric fascia and the internal obturator muscle was performed. The two areas on the left and right sides of LPLN dissection were completed with appropriate lymph node dissection.

Evaluation of LPLN metastasis using MRI. T2-weighted axial MRI scans of the pelvis with a 3-mm slice thickness were obtained for all patients using a 1.5-T scanner (Siemens Magnetom Avanto, Erlangen, Germany). Two surgeons independently performed a non-blinded evaluation of the LPLNs on the MRI scans. The maximum SA diameter of the LPLNs in the internal iliac and obturator regions that was detected by MRI was measured. The SA diameter of the LPLN before NAC was measured using pelvic MRI within 4 weeks prior to NAC. The SA diameter of the LPLNs after NAC was measured prior to surgery and after NAC. In addition, the LPLN reduction rate was calculated as the SA diameter of LPLNs before NAC, divided by the SA diameter of LPLNs after NAC. All MRIs imaging were evaluated by one surgeon and one radiologist.

Evaluation of predictive factors. Univariate and multivariate analyses were used to analyze the relationship of pLPLN metastasis with clinicopathological factors and LPLN size on MRI before and after NAC. The predictive factors evaluated were clinicopathological factors including age, sex, distance from the anal verge, tumor diameter, cT, cN, NAC regimen, pretreatment carcinoembryonic antigen (CEA) level, SA diameter of LPLNs before NAC, SA diameter of LPLNs after NAC, LPLN reduction rate on MRI, histological type, pathological T (pT), pathological N (pN), number of harvested lymph nodes, venous invasion, and lymphatic invasion.

Statistical analysis. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan). Continuous variables are presented as median (range). A p-value below 0.05 in the univariate analysis was considered statistically significant. Variables with significance in the univariate analysis were further analyzed in multiple regression analyses using the Cox proportional hazards model. The receiver operating characteristic (ROC) curves were analyzed for LPLN size to predict pathological metastasis and to calculate the area under the curve (AUC). In addition, the Youden index (24) was used to validate the optimal predictive cutoff value for metastasis and to calculate the accuracy, sensitivity, and specificity.

Results

The median observation period was 47.2 months (range=7.8-71.5 months). Sixty-one patients including 37 (60.7%) males and 24 (39.3%) females were included in the study. Table I shows the patients’ characteristics. The median age of the patients was 62 years (range=24-81 years). Eighteen (29.5%) patients had pLPLN metastases. Forty-two (68.9%) patients received the FOLFOX regimen, whereas 14 (23%) and 5 (8.1%) patients received the XELOX and SOX regimens, respectively. The median pretreatment CEA level was 3.4 ng/ml (range=1.2-546 ng/ml).

View this table:
Table I.

Patient characteristics.

The box plot shows the SA diameter of the LPLNs on MRI before and after NAC (Figure 2). The SA diameter of the LPLNs before NAC was 9.5 (3.6-19.4) mm in pLPLN-positive patients and 5.6 (2.3-14.9) mm in pLPLN-negative patients. The SA diameter of LPLNs after NAC was 6.3 (3.2-14.2) mm in pLPLN-positive patients and 5.0 (3.2-13.4) mm in pLPLN-negative patients. The LPLN reduction rate was 0.76 (0.32-1.09) in pLPLN-positive patients and 0.91 (0.77-0.99) in pLPLN-negative patients.

Figure 2.
Figure 2.

Box plot showing the SA diameter of LPLN on magnetic resonance imaging before (A) and after (B) NAC. SA: Short-axis; NAC: neoadjuvant chemotherapy; LPLN: lateral pelvic lymph node.

A univariate analysis was performed to further evaluate the risk factors for pLPLN metastasis (Table II). The SA diameter of LPLNs before NAC (p=0.001), pN (p=0.002), and lymphatic invasion (p=0.02) were significantly associated with pLPLN metastasis. Age (p=0.223), sex (p=0.78), distance from the anal verge (p=0.812), tumor size (p=0.267), cT (p=0.544), cN (p=0.304), NAC regimen (p=0.336), pretreatment CEA level (p=0.635), histological type (p=0.411), SA diameter of LPLNs after NAC (p=0.749), LPLN reduction rate (p=0.123), pT (p=0.06), number of harvested lymph nodes (p=0.141), venous invasion (p=0.452), and lymphatic invasion (p=0.02) were not significantly associated with pLPLN metastasis.

View this table:
Table II.

Univariate and multivariable logistic regression analysis for risk factor of lateral pelvic lymphonode metastasis.

A multivariate logistic regression analysis was performed to further evaluate the predictors of pLPLN metastasis. The SA diameter of LPLNs before NAC [p=0.003, odds ratio: 2.898, 95% confidence interval (CI)=1.534-9.143] and pN2 (p=0.014, odds ratio: 5.586, 95%CI=1.942-13.286) were significantly associated with pLPLN metastasis.

The ROC curves for the prediction of LPLN status are shown in Figure 3. The AUC was 0.761 (95%CI=0.723-0.932). Based on the ROC curve analysis, the cut-off value of the SA diameter of LPLNs before NAC was 6.8 mm. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of pLPLN metastasis positivity, when the cutoff value of the SA diameter of LPLNs before NAC was ≥6.8 mm, were 77.8%, 72.1%, 53.8%, 88.6%, and 73.8%, respectively (Table III).

Figure 3.
Figure 3.

The cut-off value (6.8 mm) of the short-axis diameter of lateral pelvic lymph nodes before neoadjuvant chemotherapy. According to the Youden index, the sensitivity and specificity were 0.778 and 0.279, respectively. The AUC was 0.761 (95%CI=0.703-0.932). AUC: Area under the curve; LPLN: lateral pelvic lymph node.

View this table:
Table III.

Sensitivity, specificity, positive predictive value, negative predictive value and accuracy.

Discussion

Here, we investigated MRI-related predictors of LPLNs in patients with advanced low rectal cancer treated with NAC. In the multiple regression analysis in our retrospective study, the SA diameter of LPLNs before NAC and pathological N2 were significant predictors of pLPLN. The identification of mesorectal lymph nodes (e.g., pN2) as a predictor is supported in several previous studies (18, 25, 26). These factors are reasonable predictors because advanced mesorectal lymph node metastasis may cause changes in lymphoid flow (27), which may affect pLPLN status. The JCOG0212 trial reported higher oncological benefits of LPLN dissection in patients with cStage III tumors than in those with cStage II tumors (28). Our institution also uses a similar strategy. Given that the risks of operative morbidity and urogenital dysfunction outweigh oncological benefits, patients with cStage II tumors were excluded, and LPLN dissection was only indicated for patients with cStage III. However, pN2 is a factor that can be determined only by postoperative pathological examination. The purpose of this study was to improve the preoperative predictive accuracy of pLPLN metastasis. Therefore, the analysis focused on preoperative factors and the SA diameter of LPLNs before NAC.

MRI has recently become a modality used for preoperative evaluation, which is useful in determining the treatment strategy for rectal cancer (29, 30). Lymph node size on MRI is the most reliable parameter for the diagnosis of LPLN metastases, but there is no consensus on the criterion for lymph node size. It has been reported that the SA diameter of LPLN metastasis is a more useful indicator than the long-axis diameter because it has less orientation bias (14, 31). In addition, Kim et al. (25) analyzed the largest long-axis diameter, largest short-axis diameter, and long-to-short axis diameter ratio and reported that it was better to select the largest short-axis diameter. Furthermore, another study (9) reported that analysis limited to SA diameter after excluding the typically long-stretched benign lymph nodes in the pelvis allowed a focused investigation of lymph nodes that predict the prognosis. Therefore, the SA diameter was used in the present study. According to previous studies (14, 19, 32), the optimum cut-off value of the SA diameter was 4-10 mm; the sensitivity was 43.8%-87%, the specificity was 54.7%-98.5%, and the accuracy was 63.7%-88.1%. However, the patients in the previous studies did not receive preoperative treatment.

Previous studies have reported the effects of preoperative CRT on the LPLN diameter. Ogura et al. (9) reported that preoperative CRT reduced the SA diameter of LPLNs from 5.0 mm to 3.8 mm, and that LPLN dissection was effective in patients with a SA diameter of ≥7 mm measured using pretreatment MRI. In addition, Akiyoshi et al. (33) reported that preoperative CRT reduced the short-axis diameter of LPLNs from 7 mm to 4 mm. However, they also found that only the pre-CRT SA diameter of the LPLN affects pLPLN metastasis. They both mentioned the importance of the pre-CRT SA diameter. We used NAC to reduce the risks of radiation therapy-related adverse events and secondary cancers. MRI assessments in previous similar studies, in which 60 patients with advanced rectal cancer were treated with oxaliplatin-based NAC regimens, compared pre- and post-NAC SA diameters of LPLNs; in these studies, multivariate analyses identified no SA diameter cut-off value for post-NAC. An SA diameter cut-off value of 7 mm for pre-NAC was able to independently predict lymph node metastasis (17). The difference between our study and this study (17) is that our study excluded cT2 and focused on cT3 and cT4, which is more likely to benefit from LPLN dissection. The cut off value SA diameter was approximate, and we were able to confirm reproducibility. Our study also showed a post-NAC reduction in the SA diameter. However, the SA diameter of the LPLNs after NAC and the LPLN reduction rate did not affect pLPLN metastasis. The SA diameter of the LPLNs before NAC on MRI was a preoperatively identifiable independent predictor of pLPLN. These results suggest that both NAC and CRT had small effects on the preoperative treatment of pLPLN. In contrast, Zhou et al. (34) reported that post-CRT LPLN size ≥7 mm was an independent risk factor for pLPLN metastasis. Therefore, this is open to discussion.

Several recent studies (35–37) have reported the importance of the signal intensity and border characteristics of lymph nodes measured by MRI, in addition to the lymph node size, in the prediction of lymph node metastasis. They argued that the analysis of not only the lymph node size but also the signal intensity and border characteristics improves the sensitivity and specificity of predicting metastatic lymph nodes in rectal cancer. Because of the overlap in size between metastatic and non-metastatic lymph nodes, the analysis of signal intensity and boundary lines, in addition to the size criterion, may increase the predictability of LPLN metastasis. However, it has been pointed out that the smaller size of the LPLNs may affect the evaluation of signal intensity and border characteristics with MRI, and that the evaluation may be affected by the subjectivity of the evaluator. Therefore, as in the present study, we recommend the use of the size criterion as a tool for quantifiable and reproducible evaluation of LPLN metastasis. Furthermore, 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) has recently been used to diagnose LPLN metastasis. Yukimoto et al. (38) used a cutoff value of 1.5, the maximum standardized uptake value of PET-CT for the lymph node, as a reasonable index for predicting the risk of preoperative LPLN metastasis in patients with rectal cancer and showed a high diagnostic accuracy of 92.3%. PET-CT may be a promising modality and needs to be studied in large-scale studies in the future.

The 2019 Japanese Society for Cancer of the Colon and Rectum guidelines for the treatment of colorectal cancer (10) states that LPLN dissection should be performed when the lower border of the tumor is located distally to the peritoneal reflection and the tumor has invaded regions beyond the muscularis propria. However, the JCOG0212 study, which used a short-axis diameter of <10 mm in addition to the above indication as inclusion criteria, reported a 7.4% incidence of pLPLN metastasis in locally advanced rectal cancer (39), indicating that many patients received unnecessary LPLN dissection. In contrast, relapse-free survival was significantly lower in patients with LPLN metastasis than in those without LPLN metastasis (34). Therefore, the accurate prediction of LPLN metastasis is important. The present study demonstrated a high negative predictive value. This may allow the appropriate prediction of patients requiring LPLN dissection and prevent physicians from overlooking patients requiring LPLN dissection by reducing the false negative rate.

This study had several limitations. First, the sample size was small. Second, this was a single-center, retrospective study. Third, factors other than lymph node size were not investigated in the MRI evaluation. Recently, it has been reported that the accuracy of diagnosis can be improved by combining the size criterion and MRI findings of extramural vascular invasion (40). Moreover, a multidisciplinary evaluation is necessary.

Conclusion

The ROC curve analysis in this study provided appropriate cut-off values for the SA diameter of the LPLNs and a high sensitivity, specificity, and accuracy for pLPLN metastasis. It was suggested that patients with an SA diameter of the LPLNs ≥6.8 mm before NAC in advanced low rectal cancer may be an indication for LPLN dissection. In the future, a large sample size study with a multidisciplinary evaluation should be conducted to improve the accuracy of predicting pLPLN metastasis in advanced low rectal cancer with NAC.

Acknowledgements

The Authors would like to thank Hiroshi Kuwabara MD for his support with data collection and technical support in this study.

Footnotes

  • Authors’ Contributions

    Study conception and design: Ishizaki, Enomoto and Katsumata; Data acquisition: Ishizaki, Mazaki; Statistical analysis: Ishizaki; Data interpretation: Ishizaki, Udo, Tago, Kasahara and Kuwabara; Drafting the manuscript: Ishizaki; Supervision of the manuscript: Nagakawa, Tsuchida; Critical review and approval of the manuscript: Ishizaki, Katsumata and Tsuchida

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare regarding this study.

  • Received January 21, 2022.
  • Revision received February 11, 2022.
  • Accepted February 14, 2022.

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Predictors of Lateral Pelvic Lymph Node Metastasis in Advanced Low Rectal Cancer Treated With Neoadjuvant Chemotherapy
TETSUO ISHIZAKI, KENJI KATSUMATA, MASANOBU ENOMOTO, JUNICHI MAZAKI, RYUTARO UDO, TOMOYA TAGO, KENTA KASAHARA, HIROSHI KUWABARA, YUICHI NAGAKAWA, AKIHIKO TSUCHIDA
Anticancer Research Apr 2022, 42 (4) 2113-2121; DOI: 10.21873/anticanres.15693
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