The treatment strategy of R0 resection in colorectal cancer with synchronous para-aortic lymph node metastasis

doi:10.21203/rs.3.rs-25027/v1

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The treatment strategy of R0 resection in colorectal cancer with synchronous para-aortic lymph node metastasis

https://doi.org/10.21203/rs.3.rs-25027/v1

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Journal Publication

published 28 Aug, 2020

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Background

Synchronous metastatic para-aortic lymph node (mPALN) dissectionin colorectal cancer has relatively good oncological outcomes, though many patients develop recurrence. Universal prognostic factor remain unclear and no definitive perioperative chemotherapy is available, making the treatment of mPALN controversial. In the present study, we aimed to establish a treatment strategy for synchronous mPALN.

Methods

This retrospective study involved 20 patients with pathological mPALN below the renal vein who underwent R0 resection. Long-term outcomes, recurrence type, and prognostic factors for survival were investigated.

Results

The 5-year overall survival and recurrence-free survival rates were 38% and 25%, respectively. Seventeen patients (85%) developed recurrence, including 13 (76%) within 1 year after surgery, and ~ 70% of all recurrences were multiple recurrences. Four patients (20%) survived > 5 years. Pathological T stage (p = 0.016), time to recurrence (p = 0.006), and recurrence resection (p = 0.008) were identified as prognostic factors for long-term survival.

Conclusions

R0 resection of synchronous mPALN in colorectal cancer resulted in acceptable oncological outcomes, though we found a high rate of early unresectable recurrence. If the recurrence occurs late or isolated, surgical resection should be considered for longer survival.

Surgery

Oncology

para-aortic lymph node metastasis

synchronous

colorectal cancer

In colorectal cancer (CRC), the relatively rare occurrence of metastatic para-aortic lymph node (PALN) is categorized as stage IV disease [1, 2]. The reported incidence of isolated metastatic PALN is 1–2%[3, 4]. In stage IV patients, R0 resection is usually recommended for resectable liver or lung metastases [2, 5–7]. However, metastatic PALN remains highly controversial as no multicenter-studies or randomized controlled trials have been performed on synchronous or metachronous PALN dissection (PALND).

A few studies have been published on metachronous metastatic PALN [8–11], and studies on synchronous metastatic PALN have shown that PALND below the renal veins can be performed safely, prolonging prognosis compared to non-surgical resection [12, 13]. Bae et al [12] also demonstrated that PALND results in survival rates comparable to synchronous liver metastasectomy. However, although the 5-year overall survival (OS) rates for patients who underwent synchronous PALND reached 25–53%, approximately 80% of the patients experience recurrence [4, 12–15] and few studies have discussed the recurrence pattern [12] or treatment after recurrence. Furthermore, no definitive perioperative chemotherapy has been established.

Recently, three retrospective studies have shown updated prognostic factors for synchronous PALND, including R0 resection, histological type, number of PALN, other distant metastases, metastatic lateral pelvic lymph node, and preoperative CEA values [4, 15, 16]. However, the prognostic factors for synchronous PALND identified in the previous studies are not yet universal.

These findings indicate that the treatment strategy for PALN remains highly controversial.

The aim of this study was to examine the prognostic factors, recurrence patterns, and long-term outcomes in CRC with synchronous metastatic PALN to establish the strategy for PALND.

This was a single-center retrospective cohort study at Osaka International Cancer Institute, Osaka, Japan. The study protocol was approved by the institutional review board (No. 18033-2). Written informed consent was waived because of the retrospective design.

Study population

Between September 1998 and December 2018, we reviewed the medical records of patients who underwent PALND for clinical metastatic PALN in addition to resection of the primary CRC. Twenty-two patients had pathological metastatic PALN. Two patients who could not undergo R0 resection were excluded. R0 resection was defined as having no macroscopic or microscopic residual tumor. A total of 20 patients were included in the present study.

Indication for PALND

Tumors were pathologically diagnosed as CRC and classified according to the criteria of the World Health Organization and Union for International Cancer Control, 8th edition[17]. Clinical stage was assessed based on enhanced computed tomography (CT) and positron emission tomography (PET). Surgical treatment with CRC resection and PALND was performed based on the following criteria: metastatic PALN diagnosed as clinically positive by the colorectal surgery team and at least two radiologists based on PALN with a long-axis diameter ≥ 7 mm by CT and/or a high intensity spot on PET; metastatic PALN located only below the renal vein; and expectation of R0 resection, including synchronous metastasectomy or second stage metastasectomy, such as metachronous hepatectomy.

PALND

PALND was performed after primary tumor resection. PALND was defined as a dissection of all lymphatic and connective tissues around the abdominal aorta and inferior vena cava between the left renal vein and bifurcation of the iliac artery. If lymph node dissection was not performed in this area, it was defined as lymphadenectomy.

Follow-up

After surgery, all patients underwent general follow-up with examination of tumor markers every 3 months, as well as chest and abdominal CT every 6 months. A colonoscopy was performed every year for rectal cancer, and every other year for colon cancer. If recurrence was suspected during the follow-up, CT and/or PET was added immediately. Local recurrence was defined as recurrence within the pelvic cavity for rectal cancer or around the tumor area for colon cancer.

Statistical analysis

Data are presented as medians and ranges. The rates of OS and recurrence-free survival (RFS) were calculated using the Kaplan Meier method, and the log-rank test was used to compare OS between the two group. P < 0.05 was considered significant. Statistical analyses were performed using JMP version 8.0.2 software (SAS Institute, Cary, NC).

Clinicopathological characteristics

The demographic and pathological characteristics of the 20 patients are given in Table 1.

Except for metastatic PALN, distant metastasis was confirmed in 4 patients (liver metastasis, n = 2; ovarian metastasis, n = 1; peritoneal dissemination, n = 1), all of which were resected synchronously. Adjuvant chemotherapy (AC) was performed in 12 patients (60%), 9 (75%) with camptothecin-11 or oxaliplatin, whereas neoadjuvant chemotherapy with oxaliplatin (NAC) was used in only 2 patients (10%).

Long-term outcomes and recurrence

The median follow-up duration was 24.8 months (6.6-248.1). The 5-year OS was 38% and 5-year RFS 25% (Fig. 1). Seventeen patients (85%) developed recurrence, including two cases of recurrence 8 years after surgery. Table 2 showed the pattern of first recurrence in the 17 patients.

Thirteen patients (76%) developed recurrence within 1 year after surgery. Almost all of these patients developed distant multiple recurrences that could not undergo surgical resection. However, four of the patients who developed recurrence 1 year after surgery had isolated recurrence, and three underwent surgical resection. The most common recurrence site was PALN (7/27, 26%), and three of the patients developed recurrence both above the renal vein and below the renal vein. Most patients who developed recurrent PALN also had other distant metastases, but one patient developed only isolated PALN and was resected.

Long-term and short-term survivors

Table 3 shows the clinicopathological findings of four long-term survivors over 5 years and four short-term survivors within 1 year.

All short-term survivors developed early and multiple recurrences with no surgical indication. Two patients developed recurrence during AC, and the other two presented with recurrence before the introduction of AC. Long-term survivors also developed recurrence (3/4, 75%), but most were delayed and all were isolated recurrence that could be dissected curatively. Two patients who developed delayed recurrence had received AC for a long time.

Prognostic factors in patients with R0 PALND

Pathological T stage (p = 0.016), time to recurrence (p = 0.006), and recurrence resection (p = 0.008) were identified as prognostic factors (Table 4).

The 5-year OS in the four patients who could undergo resection of recurrence (metastatic PALN, n = 1; metastatic mediastinal LN, n = 3) was 100%. The number of metastatic PALNs (p = 0.713) and PALND (p = 0.234) were not identified as prognostic factors. Distant metastasis (p = 0.151) was not identified as a risk factor, but no patients who had other distant metastases survived 5 years.

This study was conducted to examine the oncological outcomes in CRC with synchronous PALN to establish the strategy for PALND. We found that PALND is associated with the potential for long-term survival, but also early unresectable recurrences. Pathological T stage, time to recurrence, and recurrence resection were prognostic factors for long-term survival. No previous reports have discussed recurrence, including the time to recurrence and site of recurrence, but the current findings support treatment strategies for patients with synchronous metastatic PALN in CRC.

Our study was limited to patients who underwent R0 resection based on previous reports that R0 resection has a better prognosis than R1-2 resection [14, 15]. The 5-year OS and RFS rates in 20 patients with synchronous metastatic PALN who underwent PALND were 38.2% and 25%, respectively. These oncological outcomes are similar to what was reported in previous studies [4, 12–15], and relatively more favorable than general stage IV CRC (5-year OS 13.2 to 22%) [14], which indicates that PALND can prolong prognosis.

In terms of recurrence, 55% of patients received AC, but the overall recurrence rate after PALND reached 85%, and most cases were early and multiple recurrences. Although four patients with isolated recurrences after PALND could undergo resection and experienced long-term survival [18], some patients developed unresectable recurrences before or during AC and died within 1 year after PALND. These findings show that a number of patients who underwent PALND had no indication for PALND in the first place.

We found that pathological T stage, time to recurrence, and recurrence resection are prognostic factors in patients undergoing R0 PALND, though these factors were only known postoperatively and not previously reported. First, though pathological T stage is common as a prognostic factor and useful in determining chemotherapy after resection of CRC without distant metastases [2, 7], in CRC with metastatic PALN, it may be not useful for considering the treatment strategy. We also showed a relationship between recurrence more than 1 year after PALND and long-term survival. Many of the recurrences 1 year after PALND were isolated recurrences, so a longer time to recurrence was more likely to be oncologically favorable. Therefore, it is reasonable that a long time to recurrence was associated with long-term survival from a biological perspective [19].

Resection of recurrence, especially after PALND, has been reported rarely and is highly controversial. Though resection of recurrence was performed in our study, all recurrences were isolated to distant lymph node, and most recurrences occurred more than 1 year after PALND. Thus, the indication for surgical resection was limited. However, considering the number of previous reports reporting prolonged prognosis with surgical resection for lymph node recurrence or repeat hepatic resection for liver re-recurrence [3, 10, 11, 20, 21], if the recurrence is resectable and not early, it would be valuable to perform resection for long-term survival, even after PALND.

In regards to other prognostic factors, distant metastasis and PALND did not have significant differences. However, the M1b/M1c patient did not achieve long survival, and distant metastasis has potential as a prognostic factor [4, 14]. Though PALND was a statistically negative prognostic factor, it should be performed, if possible, because one patient after lymphadenectomy developed PALN recurrence and additional PALND provided long-term survival. Even with our results, universal prognostic factors for synchronous PALND have been unclear and at least a retrospective multi-institutional study is necessary.

Considering the treatment strategy for synchronous PALN, AC was a statistically negative prognostic factor for OS in the present study, though 75% of patients received intensive AC (camptothecin-11 or oxaliplatin), but two patients who developed delayed recurrence had received AC for a long time, indicating that AC had the potential to improve RFS. Although Nakai et al. [14] showed that AC is a prognostic factor after PALND, 94% of patients in their study underwent AC and requires careful interpretation. To interpret our results, it may be reasonable to refer to the previous randomized control study that showed AC (Uracil-tegafur and leucovorin) prolonged RFS, but not OS, after resection of liver metastasis [22].

Our study included only two patients who received NAC and it was difficult to investigate NAC. However, considering that some oncologically poor patients developed unresectable early recurrences and few universal prognostic factors were available preoperatively, it may be reasonable to perform NAC. Though some studies have shown the efficiency of NAC for stage IV CRC [9, 20], there is little evidence for NAC in patients with metastatic PALN and further investigation is needed.

Some limitations must be considered when interpreting the results of this study. First, this study was a single-center, retrospective analysis. Second, this study covered 20 years and the background for treatment was different, especially chemotherapy. Third, this study had a selection bias, involving only patients with pathological PALN, but did not include the patients who underwent chemotherapy without PALND; therefore, not all PALN-positive patients were included.

Our results show that R0 synchronous PALND in CRC had relatively good oncological outcomes, and pathological T stage, time to recurrence, and recurrence resection were prognostic factors for PALND. Our results also revealed a high rate of early unresectable recurrences after PALND, but recurrence resection should be considered for longer survival in isolated late recurrence.

mPALN metastatic para-aortic lymph node

CRC colorectal cancer

PALN para-aortic lymph node

PALND para-aortic lymph node dissection

OS overall survival

CT computed tomography

PET positron emission tomography

RFS recurrence-free survival

AC adjuvant chemotherapy

NAC neoadjuvant chemotherapy

LPLN lateral pelvic lymph node

Ethical approval and consent to participate

The study protocol was approved by the institutional review board (No. 18033-2). Written informed consent was waived because of the retrospective design.

Consent for publication

Not applicable

Availability of date and materials

The datasets used and analysed in this study are not publicly available (to maintain privacy) but are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

We have no funding sources.

Authors’ contributions

HU, MY and MO wrote the manuscript. NH, JN, KS, KY, HW, HT, TO performed follow-up and collected the data. HM and ST revised the manuscript.

Acknowledgement

We gratefully acknowledge the work of past and present members of department of gastroenterological surgery.

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Journal Publication

published 28 Aug, 2020

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Editorial decision: Major Revision
30 Jul, 2020
Review #2 received at journal
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Reviewer #2 agreed at journal
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Review #1 received at journal
24 May, 2020
Reviewer #1 agreed at journal
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Reviewers invited by journal
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You are reading this older preprint version

Read the latest preprint version →

The treatment strategy of R0 resection in colorectal cancer with synchronous para-aortic lymph node metastasis

Status:

Journal Publication

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Background

Materials And Methods

Study population

Indication for PALND

PALND

Follow-up

Statistical analysis

Results

Clinicopathological characteristics

Long-term outcomes and recurrence

Long-term and short-term survivors

Prognostic factors in patients with R0 PALND

Discussion

Conclusions

abbreviations

Declarations

REFERENCES

Status:

Journal Publication

Version 1