Abstract
Introduction and aim
Para-aortic lymph node metastasis associated with colorectal cancer is a very rare occurrence, but at the same time an important predictor of survival. Despite its importance, there is still no gold standard management strategy, particularly for lymph nodes detected during follow-up, after resection of the primary tumour. Therefore, this review was undertaken to examine the evidence available on the surgical and non-surgical management of metachronous para-aortic lymph node metastasis (m-PALNM) in colorectal cancer treatment.
Methods
This is a systematic review using the patient, intervention, comparison, outcome and study strategy. The literature search was undertaken using Cochrane, MEDLINE, EMBASE and PubMed databases with the following MeSH terms: lymph node excision, para-aortic lymph node, metastasis, metachronous and colorectal neoplasms.
Results
Five original papers met the study criteria including 188 patients in total (55.3% male, 44.7% female). Surgical resection of the m-PALND was the management of choice in 64% of patients. Reporting styles on survival outcomes were heterogeneous. However, patients undergoing surgical management for m-PALNM had longer disease-free survival and overall survival rates.
Conclusion
There is significant paucity in the evidence available on the management of m-PALNM. However, the evidence reported by this review suggests that surgical management should be considered whenever possible, with the aim of prolonging survival. Future randomised trials are needed in order to provide further high-level evidence on m-PALNM management.
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Introduction
Para-aortic lymph node metastasis (PALNM) associated with colorectal cancer (CRC), unlike liver and lung metastasis, is a rare occurrence with incidence rates reported as < 2% [1]. Despite this uncommon occurrence, PALNM is amongst the paramount prognostic factors for CRC [2].
There is still no clearly defined gold standard management strategy for PALNM. A significant contributing factor to this dilemma is the variation in definition of PALNM. According to the Japanese Society for Cancer of the Colon and Rectum PALNM is classified as regional or stage III disease [1, 3]. On the contrary, the American Joint Committee on Cancer defined PALNM as disseminated stage IV disease and the TNM staging system as M1 disease [1, 4]. This discrepancy unavoidably causes inconsistency in reporting and measuring management outcomes.
PALNM may occur synchronously or metachronously, with synchronous PALNM (s-PALNM) resulting in more advanced disease at diagnosis, and poorer patient survival outcomes, when compared with metachronous PALNM (m-PALNM) [5]. The lack of unambiguously clear distinctions between the two PALNM types in published reports [2, 6, 7], is also another contributing factor to the ambiguity of an optimal management strategy for PALNM in CRC.
Resection of synchronous and metachronous CRC-associated hepatic or pulmonary metastases is now widely practised after significant evidence of improved survival and morbidity outcomes has been presented [8, 9]. However, there is relative paucity in the literature available for the surgical and non-surgical management of PALNM in CRC, with a distinct lack of published randomised controlled trials, and the predominant evidence originating from retrospective studies of which a significant amount are case reports. Several studies report the outcomes of simultaneous resection of s-PALNM and the primary CRC [10,11,12,13,14,15,16]. Although the evidence supporting this approach still remains weak, the most difficult dilemma refers to the management of m-PALNM, as resection of metachronous disease requires a second laparotomy (or laparoscopy), which could increase patients’ morbidity and mortality for a questionable benefit. The aim of this study is to review and summarise the outcomes of surgical and non-surgical management of metachronous PALNM in CRC and define the pathways for further research in this field.
Materials and methods
Eligibility criteria
Eligibility criteria were determined using the population, intervention, comparison, outcome and study design (PICOS) strategy [17]. The relevant population included patients who had a diagnosis of isolated metachronous para-aortic lymph node metastasis (m-PALNM) on imaging (computed tomography and/or magnetic resonance imaging and/or positron emission tomography). Surgical management or resection was the intervention of interest. The comparison population were patients who underwent non-surgical management. The outcomes included, but were not limited to, disease-free survival, overall survival, histological characteristics and times to recurrence. Articles which included data on both m- and s-PALNM or other metastatic sites were only included if the m-PALNM-related data could be isolated from all others. Study designs included were randomised control trials, non-randomised trials, case–control studies, cohort studies (Levels I–III evidence). Levels of evidence were delineated using the Centre for Evidence-Based Medicine’s criteria for levels of evidence for therapeutic studies. (“Appendix 1”) [18, 19].
Papers containing non-published series, papers not providing original data, papers not written in English, case series, case reports and expert opinions (levels IV and V evidence) were excluded. Other exclusion criteria were: editorials, letters, non-human studies, cadaveric studies and articles in which PALNM occurred concurrently with distant metastases.
Information sources
A literature search using Cochrane, MEDLINE, EMBASE and PubMed databases was conducted independently by one reviewer (OO) using MeSH terms: lymph node excision, para-aortic lymph node, metastasis, metachronous and colorectal neoplasms (“Appendix 2”). Studies were only included if published from the year 2000 and onwards. Bibliographies of relevant studies were searched for additional papers which met the inclusion criteria. The search strategy is summarised in the PRISMA flowchart (“Appendix 2”).
Definitions
Para-aortic lymph nodes (PALNs) were defined as lymph nodes surrounding the abdominal aorta and inferior vena cava, which were located in the area from the uppermost part of the origin of the celiac trunk to the lower margin of the aortic bifurcation [3].
Data extraction
Data were extracted on the following categories: study type, participant demographics, diagnostic modalities utilised, resection margins, primary tumour locations, tumour histology, additional therapeutic modalities utilised, surgery-related morbidity and mortality, overall survival, disease or recurrence-free survival/ interval, recurrence rates and recurrence sites.
Assessment of risk of bias
The risk of bias assessment was performed using the National Heart, Lung and Blood Institute’s (NIH) Quality Assessment Tool [20]. The tool assesses quality based on 14 questions and provides an overall quality assessment of good, fair or poor.
Synthesis of results
Data were extracted to populate a pre-defined series of tables addressing the clinical characteristics described above.
Ethics review
The protocol was reviewed by the research and development department of Central Manchester University Hospitals NHS Foundation Trust who stated that as there is no direct clinical contact, and therefore further ethics committee review was not required.
Results
Search results
The search strategy provided a total of 1897 results, which were critically reviewed for eligibility of inclusion (“Appendix 1”). A final total of 5 papers met the study criteria, with two studies originating from South Korea, and one each from Canada, France and the USA (Table 1). There were a total of 188 participants (55.3% male, 44.7% female). Surgical management for metachronous para-aortic lymph node metastasis occurred in 64% of patients (121/188), compared with non-surgical management in 36% (67/188). The location of the primary tumour was the colon in 70% of patients, and the rectum in 30%. (Table 2).
Surgery and short-term outcomes
Of the 121 patients who underwent surgical resection of m-PALNM, 100% underwent an open surgical approach (Table 2). Resection margins were R0 in 88% of patients and R1/R2 in 12% of patients. Five cases were abandoned intraoperatively (Table 3). There was a lack of consistent reporting on the amount of resected and/or positive lymph nodes. The complication rate was 40% within 30 days of surgery, including all grades of complications according to the Clavien-Dindo classification system [21]. Overall reported mortality was 0.8% within 30 days of surgery (Table 2).
Neoadjuvant and adjuvant treatment
Neoadjuvant and adjuvant therapeutic interventions involved chemotherapy (CT), radiotherapy (RT) or a combination of both. CT and RT use was variable amongst the studies (Table 4). CT regimens were also variable, which reflects the long study period of this systematic review.
Survival
Reporting styles on survival characteristics were heterogeneous. Patients undergoing surgical management for m-PALNM had longer disease-free survival (DFS) and overall survival (OS) rates. Three of the studies compared survival between surgical and non-surgical cohorts. (Table 5) Min et al. reported DFS and OS between resected and non-resected groups of 22 vs 18 months (mean, p = 0.049) and 42.5 vs 18.7 months (mean, p = 0.034) respectively [22]. Kim et al. reported DFS and OS rates between resected and non-resected groups of 24.4 months vs 21.6 months (mean, p = 0.603) and 77 vs 62 months (median, p = 0.055) respectively.[23]Shibata et al. reported 2-year and 5-year OS rates for resected vs non-resected groups of 60% vs 20% and 15% vs 0% respectively [24]. Time to m-PALNM is displayed in Table 6.
Risk of bias assessment
The NIH’s quality assessment tool for observational cohort and cross-sectional studies was utilised to assess the internal and external validity of the included studies. The overall quality was good for two studies and fair for the remaining three (Table 7). All studies lacked in the justification of sample size; however, this is reasonable as PALNM is a rare pathology, and all studies were retrospective in nature. Additionally, three studies did not adequately defined survival outcome measures [22, 24, 25], whilst one did not report the definition for PALNM [24].
Discussion
Managing metachronous para-aortic lymph node metastases (m-PALNM) requires understanding of their prognostic significance, weighing up the risk of repeat resection and complications of surgery with overall survival, and comparing surgical management with systemic therapy. As isolated metachronous PALNM is a relatively rare pathology, there is no established treatment strategy. Synchronous resection of the primary tumour (s-PALNM) seems to be less controversial [11, 14, 16, 26,27,28]. Ichikawa et al. described an increased survival rate amongst patients having radical paraaortic lymph node resection at the time of primary resection compared to those having targeted lymphadenectomy [26]. Less is known about the survival benefit of resection of metachronous PALNM. The aim of this systematic review was to summarise the outcomes of surgical and non-surgical management of metachronous PALNM in colorectal cancer (CRC) to allow patients and clinicians to make informed decisions.
At the time of submission of this article, there were two very recently published review articles. Chen et al. reviewed both synchronous PALNM (s-PALNM) and m-PALNM articles [29]. Their m-PALNM articles included four of the studies also included in this article, except the study by Razik et al. [30] This article did not include a meta-analysis or risk-of-bias assessment and focused on examining survival outcomes and post-op complications. The authors were unable to make definitive recommendations and concluded that a prospective, multicentre study would be required to fully delineate the oncological outcomes of PALND. Wang et al. similarly reviewed both s-PALNM and m-PALNM articles with a focus on overall survival (OS) and post-operative complications [31]. The authors performed a meta-analysis for survival and reported that there was a 5-year OS benefit for s-PALNM and m-PALNM resection compared to non-operative treatment. This article concluded that although PALND (synchronous or metachronous) conferred survival benefits, there is significant paucity in the available literature on PALND and large randomised trials are warranted to confirm the benefits of lymphadenectomy.
This present review is not free from limitations. The number of studies extracted from the literature search is rather small, and the overall study period ranges between 1988 and 2014. Treatment strategies have changed for both operative and non-operative management of metastatic colorectal cancer within this period. Surgical strategies for managing metastases from CRC have been more aggressive during the past two decades, and chemotherapy guidelines have changed not only in terms of timing and duration of treatment but also in terms of the recommended regimens, especially after the broad utilisation of biological agents [32]. Secondly, the included studies represent small cohorts of patients, and subsequently the evidence derived from their results is rather weak. Pooling and meta-analysing the available data in order to provide a more robust conclusion from this systematic review was not feasible due to the heterogeneity in reporting of the survival outcomes. We acknowledge that the exclusion of studies not published in the English language will have contributed to this small sample size. Also, there was significant variability in the studies with regard to reports on resection margins and the use of neoadjuvant/ adjuvant chemotherapy and radiation, which makes the results difficult to generalise.
Despite the above limitations it is worth highlighting that resection of m-PALMN is reported to be a safe operation despite the fact that patients with recurrent disease undergo a second surgical procedure in a relatively short period after their colectomy. According to older reports, surgical resection for m-PALNM was thought to carry a high risk of complications [15], but this systematic review shows a 40% risk of complications of all grades and a low 30-day mortality rate of 0.8%. Given the fact that resection of m-PALMN has been reported to be open surgery in 100% of the cases, these morbidity and mortality rates should be considered reasonable.
Most importantly, this systematic review has demonstrated a significantly improved overall survival in patients undergoing surgical resection for m-PALNM compared to non-operative strategies. This is supported by three out of the five included studies, which compared survival outcomes between surgical and non-surgical management. Clear resection margins were reported in 88% of the cases, which is in keeping with the overall survival benefit observed after surgical management of m-PALNM.
In conclusion, the available evidence, as reported by this systematic review, suggests that surgical management of m-PALNM should be considered a safe procedure aiming to prolong survival. Based on the so far reported outcomes, a future randomised trial would be a safe and ethical step forward to provide more evidence in this field, ideally in a multicentre setting due to the low incidence of m-PALNM. In the era of multimodality treatment for metastatic colorectal cancer, surgical management of isolated metachronous lymph node metastases definitely represents a considerable option in carefully selected patients.
Data Availability
The data used in this study is publicly available.
References
Watanabe T, Itabashi M, Shimada Y, Tanaka S, Ito Y, Ajioka Y et al (2012) Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer. Int J Clin Oncol 17(1):1–29
Choi PW, Kim HC, Kim AY, Jung SH, Yu CS, Kim JC (2010) Extensive lymphadenectomy in colorectal cancer with isolated para-aortic lymph node metastasis below the level of renal vessels. J Surg Oncol 101(1):66–71
Committee on Classification of Regional Lymph Nodes of Japan Society of Clinical Oncology. (2023) Classification of regional lymph nodes in Japan. International journal of clinical oncology. 8(4):248–75
Edge SB BD, Compton CC et al. (Eds.). AJCC (American Joint Committee on Cancer) Cancer Staging Manual. Seventh Edition ed. New York: Springer; 2010.
Kumar R, Price TJ, Beeke C, Jain K, Patel G, Padbury R et al (2014) Colorectal cancer survival: an analysis of patients with metastatic disease synchronous and metachronous with the primary tumor. Clin Colorectal Cancer 13(2):87–93
Gagnière J, Dupré A, Chabaud S, Peyrat P, Meeus P, Rivoire M (2015) Retroperitoneal nodal metastases from colorectal cancer: curable metastases with radical retroperitoneal lymphadenectomy in selected patients. Europ J Surg Oncol 41(6):731–737
Arimoto A, Uehara K, Kato T, Nakamura H, Kamiya T, Nagino M (2015) Clinical significance of para-aortic lymph node dissection for advanced or metastatic colorectal cancer in the current era of modern chemotherapy. Dig Surg 32(6):439–444
Li J, Yuan Y, Yang F et al (2019) Expert consensus on multidisciplinary therapy of colorectal cancer with lung metastases. J Hematol Oncol 12(1):16. https://doi.org/10.1186/s13045-019-0702-0
Minagawa M, Makuuchi M, Torzilli G, Takayama T, Kawasaki S, Kosuge T et al (2000) Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer: long-term results. Ann Surg 231(4):487–499
Song SH, Park SY, Park JS, Kim HJ, Yang CS, Choi GS (2016) Laparoscopic para-aortic lymph node dissection for patients with primary colorectal cancer and clinically suspected para-aortic lymph nodes. Ann Surg Treatment Res 90(1):29–35
Lee SH, Lee JL, Kim CW, Lee HI, Yu CS, Kim JC (2017) Oncologic significance of para-aortic lymph node and inferior mesenteric lymph node metastasis in sigmoid and rectal adenocarcinoma. Europ J Surg Oncol 43(11):2076–2083
Lee J, Park HM, Lee SY, Kim CH, Kim HR (2021) Prognostic significance of enlarged paraaortic lymph nodes detected during left-sided colorectal cancer surgery: a single-center retrospective cohort study. World J Surg Oncol 19(1):9
Ushigome H, Yasui M, Ohue M, Haraguchi N, Nishimura J, Sugimura K et al (2020) The treatment strategy of R0 resection in colorectal cancer with synchronous para-aortic lymph node metastasis. World J Surg Oncol 18(1):229
Yamada K, Tsukamoto S, Ochiai H, Shida D, Kanemitsu Y (2019) Improving selection for resection of synchronous para-aortic lymph node metastases in colorectal cancer. Dig Surg 36(5):369–375
Yamamoto S, Kanai T, Yo K, Hongo K, Takano K, Tsutsui M et al (2019) Laparoscopic para-aortic lymphadenectomy for colorectal cancer with clinically suspected lymph node metastasis. Asian J Endoscopic Surg 12(4):417–422
Sahara K, Watanabe J, Ishibe A, Suwa Y, Suwa H, Ota M et al (2019) Long-term outcome and prognostic factors for patients with para-aortic lymph node dissection in left-sided colorectal cancer. Int J Colorectal Dis 34(6):1121–1129
Eriksen MB, Frandsen TF (2018) The impact of patient, intervention, comparison, outcome (PICO) as a search strategy tool on literature search quality: a systematic review. J Med Lib Ass: JMLA 106(4):420–431
Burns PB, Rohrich RJ, Chung KC (2011) The levels of evidence and their role in evidence-based medicine. Plast Reconstr Surg 128(1):305–310
Centre for Evidence-Based Medicine. Oxford Centre for Evidence-Based Medicine: levels of evidence (March 2009) https://www.cebm.ox.ac.uk/resources/levels-of-evidence/oxford-centre-for-evidence-based-medicine-levels-of-evidence-march-2009: Centre for Evidence-Based Medicine; 2009 [Available from: https://www.cebm.ox.ac.uk/resources/levels-of-evidence/oxford-centre-for-evidence-based-medicine-levels-of-evidence-march-2009.
Ma L-L, Wang Y-Y, Yang Z-H, Huang D, Weng H, Zeng X-T (2020) Methodological quality (risk of bias) assessment tools for primary and secondary medical studies: what are they and which is better? Mil Med Res 7(1):7
Dindo D, Demartines N, Clavien PA (2004) Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240(2):205–213
Min BS, Kim NK, Sohn SK, Cho CH, Lee KY, Baik SH (2008) Isolated paraaortic lymph-node recurrence after the curative resection of colorectal carcinoma. J Surg Oncol 97(2):136–140
Kim YI, Park IJ, Park JH et al (2020) Management of isolated para-aortic lymph node recurrence after surgery for colorectal cancer. Ann Surg Treat Res 98(3):130–138. https://doi.org/10.4174/astr.2020.98.3.130
Shibata D, Paty PB, Guillem JG, Wong WD, Cohen AM (2002) Surgical management of isolated retroperitoneal recurrences of colorectal carcinoma. Dis Colon Rectum 45(6):795–801
Dumont F, Kothodinis K, Goéré D, Honoré C, Dartigues P, Boige V et al (2012) Central retroperitoneal recurrences from colorectal cancer: are lymph node and locoregional recurrences the same disease? Europ J Surg Oncol 38(7):611–616
Ichikawa Y, Takahashi H, Fujii M, Hata T, Ogino T, Miyoshi N et al (2021) Radical lymphadenectomy of a para-aorta lymph node metastasis in colorectal cancer prolongs relapse-free survival. Int J Colorectal Dis 36(7):1551–1560
Bae SU, Han YD, Cho MS, Hur H, Min BS, Baik SH et al (2016) Oncologic outcomes of colon cancer patients with extraregional lymph node metastasis: comparison of isolated paraaortic lymph node metastasis with resectable liver metastasis. Ann Surg Oncol 23(5):1562–1568
Bae SU, Hur H, Min BS, Baik SH, Lee KY, Kim NK (2018) Which patients with isolated para-aortic lymph node metastasis will truly benefit from extended lymph node dissection for colon cancer? Cancer Res Treat 50(3):712–719
Chen MZ, Tay YK, Prabhakaran S et al. The management of clinically suspicious para-aortic lymph node metastasis in colorectal cancer: A systematic review. Asia Pac J Clin Oncol 19(6):596–605. https://doi.org/10.1111/ajco.13924
Razik R, Zih FS, Haase E, Mathieson A, Sandhu L, Cummings B et al (2014) Long-term outcomes following resection of retroperitoneal recurrence of colorectal cancer. Europ J Surg Oncol 40(6):739–746
Wang RC, Wang JQ, Zhou XY, Zhong CL, Chen JX, Chen JS (2023) Survival benefits of para-aortic lymphadenectomy in colorectal cancer with clinically suspected para-aortic lymph node metastasis: a meta-analysis and systematic review. World J Surg Oncol 21(1):28
National Institute for Health and Care Excellence. Colorectal cancer NICE guideline [NG151]: National Institute for Health and Care Excellence; 2021 [updated December 15th 2021; cited 2022. Available from: https://www.nice.org.uk/guidance/ng151.
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Study conception and design: MB, TS. Acquisition of data: OOO. Analysis and interpretation of data: MB, OOO, JR, AP. Drafting of manuscript: OOO, MB, JR, AP. Critical revision of manuscript: MB, TS.
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Appendices
Appendix 1
Centre for Evidence-Based Medicine’s criteria for levels of evidence for therapeutic studies.
Level | Evidence |
---|---|
1a | Systematic review (with homogeneity) of randomised controlled trials (RCT) |
1b | Individual randomised controlled trial (with narrow confidence interval) |
1c | All or none |
2a | Systematic review (with homogeneity) of cohort studies |
2b | Individual cohort study (including low quality RCT; e.g. < 80% follow-up) |
2c | “Outcomes” research; ecological studies |
3a | Systematic review (with homogeneity) of case–control studies |
3b | Individual case–control study |
4 | Case-series (and poor quality cohort and case–control studies) |
5 | Expert opinion without explicit critical appraisal, or based on physiology, bench research or “first principles” |
Appendix 2
Preferred reporting items for systematic reviews (PRISMA) flow chart.
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Onafowokan, O.O., Redfern, J., Patel, A. et al. Outcomes of metachronous para-aortic lymphadenectomy in colorectal cancer: a systematic review of the literature. Langenbecks Arch Surg 409, 4 (2024). https://doi.org/10.1007/s00423-023-03185-9
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DOI: https://doi.org/10.1007/s00423-023-03185-9