Does a Distal Surgical Margin Closer than 10 mm Increase the Risk of Recurrence in Locally Advanced Rectal Cancer in a Mid-Distal Location?

Latif Volkan Tümay; Osman Serhat Güner; Abdullah Zorluoğlu

doi:10.4274/tjcd.galenos.2020.2020-3-10

ABSTRACT

Aim:

Although many factors affecting recurrence, including surgical margin involvement, have been considered in rectum cancer surgery, there is no consensus on the definition of a safe distal surgical margin (DSM).We aimed to investigate the oncological safety of a DSM closer than 10 mm and the factors affecting relapse in mid-distal located rectum tumours.

Method:

Patients who underwent sphincter-preserving rectal curative resection following neoadjuvant chemoradiotheraphy between February 2006 and June 2019 for mid-distal lying rectum tumours were investigated retrospectively. Patients with radial or distal surgical margin involvement, having a complete pathologic response, or being lost to follow-up were excluded from the study. Patients and tumour characteristics, clinical and pathological disease stages, and recurrence and disease-free survival rates were compared between groups created along a cut-off value of 10 mm in DSM (DSM <10 and DSM ≥10).

Results:

The study group consisted of 23 patients (DSM <10, n=11; DSM ≥10, n=12). Most of the tumours were located distally (70% , n=16). Handsewn anastomosis was performed in 81.8% of patients in the DSM <10 group (Turnbull-Cutait, n=5; coloanal anastomosis, n=4) and in 33% of patients in the DSM ≥10 group (Turnbull-Cutait, n=2; coloanal anastomosis, n=2). During a median follow-up time of 72 (6-158) months, three cases of systemic recurrence developed while no local recurrence was faced. The recurrence rates and disease-free survival rates were similar (p=0.17 and p=0.184, respectively). Younger age, bulkier tumour, presence of perineural invasion, ypN stage, and number of metastatic lymph nodes were associated with recurrence (p=0.017, p=0.00, p=0.014, p=0.030, and p=0.024, respectively).

Conclusion:

Our study supports the view that obtaining a DSM closer than 10 mm but without tumour can be sufficient in terms of oncological safety, allowing permanent colostomy to be avoided. Young age, large tumour size, presence of perineural invasion and increased number of metastatic lymph nodes stand out as risk factors for recurrence.

Keywords:

Distal surgical margin, rectum cancer, recurrence, risk factor

Introduction

Significant improvement was achieved in local recurrence and survival rates for distally located rectal cancer surgery through neoadjuvant chemoradiotherapy (CRT) and the total mesorectal excision technique (TME) defined by Heald et al.¹ The development of stapler devices made it possible to perform even more sphincter-sparing surgery.

Despite these developments, it has been proven that there is microscopic involvement in up to 33% of resection margins and that the radial surgical margin (RSM) involvement adversely affects overall survival (OS) and disease-free survival (DFS).² Although the correlation of the distal surgical margin (DSM) with oncological outcomes has been examined in many publications, there is no exact distance accepted.³ It is known that tumours can spread intramurally to a distance of 1 cm from the macroscopic margin.⁴ In distal rectum cancer, surgeons try to achieve a minimum of a 2-cm DSM. While patients quality of life improves without stoma, it is not always possible to obtain a DSM of minimum 1 cm.

In our study, we aimed primarily to investigate the oncological reliability of DSM < 10 mm in patients with mid-distal rectal cancer who underwent sphincter-sparing curative surgery after neoadjuvant CRT. Secondarily, we investigated factors affecting recurrence in this group of patients.

Materials and Methods

Results

A total of 23 patients (14 males and 9 females) were followed up on for a median of 72 (6-158) months. The median DSM in the whole study group was 10 mm (1-30). In 11 patients, DSM was found to be less than 10 mm (median 4 [1-5]), while in 12 patients, DSM was more than 10 mm (median 25 [10-30]). Tumours were in distal localization in approximately 70% (n=16) of the patients. While anastomoses were made manually (Turnbull-Cutait, n=5; coloanal anastomosis, n=4) in 9 (81.8%) patients in the DSM <10 mm group, manual reconstruction was performed in 4 (33%) patients in the DSM ≥10 mm group (Turnbull-Cutait, n=2; coloanal anastomosis, n=2). The demographic characteristics of the patients, tumour location, tumour diameter, and RSM and DSM distances are summarized in Table 1. In the DSM <10 mm group, it was observed that the number of females was significantly higher than males (n=7 vs n=2, p=0.036). There was no significant difference between other parameters. The biological properties of the tumours are detailed in Table 2. Extramural venous invasion was not detected in any of the patients. When lymphatic and venous invasion were combined as lymphovascular invasion (LVI), LVI was detected in three patients, and no relation was found between LVI and recurrence (r=0.150, n=23, p=0.474; Spearman’s rho correlation test). Tumour characteristics, LN numbers removed and metastatic LN numbers were similar between groups. The distribution of the clinical and pathological stages is summarized in Table 3. There was a significant difference between the groups only in terms of the ypN status (p=0.046).

While there was no local recurrence in any of the patients, three systemic relapses were detected in the group with DSM ≥10 mm. Liver and bone metastases developed in one patient after 8 months, and the patient died at the end of the 14^th month. This patient was also the only patient who died in our study group. Lung metastasis developed at the end of the 43^rd month in the second patient and liver metastasis at the 60^thmonth in the third patient. During the median follow-up period of 72 (6-158) months, the systemic recurrence rate was 13.0% and the overall survival rate was 95.7%; there was no significant difference between the groups in terms of OS and DFS (Table 1). When the factors associated with recurrence were examined, there was a significant relationship between the presence of perineural invasion (PNI) (r=0.503, p=0.014), age (r= -0.492, p=0.017), large tumour diameter (r=0.575, p=0.004), pN stage (r=0.452, p=0.030), and metastatic LN number (r=0.469, p=0.024) (Tables 1, 2, 3).

Discussion

In our study, it was observed that obtaining a DSM of less than 10 mm in sphincter-preserving resections performed after neoadjuvant CRT in locally advanced rectal cancer did not pose an oncological risk, and the presence of large tumours, young age, metastatic LN count and PNI increased the risk of systemic recurrence.

After the application of the TME technique in rectal cancer, the 5-year local recurrence rate decreases to 4-6%, while systemic recurrence rates are around 20%.⁶ Factors affecting relapse have been considered in many studies: LVI, extramural venous invasion, metastatic LN number, PNI and especially RSM positivity have been considered as risk factors.^{2,7,8,9,10,11,12} DSM stands out as another factor affecting the decision for sphincter-sparing surgery in patients without RSM involvement. In cases of involvement, the 5-year local recurrence rate increases to 24.1%, and the systemic recurrence rate increases to 35.5%.¹³ Consensus has not been reached on the minimum safe distance. Repeated attempts at the treatment of local recurrence in rectal cancer have a low chance of success.¹⁴ For this reason, surgeons may prefer the APR technique, especially if DSM <10 mm is detected. However, life with a permanent stoma is not the first choice of any individual.

In the current NCCN rectal cancer guidelines, it is recommended to obtain a DSM of 5 cm for upper rectum tumours and 10-20 mm for sphincter-sparing surgery for middle and distal rectal tumours.³ Sufficient DSM is associated with intramural and distal mesorectal lymphatic spread.⁴ Distal intramural spread (DIS) rarely exceeds 2-3 cm.¹⁰ Apart from its direct effect on mesorectal invasion, it has been found that there is a significant relationship between DIS, the number of metastatic LNs, T stage and tumour diameter.^9,15,16 LN metastasis plays a role in mesorectal tumour spread independent of DIS.¹⁷ These results suggest that the risk of local recurrence may especially increase at a distance of <1 cm in patients with locally advanced disease.

No local recurrence was detected in any of the patients during a median follow-up period of 72 (6–158) months, while systemic recurrence was detected in 3 patients in the DSM ≥10 mm group. No statistically significant difference was found between the groups in terms of recurrence, DFS and OS (Table 1, Figure 2). However, considering that a minimum follow-up period of 5 years is required to detect 80% of local recurrences, the median follow-up period of 29 months for the group with DSM <10 mm may be misleading.¹⁸ In a recent study of 88 patients with similar methodology, the local recurrence rate was 6.1% in the DSM <10 mm group and 5.5% in the DSM ≥10 mm group, which suggested that the results might change in the following period.¹⁹ Another reason for the absence of local recurrence in our series might be performing APR in patients with worse pathological features (LVI, PNI, surgical margin positivity, poor differentiation).^17,20 In accordance with our methodology, there was no positive surgical margin and no extramural venous invasion in our study. The rates of LVI, PNI and poor differentiation were 13.4%, 17.4% and 21.7%, respectively.

It has been shown that tumour regression may occur in a scattered manner and small tumour deposits may remain after neoadjuvant CRT.^15,21,22 Mezhir et al.¹⁶ calculated this rate as 55% and reported that DIS rarely exceeded 1 cm. Chiemelik et al.²³ found similar DIS (57%) rates and recommended a minimum DSM of 1 cm. Despite these findings, many clinical studies reported that DSM <1 cm did not increase the risk of recurrence.^{4,9,11,17,18,19} Manegold et al.¹⁹ reported that there was no difference between the groups in terms of recurrence when the 1 cm threshold was accepted for DSM following neoadjuvant CRT. Although similar results were reported in the Polish cohort study, it was a handicap to include patients with short- and long-term CRT without subgrouping in the study design.²⁴ It has been suggested to obtain 5 mm DSM by Kusters et al.¹⁷ Han et al.¹¹ reported that DSM <1 cm did not increase local and systemic recurrence, even in patients not given RT. In another study sharing similar results, it was noted that the absence of neoadjuvant CRT increased the risk of local recurrence 2.2 times.²⁵ Andreola et al.⁹ reported that DSM did not pose a risk for recurrence other than margin positivity,and Bujko et al.⁴ reached the same result in a systematic review.

There are also authors who find DSM <1 cm risky.^12,13,26 Farhat et al.²⁶ reported that DSM increased recurrence. There were no homogeneous groups in that study because patients with stage 4 disease and patients who underwent APR and local excision were included. In another study, which reported that DSM < 8 mm increased the risk of recurrence, it was not possible to associate DSM with the results; this is because RSM positivity was included and patients with upper rectum tumours and stage 4 disease were included.¹² Zeng et al.¹³ reported 12.4% local and 26.4% systemic recurrence in the median 61 month follow-up period in patients with a distal margin of 1-2 mm. Although 80% of the patients in the study group consisted of individuals with stage 2-3 disease, the neoadjuvant CRT ratio was 21.6%, leading to the results being questioned.

When the factors were examined that affected the recurrence of patients who underwent sphincter-sparing resection after neoadjuvant CRT, which was our secondary aim, a significant relationship was found between young age, large tumour size, number of LN metastases, presence of PNI and recurrence. The relationship between age and recurrence is a frequently studied parameter, and it is accepted that recurrence increases and survival is shortened under the age of 55 years.^27,28 In our series, the median ages of the patients with and without recurrence were found to be 37 (30-51) and 56 (33-73) years, respectively. It was observed that there was a significant negative correlation between age and recurrence (Table 1).

Although it is accepted that tumour size has an effect on the recurrence of colon tumours, the same relationship has not been generally accepted in rectal tumours. Few publications have reported that tumour diameter > 5 cm is a prognostic risk factor and is associated with the T stage.^29,30 In our series, tumour diameters in patients with and without recurrence were 4.4±2.2 and 2.0±0.8 cm, respectively (measured as mean ± standard deviation). A significant relationship was found between size and recurrence (Table 1). However, no relationship was found between the cT/pT stage and recurrence (Table 3).

It is known that LN metastasis increases recurrence in rectal cancer.^{2,8,9,10,11,12,17,25,31} In our study, it was observed that the ypN stage was significantly higher in the DSM ≥10 mm group (p=0.046) and was significantly associated with recurrence (Table 3). The mean ± standard deviation numbers of metastatic LN in patients with and without recurrence were found to be 8.0±7.2 and 1.4±4.0, respectively. The relationship between the number of metastatic LNs and recurrence was confirmed in the analysis performed on the numerical parameters (Table 2). Our findings supported the negative role of LN metastases in recurrence.

Another independent prognostic factor that is accepted in colorectal malignancies is the presence of PNI.^8,13,25 In a recent study, it was observed that many structures, including lymph nodes, were shrunk or disappeared with neoadjuvant CRT, while the presence of PNI did not change.³¹ Based on this, the author suggested that the presence of PNI might be associated with radioresistant cells and a poor prognosis. In our series, 3 (75%) of 4 patients with PNI had LN metastasis and a strong correlation was observed between PNI and recurrence (Table 2).

“Should the stapler doughnuts be part of the surgical margin?” is a common topic of discussion. Stapler doughnut involvement is an independent determinant of OS in proximal gastrointestinal malignancy surgery.³² However, its role in rectal surgery is being discussed with increasing frequency after Pullyblank et al.³³ suggested that histological examination of the stapler doughnut has no effect on treatment. Many researchers have reported similar results, and it has even been suggested that this investigation causes a waste of time and resources.^34,35,36 Technically, the stapler doughnut cannot fully reflect the surgical margin as it cannot surround the entire rectal stump. Therefore, it is recommended to consider the surgical margin as positive in patients with margin involvement but without stapler doughnut involvement.³⁷ Apart from these considerations, the fact that there is not enough tissue left to use for the stapler in distally located tumours is another technical difficulty. In our study, reconstruction was performed manually in approximately 82% of patients with DSM <10 mm.

Study Limitations

The limitations of our study were the 29-month median follow-up period of the target group, retrospective and single-centre study design, and the low number of patients. It should be kept in mind that the absence of extramural venous invasion and low number of patients with LVI (n=3), which are among the factors known to be effective on recurrence, in our study group may have affected our recurrence results.

The decision about surgical method in locally advanced rectal cancers is multi-factorial and complex. Oncologically safe DSM distance is controversial in mid-distal rectal cancer surgery. Controversial results may arise from differences in surgical experience, patient density, and treatment protocols as well as methodological differences. Considering the functional results, the remaining distance is more important than the removed one. Intersphincteric or partial sphincteric resections can reduce quality of life while enabling life without stoma. For a comfortable life, surgeons sometimes prefer to approach the tumour. As the evidence for safe DSM becomes more sufficient, there will be changes in our surgical practice. Before making a decision about APR, the involvement of the sphincter, the presence of poor prognostic factors, the presence of negative surgical margins and patient preferences should be evaluated in detail.

Conclusion

In this study, it was observed that DSM <10 mm did not pose an oncological risk, provided that all surgical boundaries were clean. Young age, presence of perineural invasion, metastatic LN number and large tumour diameter were identified as risk factors associated with recurrence.

References

Heald RJ, Husband EM, Ryall RD. The mesorectum in rectal cancer surgery -- the clue to pelvic recurrence? Br J Surg 1982;69:613-616.

Nagtegaal ID, Quirke P. What is the role for the circumferential margin in the modern treatment of rectal cancer? J Clin Oncol 2008;26:303-312.

NCCN Clinical Practice Guidelines in Rectal Cancer.version 2.2020 — March 3, 2020. https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf

Bujko K, Rutkowski A, Chang GJ, Michalski W, Chmielik E, Kusnierz J. Is the 1-cm Rule of Distal Bowel Resection Margin in Rectal Cancer Based on Clinical Evidence? A Systematic Review. Ann Surg Oncol 2012;19:801-808.

Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, Meyer L, Gress DM, Byrd DR, Winchester DP. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin 2017;67:93-99.

Heald RJ, Ryall RD. Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1986;1:1479-1482.

Talbot IC, Ritchie S, Leighton MH, Hughes AO, Bussey HJ, Morson BC. The clinical significance of invasion of veins by rectal cancer. Br J Surg 1980;67:439-442.

Liebig C, Ayala G, Wilks J, Verstovsek G, Liu H, Agarwal N, Berger DH, Albo D. Perineural Invasion Is an Independent Predictor of Outcome in Colorectal Cancer. J Clin Oncol 2009;31:5131-5137.

Andreola S, Leo E, Belli F, Lavarino C, Bufalino R, Tomasic G, Baldini MT, Valvo F, Navarria P, Lombardi F. Distal intramural spread in adenocarcinoma of the lower third of the rectum treated with total rectal resection and coloanal anastomosis. Dis Colon Rectum 1997;40:25-29.

Scott N, Jackson P, al-Jaberi T, Dixon MF, Quirke P. Total mesorectal excision and local recurrence: a study of tumour spread in the mesorectum distal to rectal cancer. Br J Surg 1995;82:1031-1033.

Han JW, Lee MJ, Park HK, Shin JH, An MS, Ha TK, Kim KH, Bae KB, Kim TH, Choi CS, Oh SH, Oh MK, Kang MS, Hong KH. Association Between a Close Distal Resection Margin and Recurrence After a Sphincter-Saving Resection for T3 Mid- or Low-Rectal Cancer Without Radiotherapy. Ann Coloproctol 2013;29:231-237.

Nash GM, Weiss A, Dasgupta R, Gonen M, Guillem JG, Wong WD. Close Distal Margin and Rectal Cancer Recurrence After Sphincter-Preserving Rectal Resection. Dis Colon Rectum 2010;53:1365-1373.

Zeng WG, Liu MJ, Zhou ZX, Wang ZJ. A Distal Resection Margin of ≤1 mm and Rectal Cancer Recurrence After Sphincter-Preserving Surgery: The Role of a Positive Distal Margin in Rectal Cancer Surgery. Dis Colon Rectum 2017;60:1175-1183.

Stipa S, Nicolanti V, Botti C, Cosimelli M, Mannella E, Stipa F, Giannarelli D, Bangrazi C, Cavaliere R. Local recurrence after curative resection for colorectal cancer: frequency, risk factors and treatment. J Surg Oncol Suppl 1991;2:155-160.

Wang Z, Zhou ZG, Wang C, Zhao GP, Chen YD, Gao HK, Zheng XL, Wang R, Chen DY, Liu WP. Microscopic spread of low rectal cancer in regions of the mesorectum: detailed pathological assessment with whole-mount sections. World J Gastroenterol 2004;10:2949-2953.

Mezhir JJ, Smith KD, Fichera A, Hart J, Posner MC, Hurst RD. Presence of distal intramural spread after preoperative combined-modality therapy for adenocarcinoma of the rectum: What is now the appropriate distal resection margin? Surgery 2005;138:658-664.

Kusters M, Marijnen CA, van de Velde CJ, Rutten HJ, Lahaye MJ, Kim JH, Beets-Tan RG, Beets GL. Patterns of local recurrence in rectal cancer; a study of the Dutch TME trial. Eur J Surg Oncol (EJSO) 2010;36:470-476.

Moore HG, Riedel E, Minsky BD, Saltz L, Paty P, Wong D, Cohen AM, Guillem JG. Adequacy of 1-cm Distal Margin After Restorative Rectal Cancer Resection With Sharp Mesorectal Excision and Preoperative Combined-Modality Therapy. Ann Surg Oncol 2003;10:80-85.

Manegold P, Taukert J, Neeff H, Fichtner-Feigl S, Thomusch O. The minimum distal resection margin in rectal cancer surgery and its impact on local recurrence - A retrospective cohort analysis. Int J Surg 2019;69:77-83.

Ngan SY, Burmeister B, Fisher RJ, Solomon M, Goldstein D, Joseph D, Ackland SP, Schache D, McClure B, McLachlan SA, McKendrick J, Leong T, Hartopeanu C, Zalcberg J, Mackay J. Randomized Trial of Short-Course Radiotherapy Versus Long-Course Chemoradiation Comparing Rates of Local Recurrence in Patients With T3 Rectal Cancer: Trans-Tasman Radiation Oncology Group Trial 01.04. J Clin Oncol 2012;30:3827-3833.

Hayden DM, Jakate S, Pinzon MC, Giusto D, Francescatti AB, Brand MI, Saclarides TJ. Tumor scatter after neoadjuvant therapy for rectal cancer: are we dealing with an invisible margin? Dis Colon Rectum 2012;55:1206-1212.

Smith FM, Wiland H, Mace A, Pai RK, Kalady MF. Depth and lateral spread of microscopic residual rectal cancer after neoadjuvant chemoradiation: implications for treatment decisions. Colorectal Dis 2014;16:610-615.

Chmielik E, Bujko K, Nasierowska-Guttmejer A, Nowacki MP, Kepka L, Sopylo R, Wojnar A, Majewski P, Sygut J, Karmolinski A, Huzarski T, Wandzel P. Distal intramural spread of rectal cancer after preoperative radiotherapy: the results of a multicenter randomized clinical study. Int J Radiat Oncol Biol Phys 2006;65:182-188.

Rutkowski A, Bujko K, Nowacki MP, Chmielik E, Nasierowska-Guttmejer A, Wojnar A; Polish Colorectal Study Group. Distal bowel surgical margin shorter than 1 cm after preoperative radiation for rectal cancer: is it safe? Ann Surg Oncol 2008;15:3124-3131.

Lim JW, Chew MH, Lim KH, Tang CL. Close distal margins do not increase rectal cancer recurrence after sphincter-saving surgery without neoadjuvant therapy. Int J Colorectal Dis 2012;27:1285-1294.

Farhat W, Azzaza M, Mizouni A, Ammar H, Ben Ltaifa M, Lagha S, Kahloul M, Gupta R, Mabrouk MB, Ali AB. Factors predicting recurrence after curative resection for rectal cancer: a 16-year study. World J Surg Onc 2019;17:173.

Steele SR, Park GE, Johnson EK, Martin MJ, Stojadinovic A, Maykel JA, Causey MW. The impact of age on colorectal cancer incidence, treatment, and outcomes in an equal-access health care system. Dis Colon Rectum 2014;57:303-310.

Holmes AC, Riis AH, Erichsen R, Fedirko V, Ostenfeld EB, Vyberg M, Thorlacius-Ussing O, Lash TL. Descriptive characteristics of colon and rectal cancer recurrence in a Danish population-based study. Acta Oncol 2017;56:1111-1119.

Chen CH, Hsieh MC, Hsiao PK, Lin EK, Lu YJ, Wu SY. A critical reappraisal for the value of tumor size as a prognostic variable in rectal adenocarcinoma. J Cancer 2017;8:1927-1934.

Jiang Y, You K, Qiu X, Bi Z, Mo H, Li L, Liu Y. Tumor volume predicts local recurrence in early rectal cancer treated with radical resection: A retrospective observational study of 270 patients. Int J Surg 2018;49:68-73.

Kim CH, Yeom SS, Lee SY, Kim HR, Kim YJ, Lee KH, Lee JH. Prognostic Impact of Perineural Invasion in Rectal Cancer After Neoadjuvant Chemoradiotherapy. World J Surg 2019;43:260-272.

Sillah K, Griffiths EA, Pritchard SA, Swindell R, West CM, Page R, Welch IM. Clinical impact of tumour involvement of the anastomotic doughnut in oesophagogastric cancer surgery. Ann R Coll Surg Engl 2009;91:195-200.

Pullyblank AM, Kirwan C, Rigby HS, Dixon AR. Is routine histological reporting of doughnuts justified after anterior resection for colorectal cancer? Colorectal Dis 2001;3:198-200.

Sugrue J, Dagbert F, Park J, Marecik S, Prasad LM, Chaudhry V, Blumetti J, Emmadi R, Mellgren A, Nordenstam J. No clinical benefit from routine histologic examination of stapler doughnuts at low anterior resection for rectal cancer. Surgery 2017;162:147-151.

Speake WJ, Abercrombie JF. Should ’doughnut’ histology be routinely performed following anterior resection for rectal cancer? Ann R Coll Surg Engl 2003;85:26-27.

Morgan A, Dawson PM, Smith JJ. Histological examination of circular stapled ’doughnuts’: questionable routine practice? Surgeon 2006;4:75-77.

Rutkowski A, Nowacki MP, Chwalinski M, Oledzki J, Bednarczyk M, Liszka-Dalecki P, Gornicki A, Bujko K. Acceptance of a 5-mm distal bowel resection margin for rectal cancer: is it safe? Colorectal Dis 2012;14:71-78.