Rectal carcinoma is one of the commonest forms of cancer in both men and women in the Western world and the second most common cause of death. Even when disease is still localised and surgical resection is considered curative, survival is approximately 60% at 5 years and approximately 50% at 10 years.1 Although disseminated disease is the most common cause of death, local recurrence causes severe disabling symptoms, is difficult to treat and is often fatal.2,3 Local control (
Historically, the standard guidelines recommended DRM of at least 4–5 cm, which meant that sphincter-preserving rectal resection for low lying rectal cancers was practically non-existent. In 1982, Heald published his monumental work in which he recommended the removal of the entire mesorectum with sharp dissection under direct vision, a technique that became known as total mesorectal excision (TME). This ingenious technique, when done properly (
Thus, the previously applicable 5 cm rule was gradually modified to 2 cm and later with advances in surgical techniques to 1 cm rule or even less.6,7 Preoperative long course chemoradiotherapy (CRT) using 5-fluorouracil (5-FU) regimen has since emerged as the standard of care for patients with locally advanced lower and middle rectal cancer (LARC).8,9 To date, the refinements in management have led to a decrease in local recurrence rates from 25–40% to less than 6%. Seventy-five percent of local recurrences are detected within two years of diagnosing the primary tumour. Around 20% to 50% of patients with local recurrences have isolated recurrent disease without distant metastases.10,11
Several reports have shown that in approximately one fourth of cases (6.5–58%) there is a substantial, microscopical distal intramural spread of tumour cells (DIS). Whenever DIS is present, it is limited to within 2 cm in 95% of all patients. Rarely does it extend for more than 2 cm in nonirradiated tumours. When it does, it is associated with advanced disease and poor long- term prognosis even when all resection margins are free of disease.12,13 Similarly, not often does DIS extend more than 1 cm from the distal edge of the gross tumour in rectal cancer patients treated with preoperative CRT. When it does, the clinical course of such patients is usually worse, because they rapidly develop distant metastases or/ and locally recurrent disease, regardless of DRM length.14 This finding suggests that tumour biology as opposed to resection margin determines the ultimate outcome.15
A positive or close circumferential resection margin is strongly associated with local and metastatic recurrence despite CRT and TME.16,17 By contrast, the association of close DRM and its influence on recurrence and long term survival is less clear, with somewhat conflicting reports.18 Many centres around the world, including our own two Tertiary Referral Centres (University Medical Centre Ljubljana, Institute of Oncology Ljubljana) have accepted close (1 cm or even less) DRMs as oncologically safe in an effort to maximize the eligibility of patients for sphincter-preserving rectal resection.
The aim of our study was to find out whether the length of the distal resection margin (DRM) has any influence on local recurrence rate and long-term survival among patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy and sphincter-preserving rectal resection.
Between January 2006 and December 2010, 109 patients who had undergone preoperative CRT and sphincter-preserving rectal resection at two Slovene Tertiary Referral centres (University Medical Centre Ljubljana and Institute of Oncology Ljubljana) were included in our study. We included patients with histologically confirmed rectal adenocarcinoma, confined to the lower and middle third of the rectum without distant disease (M0). Patients had to have had a stage II or stage III disease, confirmed with magnetic resonance imaging (MRI) of the pelvis. Patients enrolled in the study were not supposed to have previously received radiotherapy, chemotherapy or any targeted therapy for rectal cancer. We excluded patients who had other co-existing malignancies or a malignancy within the last 5 years prior to the enrolment other than non-melanoma skin cancer or
Pre-treatment work-up consisted of a complete history, physical examination, complete blood count and serum biochemistry, carcinoembryonic antigen (CEA), chest radiography and ultrasonography or computed tomography (CT) scan of the entire abdomen. MRI was done for primary tumour and nodal staging. After discharge, followup visits were scheduled every 3 months for the first 2 years, every 6 months during the 2.–5. year, and yearly thereafter. Physical examination, CEA determination, colonoscopy, chest radiography and ultrasonography or/ and CT scan of the whole abdomen were performed. Recurrences were confirmed pathologically and/ or by sequential imaging with positron emission tomography or MRI.19
Patient data and histological tumour characteristics were prospectively collected. The study itself was retrospective and was approved by the National Ethics Committee (#61/09/14).
Surgery was performed 6–8 weeks after completion of preoperative CRT. All operations were performed by qualified, experienced colorectal surgeons who performed total mesorectal excision with autonomic nerve preservation as the standard procedure. The option for a temporary ileostomy or colostomy was left to the surgeon’s discretion. The anastomoses were performed using circular stapling devices.
Patients received preoperative capecitabine-based CRT. They received a total irradiation dose (TD) of 45 Gy to the pelvis plus 5.4 Gy as a boost to the primary tumour in 1.8 Gy daily fractions over 5.5 weeks. Radiotherapy (RT) was delivered using 15 MV photon beams and four-field box technique, once daily, 5 days per week. All fields were treated daily. Patients were irradiated in a prone position with a full bladder and using a belly board to minimise the exposure of the small bowel.
Chemotherapy was administered concomitantly with RT, started on the first day of RT and finished on the last day of RT. Chemotherapy was continuous throughout the RT period and it consisted of oral capecitabine at a daily dose of 1650 mg/m2, divided into two equal doses given 12 hours apart. One dose was taken 1 hour prior to RT. All patients received adjuvant chemotherapy with capecitabine 1250 mg/m2 orally twice daily on days 1–14 every 3 weeks; 4 cycles were recommended, beginning 6–8 weeks after surgery.
Distal bowel margins were measured in formalin-fixed, pinned specimens. The distal resection margin length was defined as the closest distance between the distal border of the gross tumour (or scar tissue in patients showing clinically complete response after chemoradiation) and the edge of the distal resection. The cutting edges of doughnuts were not included in these measurements, but were also assessed microscopically.
Differences in categorical variables between study groups were analysed using Chi-square test or likelihood ratio test as appropriate. Differences in numeric variables between groups were investigated using Kruskal-Wallis test. Cox’s proportional hazards model was used to test the association between each of the risk factors and local recurrence or overall survival. For overall survival, both univariate and multiple Cox regression models were used, but because of the low number of events, the multiple analysis was restricted to include two possible confounders. Proportional hazard assumption was tested graphically by a loglog plot. Time intervals were calculated from the date of the surgery. The p-values < 0.05 were considered statistically significant. Statistical analysis was performed using the SPSS software program (Version 23.0).
The study included 109 rectal cancer patients. There were 75 male and 34 female patients with an average age of 63 years (range, 34–83). Average length of hospitalization was 9 days (range, 3–52). Altogether, we registered 8 major complications that required surgical re-intervention. There was no postoperative 30 day mortality. Characteristics of patients with distal resection margin (DRM) < 8 mm (Group I, n = 27), 8–20 mm (Group II, n = 31) and > 20 (Group III, n = 51) mm are shown in Table 1. Groups were comparable regarding all characteristics, except for the stage of the illness. Group III consisted of a higher share (29.4%) of patients with N stage of 2 compared with Group II (12.9%) and Group I (14.8%) (p = 0.020). After the surgery, a higher share of patients in Group III had a more advanced stage of tumours (yT, p = 0.039; yN, p = 0.004) and a lower share had regression levels of 3 and 4 (p = 0.003).
Clinicopathological features of patients according to distal resection margin (DRM)
Group I (n = 27) | Group II (n = 31) | Group III (n = 51) | All (n = 109) | p | |
---|---|---|---|---|---|
Male gender | 21 (77.8) | 21 (67.7) | 33 (64.7) | 75 (68.8) | 0.490 |
Age (years) | 60 (44–83) | 64 (37–76) | 66 (34–82) | 63 (34–83) | 0.453 |
Length of hospitalisation (days) | 10 (7–52) | 9 (5–31) | 9 (3–36) | 9 (3–52) | 0.189 |
Median distance from anal verge to tumor (cm) | 5 | 6 | 8 | 8 | 0.002 |
DRM (mm) DRM = distal resection margin; Group I, DRM < 8mm; Group II, 8 ≤ DRM ≤ 20 mm; Group III, DRM > 20 mm | 5 (1–8) | 15 (9–20) | 40 (25–80) | 20 (1–80) | < 0.001 |
CRM (mm) CRM = circumferential resection margin. | 10 (1–25) | 10 (4–30) | 10 (2–40) | 10 (1–40) | 0.284 |
Ileostomy / Transversostomy | 22 (81.5) | 21 (67.7) | 35 (68.6) | 78 (71.6) | 0.509 |
Surgical complications | 2 (7.4) | 5 (16.1) | 1 (2) | 8 (7.3) | 0.058 |
T | 0.103 | ||||
1 | 0 (0) | 0 (0) | 1 (2) | 1 (0.9) | |
2 | 1 (3.7) | 4 (12.9) | 1 (2) | 6 (5.5) | |
3 | 26 (96.3) | 26 (83.9) | 42 (82.4) | 94 (86.2) | |
4 | 0 (0) | 1 (3.2) | 5 (9.8) | 6 (5.5) | |
Missing data | 0 (0) | 0 (0) | 2 (3.9) | 2 (1.8) | |
N | 0.047 | ||||
0 | 14 (51.9) | 12 (38.7) | 9 (17.6) | 35 (32.1) | |
1 | 8 (29.6) | 15 (48.4) | 24 (47.1) | 47 (43.1) | |
2 | 4 (14.8) | 4 (12.9) | 15 (29.4) | 22 (20.2) | |
Missing data | 1 (3.7) | 0 (0) | 3 (5.9) | 4 (3.7) | |
yT yT, yN = stage as assessed by pathologic examination of the surgical specimen (after CRT and resection) | 0.039 | ||||
0 | 3 (11.1) | 4 (12.9) | 3 (5.9) | 10 (9.2) | |
1 | 5 (18.5) | 7 (22.6) | 2 (3.9) | 14 (12.8) | |
2 | 7 (25.9) | 10 (32.3) | 13 (25.5) | 30 (27.5) | |
3 | 12 (44.4) | 9 (29) | 33 (64.7) | 54 (49.5) | |
4 | 0 (0) | 1 (3.2) | 0 (0) | 1 (0.9) | |
yN yT, yN = stage as assessed by pathologic examination of the surgical specimen (after CRT and resection) | 0.004 | ||||
0 | 22 (81.5) | 27 (87.1) | 26 (51) | 75 (68.8) | |
1 | 3 (11.1) | 3 (9.7) | 17 (33.3) | 23 (21.1) | |
2 | 2 (7.4) | 1 (3.2) | 8 (15.7) | 11 (10.1) | |
Regression level | 0.003 | ||||
1 | 0 (0) | 4 (20) | 14 (35.9) | 18 (23.7) | |
2 | 8 (47.1) | 5 (25) | 18 (46.2) | 31 (40.8) | |
3 | 6 (35.3) | 6 (30) | 4 (10.3) | 16 (21.1) | |
4 | 3 (17.6) | 5 (25) | 3 (7.7) | 11 (14.5) | |
Vascular invasion | 1 (8.3) | 4 (21.1) | 4 (10.3) | 9 (12.9) | 0.477 |
Perineural invasion | 0 (0) | 1 (5.6) | 4 (10) | 5 (7.2) | 0.342 |
Positive lymph nodes | 5 (18.5) | 4 (12.9) | 25 (49) | 34 (31.2) | 0.001 |
Values are shown as median (range) for ordinal and numeric variables and as frequency (percentage) for nominal variable
Median (range) follow-up time in Group I was 89 (51–111), in Group II 83 (57–111) and in Group III 80 (45–116) months (p = 0.326), respectively. There were 4 (14.8%) deaths due to rectal cancer in Group I, 6 (19.4%) in Group II and 12 (23.5%) in Group III. There were no local recurrences in Group I, 1 in Group II and 3 in Group III. Univariate survival analysis showed DRM length was not statistically significantly associated with overall survival or local recurrence rate (p > 0.05; Table 2, Figure 1).
Risk factors for time to local recurrence or death using univariate Cox regression analysis
Local recurrence-free survival | Overall survival | |||||
---|---|---|---|---|---|---|
Variable (reference group) | Hazard Ratio (95 % CI) | P-value | Hazard Ratio (95 % CI) | P-value | ||
Female gender (male) | 2.3 (0.3; 16.2) | 0.411 | 0.6 (0.2; 1.6) | 0.279 | ||
Age (years) | 1.1 (0.9; 1.2) | 0.395 | 1 (1; 1.1) | 0.125 | ||
Length of hospitalisation (days) | 1.0 (0.8; 1.2) | 0.762 | 1 (1; 1.1) | 0.812 | ||
DRM (mm) DRM = distal resection margin; Group I, DRM < 8 mm; Group II, 8 ≤ DRM ≤ 20 mm; Group III, DRM > 20 mm | 1 (1; 1.1) | 0.218 | 1 (1; 1) | 0.838 | ||
DRM Group III (Group I + Group II) DRM = distal resection margin; Group I, DRM < 8 mm; Group II, 8 ≤ DRM ≤ 20 mm; Group III, DRM > 20 mm | 3.5 (0.4; 33.8) | 0.276 | 1.4 (0.6; 3.3) | 0.402 | ||
DRM DRM = distal resection margin; Group I, DRM < 8 mm; Group II, 8 ≤ DRM ≤ 20 mm; Group III, DRM > 20 mm | 0.667 | |||||
DRM Group II ( Group I) DRM = distal resection margin; Group I, DRM < 8 mm; Group II, 8 ≤ DRM ≤ 20 mm; Group III, DRM > 20 mm | – | – | 1.3 (0.4; 4.5) | 0.714 | ||
DRM Group III (Group I) | – | – | 1.6 (0.5; 5.1) | 0.392 | ||
CRM (mm) CRM = circumferential resection margin. | 1 (0.9; 1.2) | 0.524 | 1 (0.9; 1) | 0.343 | ||
N 2 - 3 (0 - 1) | 3.6 (0.5; 25.6) | 0.199 | 1.7 (0.6; 4.4) | 0.293 | ||
yT 0 - 1 (2 - 4) yT, yN = stage as assessed by pathologic examination of the surgical specimen (after CRT and resection) | 3.1 (0.3; 29.4) | 0.333 | 1.2 (0.4; 3.7) | 0.699 | ||
yT yT, yN = stage as assessed by pathologic examination of the surgical specimen (after CRT and resection) | – | – | 0.017 | |||
1 (0) | – | – | 0.2 (0; 1.8) | 0.15 | ||
2 (0) | – | – | 0.4 (0.1; 1.7) | 0.215 | ||
3 (0) | – | – | 0.7 (0.2; 2.3) | 0.517 | ||
4 (0) | – | – | 19.5 (1.6; 234.6) | 0.019 | ||
yN 0 (1-2) yT, yN = stage as assessed by pathologic examination of the surgical specimen (after CRT and resection) | 7 (0.7; 67.2) | 0.092 | 2.4 (1.1; 5.6) | 0.040 | ||
yN yT, yN = stage as assessed by pathologic examination of the surgical specimen (after CRT and resection) | – | – | 0.020 | |||
1 (0) | – | – | 1.6 (0.6; 4.6) | 0.382 | ||
2 (0) | – | – | 4.1 (1.5; 11.2) | 0.005 | ||
Vascular invasion | 2.4 (0.3; 23.4) | 0.441 | 0.9 (0.2; 4) | 0.892 | ||
Perineural invasion | 6.5 (0.7; 62.8) | 0.105 | 0.9 (0.1; 6.9) | 0.920 |
Values are shown as median (range) for ordinal and numeric variables and as frequency (percentage) for nominal variables
Overall survival was statistically significantly associated with tumour stage after surgery (yT, p = 0.017; yN, p = 0.02). Patients with pathologic T stage 4 (yT4) after the surgery had 19.5 (95% CI, 1.6–234.6) times higher risk of death than patients with pathologic T stage 1 (yT1). Patients with pathologic N stage 2 after the surgery (yN2) had 4.1 (95% CI, 1.5–5.6) times higher risk of death than patients with N stage 0 (yN0). None of the other risk factors was statistically significantly associated with overall survival. No association between examined risk factors and recurrence-free survival could be found (Table 2, Figure 1).
After adjusting for pathologic stage T and N after surgery (yT, yN), DRM length was still not statistically significantly associated with overall survival. Factors deemed statistically significant in univariate model were also statistically significantly associated with overall survival in multiple survival regression model (Table 3; Figure 2).
Risk factors for time to death using multiple Cox regression analysis
Variable (reference group) | Overall survival | |
---|---|---|
Hazard Ratio (95% CI) | P-value | |
yT yT, yN = stage as assessed by pathologic examination of the surgical specimen (after CRT and resection) | 0.014 | |
1 (0) | 0.2 (0; 2.3) | 0.212 |
2 (0) | 0.3 (0.1; 1.5) | 0.158 |
3 (0) | 0.5 (0.1; 1.9) | 0.309 |
4 (0) | 23.1 (1.8; 302.3) | 0.017 |
yN yT, yN = stage as assessed by pathologic examination of the surgical specimen (after CRT and resection) | 0.034 | |
1 (0) | 1.5 (0.4; 5.4) | 0.489 |
2 (0) | 4.2 (1.4; 12.6) | 0.011 |
DRM DRM = distal resection margin; Group I, DRM < 8mm; Group II, 8 ≤ DRM ≤ 20 mm; Group III, DRM > 20 mm | 0.871 | |
DRM Group II ( Group I) | 1.3 (0.3; 5.1) | 0.690 |
DRM Group III (Group I) | 1.4 (0.4; 4.4) | 0.609 |
Values are shown as median (range) for ordinal and numeric variables and as frequency (percentage) for nominal variables
The management of locally advanced rectal cancer (T3, T4, and /or N+) is multimodal and is based on preoperative CRT followed by surgery with TME. The latter can be done either as sphincter-preserving low rectal resection or abdominoperineal excision (APE). Preoperative CRT results in downsizing and down-staging of rectal cancer, which often facilitates or even makes possible radical,
The present study shows that in patients with rectal cancer after CRT and sphincter-preserving rectal resection, the length of DRM has no statistically significant influence on local recurrence and long-term survival, as long as all the resection margins (proximal, distal, circumferential) have no microscopic cancer cell residua.
Patients in our study were divided into three groups based on the length of the distal resection margins (DRM < 8, 8–20 and > 20 mm, respectively). The cut of values for the subgroups were set theoretically, based on previously published reports.23-28 We observed 4 (14.8%) deaths due to rectal cancer in Group I, 6 (19.4%) in Group II and 12 (23.5%) in Group III. There were no local recurrences in Group I, one in Group II and three in Group III. Univariate survival analysis showed DRM length was not statistically significantly associated with overall survival or local recurrence rate (p > 0.05; Table 2, Figure 1,2). After adjusting for pathologic stages T and N after surgery (yT, yN), the DRM length was still not statistically significantly associated with overall survival (Table 3; Figure 3). However, the multiple Cox regression analysis could not be done to the second endpoint of the study (
Our results are supported with several recent reports in the literature. Hong
By contrast, Vernava
Another possible limitation of our study is that the lengths of DRMs were measured on fixed pinned specimens, whereas the 1 cm rule refers to margins measured by surgeons under fresh anatomically restored
Finally, although it is a well-established fact, that sphincter-preserving rectal resection improves quality of life, such improvement of functional results must be objectively measured, preferably through reliable, validated and sensitive instruments (
In summary, our study shows that in patients with rectal cancer after CRT and sphincter-preserving rectal resection, the length of the distal resection margin has no statistically significant influence on local recurrence and long- term survival, as long as all the resection margins (proximal, distal, circumferential) have no microscopic cancer cell residua. Based on our results, taken in context with current reports in literature, we believe it is reasonable to accept short (1 cm or even less) lengths of DRM in order to perform sphincter-preserving rectal resections after CRT, as long as the TME principles are strictly followed.