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Is lateral pelvic node dissection necessary after preoperative chemoradiotherapy for rectal cancer patients with initially suspected lateral pelvic node?
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Is lateral pelvic node dissection necessary after preoperative chemoradiotherapy for rectal cancer patients with initially suspected lateral pelvic node? Min Ju Kim, MD, Sung Chan Park, MD, Tae Hyun Kim, MD, Dae Yong Kim, MD, Sun Young Kim, MD, Ji Yeon Baek, MD, Hee Jin Chang, MD, Ji Won Park, MD, and Jae Hwan Oh, MD, Goyang, Republic of Korea
Background. Little is known about the effect of lateral pelvic node dissection after preoperative chemoradiotherapy on rectal cancer patients with initially suspected lateral pelvic nodes. The purpose of this study was to identify a subgroup of patients receiving preoperative chemoradiotherapy who can benefit from lateral pelvic node dissection. Methods. The study included 580 patients who underwent preoperative chemoradiotherapy and total mesorectal excision. The lateral pelvic node responses to preoperative chemoradiotherapy were divided: group I (no suspected lateral pelvic node), lateral pelvic node <5 mm pre- and post-chemoradiotherapy; group II (responsive lateral pelvic node), lateral pelvic node $5 mm pre-chemoradiotherapy but <5 mm post-chemoradiotherapy; and group III (persistent lateral pelvic node), lateral pelvic node $5 mm preand post-chemoradiotherapy. Prognostic factors for lateral pelvic node recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival were analyzed. Results. In a multivariate analysis, lateral pelvic node response was an independent factor associated with lateral pelvic node recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival (P < .05). Group III had significantly poorer lateral pelvic node recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival than groups II and I (74.1%, 93.4%, and 98.6%; 71.7%, 89.4%, and 97%; 56.9%, 76.6%, and 81.7%; 74.9%, 85.7%, and 89.1%, respectively; P < .05). Group II tended to have poorer lateral pelvic node recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival than group I, and the differences in relapse-free survival and overall survival between the 2 groups were not significant (P > .05). Conclusion. Our data suggest that the subgroup with lateral pelvic nodes responsive to preoperative chemoradiotherapy may not benefit from lateral pelvic node dissection, and the subgroup with persistent lateral pelvic node may benefit from lateral pelvic node dissection. (Surgery 2016;j:j-j.) From the Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea
Supported by National Cancer Center Grants (1510160, 1410160 and 1610590). MJ Kim and SC Park contributed equally to this study. The authors have nothing to disclose. Accepted for publication April 9, 2016. Reprint requests: Tae Hyun Kim, MD, Center for Colorectal Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2016.04.006
RECENT PROGRESS IN OPERATIVE PROCEDURES for rectal cancer patients, such as total mesorectal excision (TME), which involves almost complete removal of the lymphoid channels in the mesorectum, has greatly reduced the incidence of locoregional recurrence, and circumferential radial margin involvement has prognostic significance for locoregional recurrence. However, approximately 10–25% of patients with locally advanced mid/ low rectal cancer show extramesorectal spread to lateral pelvic nodes (LPNs) outside the pelvic SURGERY 1
ARTICLE IN PRESS 2 Kim et al
plexus, which are not removed during conventional TME, and LPNs can be a potential site of locoregional recurrence even in the absence of circumferential margin involvement.1-3 Thus, the strategies to treat LPN involvement are TME combined with chemoradiotherapy (CRT)3-10 and/or LPN dissection.6,8,11-15 Preoperative CRT can reduce and eradicate not only the primary tumor but also involved regional lymph nodes, including the LPNs. Several studies in patients with locally advanced rectal cancer treated with TME have indicated no differences in locoregional recurrence or survival between preoperative CRT and LPN dissection.6,8,9,16 However, this result does not indicate that preoperative CRT can replace LPN dissection in all patients, particularly those with a suspected metastatic LPN, because these studies did not include those patients. Therefore, the indication and benefit of LPN dissection for rectal cancer patients treated with preoperative CRT and TME remain unclear. Because LPN dissection is not without side effects,6,13,15 careful studies about predictive pretreatment parameters for LPN recurrence should be required before performing dissection to address a suspected metastatic LPN. Such studies will identify patients who are most likely to benefit from LPN dissection. In this study, a key question was whether LPN dissection would be necessary for patients with suspected metastatic LPN who responded to preoperative CRT. Therefore, we retrospectively compared effects of the LPN response to preoperative CRT with the other pretreatment parameters on LPN recurrence in patients with locally advanced mid/low rectal cancer who were treated with preoperative CRT followed by TME. We then attempted to identify a subgroup of patients who can benefit from LPN dissection. MATERIAL AND METHODS Patients. A total of 779 patients with primary rectal cancer underwent preoperative CRT between October 2001 and September 2009. The study inclusion criteria were: (1) histologically confirmed adenocarcinoma of the middle or low rectum (within 10 cm above the anal verge); (2) locally advanced resectable disease (cT3 or cT4) evaluated using magnetic resonance imaging (MRI), with or without transrectal ultrasonography; (3) no previous or concurrent malignancy; and (4) no distant metastasis. Of the 779 patients who fulfilled the criteria, 199 were excluded from this study for the following reasons: 105 had no post-CRT MRI; 32 refused an operation; 24 were
Surgery j 2016
treated by TME with LPN dissection; 22 were treated by local excision due to comorbidities or strong refusal against anal ablation; and 16 were transferred to other hospitals. The remaining 580 patients were analyzed in this study. This study was approved by the institutional review boards of the National Cancer Center (NCCNCS-11-509), which deemed that informed consent was not required because of the retrospective nature of the study. Staging workups were performed in all patients before preoperative CRT; workups included digital rectal examination, complete blood count, liver function tests, carcinoembryonic antigen (CEA) level, video colonoscopy, chest radiography, computed tomography (CT) of the abdomen and pelvis, and MRI with or without transrectal ultrasound. Tumor staging was determined by MRI, using the protocol described in our previous report.17 MRIs were performed 2–4 days before the operation to evaluate the response to preoperative CRT, and we used the same protocols from the initial workup. The patient characteristics are shown in Table I. A total of 398 men and 182 women were included, with a median age of 59 years (range, 22–83 years). The median distance from the anal verge to the caudal tumor edge was 5.5 cm (range, 0–10 cm), and median tumor size was 5 cm (range, 1–11 cm). The major histologic grade was low (95%), and 31.7% of patients had serum CEA levels above the upper normal limit (ie, >5 ng/ mL) at diagnosis. Clinical T classification was cT3 in 559 (96.4%) and cT4 in 21 (3.6%). Clinical circumferential radial margin involvement was positive in 23 patients (4%). Treatment. Preoperative radiotherapy was delivered to the whole pelvis with a dose of 45 Gy in 25 fractions followed by a boost of 5.4 Gy in 3 fractions to the primary tumor within 6 weeks. All patients underwent CT simulation for 3dimensional conformal radiotherapy planning, and a 3-field treatment plan was used with a 6MV posterior-anterior photon field and 15 MV opposed lateral photon beams. Chemotherapy was administered concurrently with radiotherapy to all patients, and one of the following chemotherapeutic regimens was used: 5-fluorouracil (n = 326), capecitabine (n = 139), irinotecan (n = 73), cetuximab (n = 23), or an oral tegafur/uracil-based regimen (n = 19). After completion of preoperative CRT, all patients underwent curative resection, including high ligation of the inferior mesenteric vessels and TME. The median interval between CRT and
ARTICLE IN PRESS Kim et al 3
Surgery Volume j, Number j Table I. Clinicopathologic characteristics based on the LPN response group Characteristics
Total (n = 580)
Group I (n = 423)
Group II (n = 98)
Group III (n = 59)
n (%)
n (%)
n (%)
n (%)
Gender M 398 (68.6) F 182 (31.4) Age (y) Median (range) 59 (22–83) #60 338 (58.3) >60 242 (41.7) Distance from anal verge* (cm) Median (range) 5.5 (0–10) <5 205 (35.3) $5 375 (64.7) Tumor sizey (cm) Median (range) 5 (1–11) <5 286 (49.3) $5 294 (50.7) Histologic grade Low 551 (95) High 29 (5) CEA level at pre-CRT (ng/mL) #5 396 (68.3) >5 184 (31.7) CEA level at post-CRT (ng/mL) #5 527 (90.9) >5 53 (9.1) cT classification cT3 559 (96.4) cT4 21 (3.6) cN classification cN0 121 (20.9) cN+ 459 (79.1) cCRM Negative 557 (96) Positive 23 (4) Operation SPS 492 (84.8) APR 88 (15.2) Preoperative chemotherapy FL 326 (56.2) Others 254 (43.8) Adjuvant chemotherapy Yes 561 (96.7) No 19 (3.3) Tumor regression grade Grade 1 87 (15.0) Grade 2 320 (55.2) Grade 3 86 (14.8) Grade 4 87 (15.0)
P value
288 (68.1) 135 (31.9)
66 (67.3) 32 (32.7)
44 (74.6) 15 (25.4)
.601z
59 (22–82) 236 (55.8) 187 (44.2)
56 (31–76) 65 (66.3) 33 (33.7)
58 (34–83) 37 (62.7) 22 (37.3)
.424x .130z
6 (0–9) 139 (32.9) 284 (67.1)
5.3 (0–10) 40 (40.8) 58 (59.2)
5 (0.5–8) 26 (44.1) 33 (55.9)
.112x .105z
4 (1–9) 223 (52.7) 294 (47.3)
5 (1.5–11) 39 (39.8) 59 (60.2)
5 (1.5–7) 24 (40.7) 35 (59.4)
.001x .028z
407 (96.2) 16 (3.8)
91 (92.9) 7 (7.1)
53 (89.8) 6 (10.2)
.061z
291 (68.8) 132 (31.2)
70 (71.4) 28 (28.6)
35 (59.3) 24 (40.7)
.276z
383 (90.5) 40 (9.5)
94 (95.9) 4 (4.1)
50 (84.8) 9 (10.2)
.054z
410 (96.9) 13 (3.1)
92 (93.9) 6 (6.1)
57 (96.6) 2 (3.4)
.354z
108 (25.5) 315 (74.5)
9 (9.8) 89 (90.8)
4 (6.8) 55 (93.2)
<.001z
409 (96.7) 14 (3.3)
94 (95.9) 4 (4.1)
54 (91.5) 5 (8.5)
.171z
361 (85.3) 62 (14.7)
80 (81.6) 18 (18.4)
51 (86.4) 8 (13.6)
.611z
237 (56.0) 186 (44.0)
51 (52.0) 47 (48.0)
38 (64.4) 21 (35.6)
.313z
407 (96.2) 16 (3.8)
96 (98.0) 2 (2.0)
58 (98.3) 1 (1.7)
.681z
62 222 70 69
15 59 11 13
10 39 5 5
.024k
(14.7) (52.5) (16.6) (16.3)
(15.3) (60.2) (11.2) (13.3)
(16.9) (66.1) (8.5) (8.5)
*Distance of the distal end of the tumor from the anal verge. yMaximum diameter of the primary tumor. zFisher exact test. xOne-way analysis of variance. kMantel-Haeszel test. LPN, Lateral pelvic node; CEA, carcinoembryonic antigen; CRT, chemoradiotherapy; cCRM, clinical circumferential resection margin; SPS, sphincterpreserving operation; APR, abdominoperineal resection; FL, 5-fluorouracil and leucovorin; group I, short-axis diameter of LPN <5 mm pre- and postCRT <5 mm; group II, short-axis diameter of LPN pre-CRT $5 mm and short-axis diameter of LPN post-CRT <5 mm; group III, short-axis diameter of LPN $5 mm pre- and post-CRT.
ARTICLE IN PRESS 4 Kim et al
an operation was 6 weeks (range, 4–8 weeks). A sphincter-preserving operation was performed in 492 (84.8%) patients (Table I). After the operation, all patients were considered for adjuvant chemotherapy regardless of pathologic stage. Of all patients, 561 (96.7%) received adjuvant chemotherapy and the remaining 19 (3.3%) did not because of refusal (n = 12), perioperative complications (n = 4), or poor performance status (n = 3). Adjuvant chemotherapy commenced 3–6 weeks after curative resection, and one of the following chemotherapeutic regimens was used: fluoropyrimidine (n = 538) or an oxaliplatinbased regimen (n = 23). The radiotherapy techniques and chemotherapy regimens have been described previously.3,17 Pathologic findings. After radical operations, all tumor specimens were reviewed, and the entire tumor plus the mesorectal fat was serially sliced into 4-mm–thick sections and embedded in paraffin. Tumor regression grade was microscopically evaluated using the scale proposed by Dworak et al.18 Regression was graded as follows: Grade 0 = no regression, Grade 1 = dominant tumor mass with obvious fibrosis and/or vasculopathy, Grade 2 = dominant fibrotic changes with some obvious tumor cells or groups of cells, Grade 3 = fibrotic tissue with or without mucous substance containing tumor cells that were few in number and difficult to detect microscopically, and Grade 4 = fibrotic mass or acellular mucin pools only with no detectable tumor cells (ie, complete response). The Dworak’s tumor regression grade distribution was: Grade 1 in 87 patients (15%), Grade 2 in 320 patients (55.2%), Grade 3 in 86 patients (14.8%), and Grade 4 in 87 patients (15%). Follow-up and evaluation. All patients underwent a standardized follow-up consisting of a physical examination, complete blood count, serum CEA level, liver function tests, and chest x-ray every 3 months for the first 2 years and every 6 months thereafter. Patients were also subject to an abdominopelvic CT every 6 months. A colonoscopy was performed 1-year postoperatively and then once every 2 years. The median follow-up for all patients was 69.1 months (range, 4–118 months). Recurrence was confirmed by operative resection, biopsy, cytology, and/or radiologic findings, the latter of which increased in size over time. Locoregional recurrence was defined as tumor recurrence within the pelvic cavity, and distant metastasis was defined as any recurrence outside the pelvic cavity. Locoregional recurrence was subdivided into central pelvic and LPN recurrences. Central pelvic
Surgery j 2016
recurrence was defined as recurrence in the tumor bed, anastomosis site, anterior pelvic organs (bladder, prostate, vagina, etc), or the pelvic nerve plexus and perineum. LPN recurrence was defined as recurrence in the LPN-bearing areas outside the pelvic nerve plexus, along the obturator and the internal, external, and common iliac vessels. One radiologist (MJK, 9 years of experience) who was blinded to the clinical and pathologic results assessed all pre-CRT and post-CRT MRI images retrospectively. It is difficult to differentiate the other characteristics of LPN, such as a spiculated or indistinct border or a mottled heterogeneic pattern, with the post-CRT changes of LPN seen on MRI.19 Thus, all visible LPNs in the pelvic sidewall were inspected thoroughly, regardless of image findings of primary tumor and perirectal nodes, and the largest long-axis diameter, largest short-axis diameter, and multiplicity of LPN were recorded. Positive LPN involvement was defined as LN $5 mm in the short-axis diameter on MRI,3,20,21 and multiplicity of the LPNs was considered positive when the short-axis diameter of LPNs $5 mm was >2. Of the study’s 580 patients, 157 (27.1%) presented with an LPN with short-axis diameter $5 mm at pre-CRT, and multiple LPNs were detected in 66 patients (11.4%). The median long-axis diameter of the detected LPNs at preand post-CRT were 8 mm (range, 3–27 mm) and 5 mm (range, 2–25 mm), respectively, and the median short-axis diameter of the detected LPNs at pre- and post-CRT were 5 mm (range, 1–19 mm) and 3 mm (range, 2–19 mm), respectively. The LPN responses to preoperative CRT were divided into 3 groups: group I (no suspected LPN), shortaxis diameter of LPNs <5 mm at pre- and post-CRT; group II (responsive LPNs), short-axis diameter of LPNs $5 mm at pre-CRT and shortaxis diameter of LPNs <5 mm at post-CRT; and group III (persistent LPNs), short-axis diameter of LPNs $5 mm at pre- and post-CRT. Statistical analysis. LPN recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival were calculated based on the time interval from the first day of treatment until detection of LPN recurrence, locoregional recurrence, relapse, or death from any cause, respectively, and their probabilities were calculated using the Kaplan–Meier method. The log-rank test was used in univariate analysis to evaluate the effects of pretreatment clinical parameters on LPN recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival. A stepwise procedure was
ARTICLE IN PRESS Surgery Volume j, Number j
performed for multivariate analysis using a Cox proportional hazards model containing all variables that either attained or showed a trend toward statistical significance in a univariate analysis (P < .10). All tests were 2-sided and were performed using STATA software (version 9.0; Stata Corp, College Station, TX). RESULTS Pattern of failure. Disease had recurred in 131 of 580 patients (22.6%) at the time of analysis: locoregional recurrence developed in 41 (7.1%); distant metastasis developed in 119 (20.5%); and both occurred in 29 patients (5%). Locoregional recurrence was pathologically proven in 17 of the 41 patients, and the remaining cases were detected by a combination of radiologic and clinical findings. Of the 41 patients with locoregional recurrence, 14 had a central pelvic recurrence, and 29 had an LPN recurrence, including 2 patients who had both central pelvic and LPN recurrence. At the time of developing LPN recurrence, 13 of 29 patients had no distant metastasis, and 16 had simultaneous distant metastasis. The median times of LPN recurrence, locoregional recurrence, and distant metastasis were 22.7 months (range, 8–72.6 months), 24.4 months (range, 8–89.4 months), and 19.1 months (range, 3.3–97.4 months), respectively. LPN responses to CRT and LPN recurrence, locoregional recurrence, relapse, and survival. The LPN responses to preoperative CRT were 423 patients (72.9%) in group I, 98 patients (16.9%) in group II, and 59 patients (10.2%) in group III. All LPN recurrence and LPN recurrence without distant metastasis, according to the LPN responses to preoperative CRT, were 4 of 423 patients (1.4%) and 3 of 423 patients (0.7%) in group I, 8 of 98 patients (8.2%) and 4 of 98 patients (4.1%) in group II, and 15 of 59 patients (25.4%) and 6 of 59 patients (10.2%) in group III, respectively (P < .05). A comparison of the pre- and post-CRT clinicopathologic parameters according to the LPN response is summarized in Table I. The percentages of patients with tumor size $5 cm and cN+ were higher in groups II and III than in group I (P < .05), but the other preoperative parameters were not significantly different among the 3 groups (Table I). The higher tumor response grade (grades 3–4) was a significantly higher trend according to LPN response to preoperative CRT (group I [no suspected LPN], group II [responsive LPNs], and group III [persistent LPNs]; 32.9%, 24.5%, and 17.0%, P = .024; Table I).
Kim et al 5
Univariate analysis evaluating the associations between clinicopathologic parameters and LPN recurrence-free survival, locoregional recurrencefree survival, relapse-free survival, and overall survival is summarized in Table II. Histologic grade, cT classification, long-axis diameter, short-axis diameter of LPNs at pre- and post-CRT, multiplicity of LPNs at post-CRT, the LPN response, and tumor regression grade were significantly associated with LPN recurrence-free survival (P < .05). Distance from the anal verge, histologic grade, cT classification, clinical circumferential radial margin, long-axis diameter, short-axis diameter, multiplicity of LPNs at pre- and post-CRT, the LPN response, and tumor regression grade were significantly associated with locoregional recurrence-free survival (P < .05; Table II). Distance from the anal verge, histologic grade, CEA level at pre- and post-CRT, short-axis diameter of the LPN at pre- and post-CRT, LPN response, the operation, and tumor regression grade were significantly associated with relapse-free survival (P < .05; Table II). Histologic grade, CEA level at pre- and postCRT, short-axis diameter of the LPN at pre- and post-CRT, multiplicity of the LPNs at post-CRT, LPN response, adjuvant chemotherapy, and tumor regression grade were significantly associated with overall survival (P < .05; Table II). In multivariate analyses, cT classification, the LPN response, and tumor regression grade were significantly associated with LPN recurrence-free survival and locoregional recurrence-free survival (P < .05), whereas distance from the anal verge, the LPN response, and tumor regression grade were significantly associated with relapse-free survival (P < .05). Histologic grade, CEA level at pre-CRT, LPN response, adjuvant chemotherapy, and tumor regression grade were significantly associated with overall survival (P < .05; Table II). The results of univariate and multivariate analyses showed that the LPN response, together with tumor regression grade, was a consistent independent factor associated with LPN recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival (P < .05; Tables II and III). The results regarding LPN response indicated that group I had the best 5-year LPN recurrencefree survival, locoregional recurrence-free survival, relapse-free survival, and overall survival, followed by groups II and III. Group III had significantly poorer LPN recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival than groups I and II (P < .05; Fig).
No. of patients
LPN recurrence-free survival (%) 5-year (95% CI)
5-year (95% CI)
P value*
Relapse-free survival (%) 5-year (95% CI)
P value*
Overall survival (%) 5-year (95% CI)
P value*
(92.4–97.0) (93.8–99.3)
.369
92.3 (89.5–95.0) 95.4 (92.3–98.5)
.171
77.6 (73.4–81.9) 79.8 (73.9–85.8)
.633
84.5 (81.1–87.9) 86.9 (81.8–92.0)
.584
(92.6–97.4) (93.0–98.3)
.745
91.9 (88.9–94.9) 95.3 (92.5–98.0)
.133
77.6 (73.1–82.2) 79.3 (73.9–84.0)
.349
88.7 (85.2–92.2) 84.6 (79.7–89.5)
.166
(91.0–97.6) (93.7–97.9)
.302
90.0 (85.8–94.2) 94.9 (92.6–97.2)
.037
69.8 (63.2–76.3) 83.1 (79.2–87.0)
<.001
83.7 (78.5–89.0) 88.9 (85.6–92.3)
.085
(91.4–97.0) (94.2–98.6)
.344
93.1 (90.1–96.1) 93.4 (90.5–96.4)
.874
78.5 (73.5–83.4) 78.2 (73.3–83.1)
.767
87.5 (83.4–91.6) 86.6 (82.6–90.7)
.444
(94.3–97.7) (71.6–98.6)
.009
93.9 (91.8–95.9) 80.1 (64.2–96.0)
.010
79.6 (76.1–83.0) 55.4 (36.1–74.7)
.001
88.1 (85.2–90.9) 68.2 (51.0–85.5)
.001
(93.3–97.6) (91.5–98.1)
.381
94.1 (91.7–96.5) 91.4 (87.3–95.6)
.058
81.7 (77.8–85.7) 70.9 (64.1–77.8)
<.001
90.3 (87.2–93.4) 80.1 (74.1–86.1)
<.001
(93.3–97.1) (90.1–100)
.722
93.4 (91.2–95.6) 91.6 (83.7–99.5)
.431
79.2 (75.6–82.8) 68.9 (55.8–82.1)
.034
88.4 (85.5–91.3) 74.1 (61.8–86.3)
<.001
(93.9–97.4) (69.7–100)
.029
93.9 (91.8–95.9) 76.2 (58.0–94.4)
.001
78.6 (75.1–82.2) 70.2 (50.2–90.2)
.206
87.1 (84.2–90.0) 85.7 (70.7–100)
.988
(95.9–100) (92.3–96.6)
.065
95.7 (91.9–99.4) 92.6 (90.1–95.1)
.172
80.7 (73.5–88.0) 78.0 (74.1–81.9)
.683
86.1 (79.8–92.5) 87.3 (84.1–90.5)
.980
(93.9–97.4) (70.7–100)
.073
93.9 (91.9–96.0) 77.5 (59.9–95.0)
.006
79.1 (75.6–82.6) 60.9 (40.9–80.8)
.062
87.7 (84.9–90.6) 72.7 (53.6–91.4)
.207
(97.0–99.7) (85.7–94.1)
<.001
96.6 (94.6–98.5) 87.4 (82.8–92.1)
<.001
80.6 (76.4–84.8) 74.4 (68.2–80.5)
.085
89.1 (85.7–92.4) 83.9 (78.5–89.3)
.093
Surgery j 2016
(continued)
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Gender M 398 94.7 F 182 96.5 Age (y) #60 338 95.0 >60 242 95.7 Distance from anal verge (cm) <5 205 94.3 $5 375 95.6 Tumor size (cm) <5 286 94.2 $5 294 96.4 Histologic grade Low 551 96.0 High 29 85.1 CEA level at pre-CRT (ng/mL) #5 396 95.5 >5 184 94.8 CEA level at post-CRT (ng/mL) #5 527 95.2 >5 53 95.8 cT classification cT3 559 95.6 cT4 21 85.2 cN classification cN0 121 98.3 cN+ 459 94.5 cCRM Negative 557 95.7 Positive 23 85.7 LAD of LPN at pre-CRT (mm) <5 367 98.3 $5 213 89.9
P value*
Locoregional recurrence-free survival (%)
6 Kim et al
Table II. Univariate analysis according to clinicopathologic factors for LPN recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival
No. of patients
LPN recurrence-free survival (%)
Relapse-free survival (%)
Overall survival (%)
5-year (95% CI)
P value*
5-year (95% CI)
P value*
5-year (95% CI)
(97.4–99.7) (80.6–91.9)
<.001
97.0 (95.4–98.7) 82.9 (76.7–89.0)
<.001
81.7 (77.9–85.5) 69.2 (61.6–76.8)
<.001
89.1 (86.0–92.2) 81.6 (74.9–88.3)
.032
(93.8–97.5) (85.8–98.8)
.089
94.3 (92.2–96.3) 86.9 (78.4–95.5)
.020
78.7 (75.0–82.3) 74.0 (62.8–85.1)
.428
87.5 (84.2–90.2) 85.5 (76.1–95.0)
.813
(96.3–99.1) (80.1–92.6)
<.001
95.8 (93.9–97.7) 83.8 (77.0–90.5)
<.001
80.0 (76.1–83.8) 72.5 (64.5–80.6)
.059
88.3 (85.2–91.4) 82.7 (75.7–89.6)
.121
(96.2–98.9) (62.3–85.9)
<.001
95.6 (93.8–97.4) 71.7 (59.4–84.0)
<.001
80.8 (77.2–84.3) 56.9 (43.8–70.1)
<.001
88.5 (85.6–91.4) 74.9 (63.4–86.3)
.001
(94.1–97.5) (61.4–97.4)
<.001
94.0 (91.9–96.0) 70.6 (47.7–93.4)
<.001
78.7 (75.2–82.2) 62.2 (39.3–85.1)
.116
87.6 (84.7–90.5) 71.6 (50.0–93.1)
.023
(97.4–99.7) (88.3–98.5) (62.3–85.9)
<.001
97.0 (95.4–98.7) 89.4 (83.2–95.6) 71.7 (59.4–84.0)
<.001
81.7 (77.9–85.5) 76.6 (67.8–85.4) 56.9 (43.4–70.4)
<.001
89.1 (86.0–92.2) 85.7 (78.1–93.3) 74.9 (63.4–86.3)
.006
(93.3–97.2) (90.6–99.8)
.904
94.1 (92.0–96.3) 88.2 (81.4–95.1)
.073
80.7 (77.1–84.3) 65.0 (54.6–75.3)
<.001
88.0 (85.0–91.0) 81.7 (73.2–90.1)
.305
(92.7–97.5) (92.9–98.1)
.621
92.4 (89.4–95.4) 94.3 (91.4–97.2)
.236
76.6 (71.8–81.5) 80.4 (75.4–85.4)
.173
86.4 (82.5–90.3) 88.1 (84.0–92.3)
.111
(93.5–97.1) (83.9–100)
.837
93.4 (91.3–95.5) 88.9 (74.4–100)
.435
78.6 (75.1–82.1) 69.2 (46.3–92.2)
.284
87.6 (84.7–90.5) 70.4 (48.2–92.6)
.002
68.6 (58.6–78.7) 86.8 (82.8–90.7) 96.9 (94.2–99.6)
<.001
(95.6–81.3) (92.1–97.2) (98.2–100)
.002
87.8 (73.0–90.5) 93.1 (90.2–95.6) 98.8 (97.2–100)
<.001
55.6 (40.5–62.6) 77.8 (73.0–82.5) 91.6 (87.4–95.8)
<.001
P value*
Kim et al 7
*Log-rank test. LPN, Lateral pelvic node; CI, confidence interval; CEA, carcinoembryonic antigen; CRT, chemoradiotherapy; cCRM, clinical circumferential resection margin; LAD, long-axis diameter; SAD, short-axis diameter.
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P value*
5-year (95% CI)
SAD of LPN at pre-CRT (mm) <5 423 98.6 $5 157 86.2 Multiplicity of LPN at pre-CRT No 514 95.7 Yes 66 92.3 LAD of LPN at post-CRT (mm) <5 454 97.7 $5 126 86.4 SAD of LPN at post-CRT (mm) <5 521 97.6 $5 59 74.1 Multiplicity of LPN at post-CRT No 560 95.8 Yes 20 79.4 LPN response Group I 423 98.6 Group II 98 93.4 Group III 59 74.1 Operation SPS 492 95.3 APR 88 95.2 Preoperative chemotherapy FL 326 95.1 Others 254 95.5 Adjuvant chemotherapy Yes 561 95.3 No 19 94.4 Tumor regression grade Grade 1 87 88.4 Grade 2 320 94.7 Grades 3–4 173 99.4
Locoregional recurrence-free survival (%)
Surgery Volume j, Number j
Table II. (continued)
8 Kim et al
Table III. Multivariate analysis according to clinicopathologic factors for LPN recurrence-free survival, locoregional recurrence-free survival, relapsefree survival, and overall survival LPN recurrence-free survival HR
95% CI
Relapse-free survival
P value*
HR
95% CI
P value*
HR
95% CI
—
— —
— —
—
1.000 0.596
— 0.422–0.843
—
— —
— —
—
— —
— —
—
— —
— —
—
— —
.035
1.000 4.202
— 1.593–11.084
.004
.003 <.001
1.000 3.575 10.327
— 1.612–7.932 4.932–21.624
—
— — 1.000 0.374 0.105
.034 .006
Overall survival
P value*
HR
95% CI
P value*
— —
—
—
—
1.000 2.022
— 1.010–4.048
.047
— —
—
1.000 1.836
— 1.191–2.830
.006
— —
— —
—
— —
— —
.002 <.001
1.000 1.273 2.284
— 0.812–1.996 1.449–3.600
.293 <.001
1.000 1.137 2.280
— 0.628–2.057 1.301–3.996
.672 .004
— —
—
— —
— —
—
1.000 3.620
— 1.634–8.016
.002
— 0.192–0.727 0.030–0.369
.004 <.001
1.000 0.361 0.153
— 0.246–0.529 0.087–0.269
<.001 <.001
1.000 0.406 0.121
— 0.253–0.650 0.052–0.278
<.001 <.001
.003
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Distance from anal verge (cm) <5 — — $5 — — Histologic grade Low — — High — — CEA level at pre-CRT (ng/mL) #5 — — >5 — — cT classification cT3 1.000 — cT4 3.826 1.098–13.334 LPN response Group I 1.000 — Group II 5.181 1.774–15.128 Group III 20.553 7.910–53.407 Adjuvant chemotherapy Yes — — No — — Tumor regression grade Grade 1 1.000 — Grade 2 0.338 0.172–0.875 Grades 3–4 0.110 0.023–0.512
Locoregional recurrence-free survival
—
*Multivariate analysis using Cox proportional hazards model. LPN, Lateral pelvic node; HR, hazard ratio; CI, confidence interval; CEA, carcinoembryonic antigen; CRT, chemoradiotherapy.
Surgery j 2016
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Kim et al 9
Fig. LPN recurrence-free survival (A), locoregional recurrence-free survival (B), relapse-free survival (C), and overall survival curves (D) according to the LPN responses: group I, short-axis diameter of LPN <5 mm at pre- and postCRT; group II, short-axis diameter of LPN $5 mm at pre-CRT and short-axis diameter of LPN <5 mm at post-CRT; and group III, short-axis diameter of LPN $5 mm at pre- and post-CRT. *log-rank test. LPN, Lateral pelvic node; CRT, chemoradiotherapy.
Group II tended to have poorer LPN recurrencefree survival, locoregional recurrence-free survival, relapse-free survival, and overall survival than group I, but the differences were significant only for LPN recurrence-free survival and locoregional recurrence-free survival (P < .05; Fig). DISCUSSION The question of whether LPN metastasis should be considered a sign of systemic disease5,14 or a potentially curable regional disease is
controversial.1,3,13,15,22 Our previous studies and others indicate that LPN metastasis is associated with an increased risk of locoregional recurrence and that about 50% of locoregional recurrences occur within the LPN-bearing pelvic sidewall without evidence of distant metastasis.1,13,15,22 A recent large multicenter study by Akiyoshi et al11 analyzed 11,567 patients with low rectal cancer and showed that patients with LPN metastasis have survival rates similar to those with N2 disease and better survival rates than those with stage IV
ARTICLE IN PRESS 10 Kim et al
disease. Similarly, the present study analyzed 580 patients with locally advanced mid/low rectal cancer treated with preoperative CRT followed by TME and showed that the LPN response to preoperative CRT, together with tumor regression grade, was consistently an independently significant prognostic factor for LPN recurrence, locoregional recurrence, relapse, and survival in these patients. The LPN responses to preoperative CRT in this study included 3 different groups: group I (no suspected LPN), group II (responsive LPNs), and group III (persistent LPNs); these findings imply that LPN involvement and LPN response to preoperative CRT could be among the most important prognostic factors for influencing recurrence and overall survival. In addition, 13 of 29 patients (44.8%) with LPN recurrence had no evidence of distant metastasis at the time of recurrence, and 6 of 13 patients (46.2%) with LPN recurrence without distant metastasis had persistent LPN following preoperative CRT (group III). These findings suggest that LPN recurrence is one of the important potential sites for locoregional recurrence in patients with locally advanced mid/ low rectal cancer treated with preoperative CRT followed by TME and could potentially be cured using strategies to treat LPN, including LPN dissection, in selected patients. The indications and benefits of LPN dissection for patients with locally advanced rectal cancer treated with preoperative CRT followed by TME have remained unclear.6,8,9,16 A randomized study showed that LPN dissection is associated with a high frequency of unnecessary urinary and/or sexual dysfunction without significant differences in locoregional recurrence and overall survival compared with patients receiving preoperative CRT.8 Watanabe et al9 reported no differences in locoregional recurrence or overall survival between patients who underwent preoperative CRT with TME and those who underwent TME with LPN dissection. These findings suggest that routine LPN dissection for all patients with locally advanced mid/low rectal cancer may be overtreatment. Although no conclusions regarding the benefit of LPN dissection for patients with suspected metastatic LPNs who received preoperative CRT followed by TME could be drawn, the LPN dissection indication for patients with suspected metastatic LPNs may be affected by preoperative CRT due to its cytotoxic effects on metastatic LPNs and the primary tumor. A recent retrospective analysis of 66 patients with suspected metastatic LPNs who underwent preoperative CRT followed by TME and LPN dissection
Surgery j 2016
showed that the group with persistent LPNs following preoperative CRT had a significantly higher incidence of residual tumors and poorer oncologic outcomes, ie, higher recurrence and lower survival, than the group with LPNs responsive to preoperative CRT.23 Similarly, we showed here that group III (persistent LPN) had significantly poorer LPN recurrence-free survival, locoregional recurrencefree survival, relapse-free survival, and overall survival than groups II (responsive LPN) and I (no suspected LPN). Furthermore, although group II (responsive LPN) tended to have poorer LPN recurrence-free survival, locoregional recurrencefree survival, relapse-free survival, and overall survival than group I (no suspected LPN), the differences in relapse-free survival and overall survival between the groups were not significant (Fig). These findings suggest that, among patients with suspected metastatic LPN, the patients with LPN responsive to preoperative CRT (group II) may not benefit from LPN dissection, and the patients with persistent LPN following preoperative CRT (group III) may benefit from LPN dissection. Therefore, further large-scale studies are warranted to assess the risks and benefits of LPN dissection in these patients. The present study had some limitations. First, the accuracy of nodal staging using MRI is less reliable than that of local tumor staging, and there is no consensus regarding the size criteria for predicting metastatic lymph nodes.24 In addition, the study has been analyzed by a single radiologist, and the criteria for MRI assessments of LPN response to treatment have not been well validated; thus, further study of how to validate MRI assessments of LPN responses to treatment is warranted. Lymph node size, however, remains the most reliable parameter to diagnose metastatic lymph nodes by MRI, and 5 mm is the most common criterion for the upper limit of a normal lymph node.20,25,26 Second, the study did not have an LPN dissection component and did not evaluate the effects of LPN dissection in patients with persistent LPNs following preoperative CRT. However, because invasive operative procedures, such as LPN dissection, can result in urinary and sexual dysfunction,6,7,10 it is important to use strict selection criteria to identify the subgroup of patients who can benefit from LPN dissection. Third, the study did not examine and compare the effectiveness of strategies to treat LPN. These strategies include operation, additional
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chemotherapy, radiotherapy (including intraoperative radiotherapy), and combinations thereof. Thus, further large-scale and comprehensive studies of various strategies to treat LPN are needed. In conclusion, our data show that the LPN responses to preoperative CRT were significant prognostic factors associated with LPN recurrence and survival in patients with locally advanced mid/ low rectal cancer treated with preoperative CRT followed by TME. These findings suggest that LPN responses to preoperative CRT could be useful therapeutic indicators to identify patients who could benefit from LPN dissection and that LPN dissection might be considered in patients with initially suspected LPN according to the LPN response to preoperative CRT. REFERENCES 1. Ueno M, Oya M, Azekura K, Yamaguchi T, Muto T. Incidence and prognostic significance of lateral lymph node metastasis in patients with advanced low rectal cancer. Br J Surg 2005;92:756-63. 2. Yano H, Moran BJ. The incidence of lateral pelvic side-wall nodal involvement in low rectal cancer may be similar in Japan and the West. Br J Surg 2008;95:33-49. 3. Kim TH, Jeong SY, Choi DH, Kim DY, Jung KH, Moon SH, et al. Lateral lymph node metastasis is a major cause of locoregional recurrence in rectal cancer treated with preoperative chemoradiotherapy and curative resection. Ann Surg Oncol 2008;15:729-37. 4. Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638-46. 5. Kusters M, Holman FA, Martijn H, Nieuwenhuijzen GA, Creemers GJ, Daniels-Gooszen AW, et al. Patterns of local recurrence in locally advanced rectal cancer after intraoperative radiotherapy containing multimodality treatment. Radiother Oncol 2009;92:221-5. 6. Georgiou P, Tan E, Gouvas N, Antoniou A, Brown G, Nicholls RJ, et al. Extended lymphadenectomy versus conventional surgery for rectal cancer: A meta-analysis. Lancet Oncol 2009;10:1053-62. 7. Lee JW, Lee JH, Kim JG, Oh ST, Chung HJ, Lee MA, et al. Comparison between preoperative and postoperative concurrent chemoradiotherapy for rectal cancer: An institutional analysis. Radiat Oncol J 2013;31:155-61. 8. Nagawa H, Muto T, Sunouchi K, Higuchi Y, Tsurita G, Watanabe T, et al. Randomized, controlled trial of lateral node dissection vs. nerve-preserving resection in patients with rectal cancer after preoperative radiotherapy. Dis Colon Rectum 2001;44:1274-80. 9. Watanabe T, Tsurita G, Muto T, Sawada T, Sunouchi K, Higuchi Y, et al. Extended lymphadenectomy and preoperative radiotherapy for lower rectal cancers. Surgery 2002; 132:27-33. 10. Kim MS, Keum KC, Rhee WJ, Kim H, Kim M, Choi S, et al. The location of locoregional recurrence in pathologic T3N0, non-irradiated lower rectal cancer. Radiat Oncol J 2013;31:97-103.
Kim et al 11
11. Akiyoshi T, Watanabe T, Miyata S, Kotake K, Muto T, Sugihara K, et al. Results of a Japanese nationwide multiinstitutional study on lateral pelvic lymph node metastasis in low rectal cancer: Is it regional or distant disease? Ann Surg 2012;255:1129-34. 12. Liang JT. Technical feasibility of laparoscopic lateral pelvic lymph node dissection for patients with low rectal cancer after concurrent chemoradiation therapy. Ann Surg Oncol 2011;18:153-9. 13. Sugihara K, Kobayashi H, Kato T, Mori T, Mochizuki H, Kameoka S, et al. Indication and benefit of pelvic sidewall dissection for rectal cancer. Dis Colon Rectum 2006;49:1663-72. 14. Syk E, Torkzad MR, Blomqvist L, Ljungqvist O, Glimelius B. Radiological findings do not support lateral residual tumour as a major cause of local recurrence of rectal cancer. Br J Surg 2006;93:113-9. 15. Ueno H, Mochizuki H, Hashiguchi Y, Ishiguro M, Miyoshi M, Kajiwara Y, et al. Potential prognostic benefit of lateral pelvic node dissection for rectal cancer located below the peritoneal reflection. Ann Surg 2007;245:80-7. 16. Kim JC, Takahashi K, Yu CS, Kim HC, Kim TW, Ryu MH, et al. Comparative outcome between chemoradiotherapy and lateral pelvic lymph node dissection following total mesorectal excision in rectal cancer. Ann Surg 2007;246:754-62. 17. Kim YH, Kim DY, Kim TH, Jung KH, Chang HJ, Jeong SY, et al. Usefulness of magnetic resonance volumetric evaluation in predicting response to preoperative concurrent chemoradiotherapy in patients with resectable rectal cancer. Int J Radiat Oncol Biol Phys 2005;62:761-8. 18. Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 1997;12:19-23. 19. Kim DJ, Kim JH, Lim JS, Yu JS, Chung JJ, Kim MJ, et al. Restaging of rectal cancer with MR imaging after concurrent chemotherapy and radiation therapy. Radiographics 2010; 30:503-16. 20. Kim JH, Beets GL, Kim MJ, Kessels AG, Beets-Tan RG. Highresolution MR imaging for nodal staging in rectal cancer: Are there any criteria in addition to the size? Eur J Radiol 2004;52:78-83. 21. Kim MJ, Kim TH, Kim DY, Kim SY, Baek JY, Chang HJ, et al. Can chemoradiation allow for omission of lateral pelvic node dissection for locally advanced rectal cancer? J Surg Oncol 2015;111:459-64. 22. Sato H, Maeda K, Maruta M, Masumori K, Koide Y. Who can get the beneficial effect from lateral lymph node dissection for Dukes C rectal carcinoma below the peritoneal reflection? Dis Colon Rectum 2006;49:S3-12. 23. Oh HK, Kang SB, Lee SM, Lee SY, Ihn MH, Kim DW, et al. Neoadjuvant chemoradiotherapy affects the indications for lateral pelvic node dissection in mid/low rectal cancer with clinically suspected lateral node involvement: A multicenter retrospective cohort study. Ann Surg Oncol 2014;21:2280-7. 24. Bipat S, Glas AS, Slors FJ, Zwinderman AH, Bossuyt PM, Stoker J. Rectal cancer: Local staging and assessment of lymph node involvement with endoluminal US, CT, and MR imaging---A meta-analysis. Radiology 2004;232:773-83. 25. Matsuoka H, Nakamura A, Masaki T, Sugiyama M, Nitatori T, Ohkura Y, et al. Optimal diagnostic criteria for lateral pelvic lymph node metastasis in rectal carcinoma. Anticancer Res 2007;27:3529-33. 26. Blomqvist L, Rubio C, Holm T, Machado M, Hindmarsh T. Rectal adenocarcinoma: Assessment of tumour involvement of the lateral resection margin by MRI of resected specimen. Br J Radiol 1999;72:18-23.
Is lateral pelvic node dissection necessary after preoperative chemoradiotherapy for rectal cancer patients with initially suspected lateral pelvic node? Min Ju Kim, MD, Sung Chan Park, MD, Tae Hyun Kim, MD, Dae Yong Kim, MD, Sun Young Kim, MD, Ji Yeon Baek, MD, Hee Jin Chang, MD, Ji Won Park, MD, and Jae Hwan Oh, MD, Goyang, Republic of Korea
Background. Little is known about the effect of lateral pelvic node dissection after preoperative chemoradiotherapy on rectal cancer patients with initially suspected lateral pelvic nodes. The purpose of this study was to identify a subgroup of patients receiving preoperative chemoradiotherapy who can benefit from lateral pelvic node dissection. Methods. The study included 580 patients who underwent preoperative chemoradiotherapy and total mesorectal excision. The lateral pelvic node responses to preoperative chemoradiotherapy were divided: group I (no suspected lateral pelvic node), lateral pelvic node <5 mm pre- and post-chemoradiotherapy; group II (responsive lateral pelvic node), lateral pelvic node $5 mm pre-chemoradiotherapy but <5 mm post-chemoradiotherapy; and group III (persistent lateral pelvic node), lateral pelvic node $5 mm preand post-chemoradiotherapy. Prognostic factors for lateral pelvic node recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival were analyzed. Results. In a multivariate analysis, lateral pelvic node response was an independent factor associated with lateral pelvic node recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival (P < .05). Group III had significantly poorer lateral pelvic node recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival than groups II and I (74.1%, 93.4%, and 98.6%; 71.7%, 89.4%, and 97%; 56.9%, 76.6%, and 81.7%; 74.9%, 85.7%, and 89.1%, respectively; P < .05). Group II tended to have poorer lateral pelvic node recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival than group I, and the differences in relapse-free survival and overall survival between the 2 groups were not significant (P > .05). Conclusion. Our data suggest that the subgroup with lateral pelvic nodes responsive to preoperative chemoradiotherapy may not benefit from lateral pelvic node dissection, and the subgroup with persistent lateral pelvic node may benefit from lateral pelvic node dissection. (Surgery 2016;j:j-j.) From the Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea
Supported by National Cancer Center Grants (1510160, 1410160 and 1610590). MJ Kim and SC Park contributed equally to this study. The authors have nothing to disclose. Accepted for publication April 9, 2016. Reprint requests: Tae Hyun Kim, MD, Center for Colorectal Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2016.04.006
RECENT PROGRESS IN OPERATIVE PROCEDURES for rectal cancer patients, such as total mesorectal excision (TME), which involves almost complete removal of the lymphoid channels in the mesorectum, has greatly reduced the incidence of locoregional recurrence, and circumferential radial margin involvement has prognostic significance for locoregional recurrence. However, approximately 10–25% of patients with locally advanced mid/ low rectal cancer show extramesorectal spread to lateral pelvic nodes (LPNs) outside the pelvic SURGERY 1
ARTICLE IN PRESS 2 Kim et al
plexus, which are not removed during conventional TME, and LPNs can be a potential site of locoregional recurrence even in the absence of circumferential margin involvement.1-3 Thus, the strategies to treat LPN involvement are TME combined with chemoradiotherapy (CRT)3-10 and/or LPN dissection.6,8,11-15 Preoperative CRT can reduce and eradicate not only the primary tumor but also involved regional lymph nodes, including the LPNs. Several studies in patients with locally advanced rectal cancer treated with TME have indicated no differences in locoregional recurrence or survival between preoperative CRT and LPN dissection.6,8,9,16 However, this result does not indicate that preoperative CRT can replace LPN dissection in all patients, particularly those with a suspected metastatic LPN, because these studies did not include those patients. Therefore, the indication and benefit of LPN dissection for rectal cancer patients treated with preoperative CRT and TME remain unclear. Because LPN dissection is not without side effects,6,13,15 careful studies about predictive pretreatment parameters for LPN recurrence should be required before performing dissection to address a suspected metastatic LPN. Such studies will identify patients who are most likely to benefit from LPN dissection. In this study, a key question was whether LPN dissection would be necessary for patients with suspected metastatic LPN who responded to preoperative CRT. Therefore, we retrospectively compared effects of the LPN response to preoperative CRT with the other pretreatment parameters on LPN recurrence in patients with locally advanced mid/low rectal cancer who were treated with preoperative CRT followed by TME. We then attempted to identify a subgroup of patients who can benefit from LPN dissection. MATERIAL AND METHODS Patients. A total of 779 patients with primary rectal cancer underwent preoperative CRT between October 2001 and September 2009. The study inclusion criteria were: (1) histologically confirmed adenocarcinoma of the middle or low rectum (within 10 cm above the anal verge); (2) locally advanced resectable disease (cT3 or cT4) evaluated using magnetic resonance imaging (MRI), with or without transrectal ultrasonography; (3) no previous or concurrent malignancy; and (4) no distant metastasis. Of the 779 patients who fulfilled the criteria, 199 were excluded from this study for the following reasons: 105 had no post-CRT MRI; 32 refused an operation; 24 were
Surgery j 2016
treated by TME with LPN dissection; 22 were treated by local excision due to comorbidities or strong refusal against anal ablation; and 16 were transferred to other hospitals. The remaining 580 patients were analyzed in this study. This study was approved by the institutional review boards of the National Cancer Center (NCCNCS-11-509), which deemed that informed consent was not required because of the retrospective nature of the study. Staging workups were performed in all patients before preoperative CRT; workups included digital rectal examination, complete blood count, liver function tests, carcinoembryonic antigen (CEA) level, video colonoscopy, chest radiography, computed tomography (CT) of the abdomen and pelvis, and MRI with or without transrectal ultrasound. Tumor staging was determined by MRI, using the protocol described in our previous report.17 MRIs were performed 2–4 days before the operation to evaluate the response to preoperative CRT, and we used the same protocols from the initial workup. The patient characteristics are shown in Table I. A total of 398 men and 182 women were included, with a median age of 59 years (range, 22–83 years). The median distance from the anal verge to the caudal tumor edge was 5.5 cm (range, 0–10 cm), and median tumor size was 5 cm (range, 1–11 cm). The major histologic grade was low (95%), and 31.7% of patients had serum CEA levels above the upper normal limit (ie, >5 ng/ mL) at diagnosis. Clinical T classification was cT3 in 559 (96.4%) and cT4 in 21 (3.6%). Clinical circumferential radial margin involvement was positive in 23 patients (4%). Treatment. Preoperative radiotherapy was delivered to the whole pelvis with a dose of 45 Gy in 25 fractions followed by a boost of 5.4 Gy in 3 fractions to the primary tumor within 6 weeks. All patients underwent CT simulation for 3dimensional conformal radiotherapy planning, and a 3-field treatment plan was used with a 6MV posterior-anterior photon field and 15 MV opposed lateral photon beams. Chemotherapy was administered concurrently with radiotherapy to all patients, and one of the following chemotherapeutic regimens was used: 5-fluorouracil (n = 326), capecitabine (n = 139), irinotecan (n = 73), cetuximab (n = 23), or an oral tegafur/uracil-based regimen (n = 19). After completion of preoperative CRT, all patients underwent curative resection, including high ligation of the inferior mesenteric vessels and TME. The median interval between CRT and
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Surgery Volume j, Number j Table I. Clinicopathologic characteristics based on the LPN response group Characteristics
Total (n = 580)
Group I (n = 423)
Group II (n = 98)
Group III (n = 59)
n (%)
n (%)
n (%)
n (%)
Gender M 398 (68.6) F 182 (31.4) Age (y) Median (range) 59 (22–83) #60 338 (58.3) >60 242 (41.7) Distance from anal verge* (cm) Median (range) 5.5 (0–10) <5 205 (35.3) $5 375 (64.7) Tumor sizey (cm) Median (range) 5 (1–11) <5 286 (49.3) $5 294 (50.7) Histologic grade Low 551 (95) High 29 (5) CEA level at pre-CRT (ng/mL) #5 396 (68.3) >5 184 (31.7) CEA level at post-CRT (ng/mL) #5 527 (90.9) >5 53 (9.1) cT classification cT3 559 (96.4) cT4 21 (3.6) cN classification cN0 121 (20.9) cN+ 459 (79.1) cCRM Negative 557 (96) Positive 23 (4) Operation SPS 492 (84.8) APR 88 (15.2) Preoperative chemotherapy FL 326 (56.2) Others 254 (43.8) Adjuvant chemotherapy Yes 561 (96.7) No 19 (3.3) Tumor regression grade Grade 1 87 (15.0) Grade 2 320 (55.2) Grade 3 86 (14.8) Grade 4 87 (15.0)
P value
288 (68.1) 135 (31.9)
66 (67.3) 32 (32.7)
44 (74.6) 15 (25.4)
.601z
59 (22–82) 236 (55.8) 187 (44.2)
56 (31–76) 65 (66.3) 33 (33.7)
58 (34–83) 37 (62.7) 22 (37.3)
.424x .130z
6 (0–9) 139 (32.9) 284 (67.1)
5.3 (0–10) 40 (40.8) 58 (59.2)
5 (0.5–8) 26 (44.1) 33 (55.9)
.112x .105z
4 (1–9) 223 (52.7) 294 (47.3)
5 (1.5–11) 39 (39.8) 59 (60.2)
5 (1.5–7) 24 (40.7) 35 (59.4)
.001x .028z
407 (96.2) 16 (3.8)
91 (92.9) 7 (7.1)
53 (89.8) 6 (10.2)
.061z
291 (68.8) 132 (31.2)
70 (71.4) 28 (28.6)
35 (59.3) 24 (40.7)
.276z
383 (90.5) 40 (9.5)
94 (95.9) 4 (4.1)
50 (84.8) 9 (10.2)
.054z
410 (96.9) 13 (3.1)
92 (93.9) 6 (6.1)
57 (96.6) 2 (3.4)
.354z
108 (25.5) 315 (74.5)
9 (9.8) 89 (90.8)
4 (6.8) 55 (93.2)
<.001z
409 (96.7) 14 (3.3)
94 (95.9) 4 (4.1)
54 (91.5) 5 (8.5)
.171z
361 (85.3) 62 (14.7)
80 (81.6) 18 (18.4)
51 (86.4) 8 (13.6)
.611z
237 (56.0) 186 (44.0)
51 (52.0) 47 (48.0)
38 (64.4) 21 (35.6)
.313z
407 (96.2) 16 (3.8)
96 (98.0) 2 (2.0)
58 (98.3) 1 (1.7)
.681z
62 222 70 69
15 59 11 13
10 39 5 5
.024k
(14.7) (52.5) (16.6) (16.3)
(15.3) (60.2) (11.2) (13.3)
(16.9) (66.1) (8.5) (8.5)
*Distance of the distal end of the tumor from the anal verge. yMaximum diameter of the primary tumor. zFisher exact test. xOne-way analysis of variance. kMantel-Haeszel test. LPN, Lateral pelvic node; CEA, carcinoembryonic antigen; CRT, chemoradiotherapy; cCRM, clinical circumferential resection margin; SPS, sphincterpreserving operation; APR, abdominoperineal resection; FL, 5-fluorouracil and leucovorin; group I, short-axis diameter of LPN <5 mm pre- and postCRT <5 mm; group II, short-axis diameter of LPN pre-CRT $5 mm and short-axis diameter of LPN post-CRT <5 mm; group III, short-axis diameter of LPN $5 mm pre- and post-CRT.
ARTICLE IN PRESS 4 Kim et al
an operation was 6 weeks (range, 4–8 weeks). A sphincter-preserving operation was performed in 492 (84.8%) patients (Table I). After the operation, all patients were considered for adjuvant chemotherapy regardless of pathologic stage. Of all patients, 561 (96.7%) received adjuvant chemotherapy and the remaining 19 (3.3%) did not because of refusal (n = 12), perioperative complications (n = 4), or poor performance status (n = 3). Adjuvant chemotherapy commenced 3–6 weeks after curative resection, and one of the following chemotherapeutic regimens was used: fluoropyrimidine (n = 538) or an oxaliplatinbased regimen (n = 23). The radiotherapy techniques and chemotherapy regimens have been described previously.3,17 Pathologic findings. After radical operations, all tumor specimens were reviewed, and the entire tumor plus the mesorectal fat was serially sliced into 4-mm–thick sections and embedded in paraffin. Tumor regression grade was microscopically evaluated using the scale proposed by Dworak et al.18 Regression was graded as follows: Grade 0 = no regression, Grade 1 = dominant tumor mass with obvious fibrosis and/or vasculopathy, Grade 2 = dominant fibrotic changes with some obvious tumor cells or groups of cells, Grade 3 = fibrotic tissue with or without mucous substance containing tumor cells that were few in number and difficult to detect microscopically, and Grade 4 = fibrotic mass or acellular mucin pools only with no detectable tumor cells (ie, complete response). The Dworak’s tumor regression grade distribution was: Grade 1 in 87 patients (15%), Grade 2 in 320 patients (55.2%), Grade 3 in 86 patients (14.8%), and Grade 4 in 87 patients (15%). Follow-up and evaluation. All patients underwent a standardized follow-up consisting of a physical examination, complete blood count, serum CEA level, liver function tests, and chest x-ray every 3 months for the first 2 years and every 6 months thereafter. Patients were also subject to an abdominopelvic CT every 6 months. A colonoscopy was performed 1-year postoperatively and then once every 2 years. The median follow-up for all patients was 69.1 months (range, 4–118 months). Recurrence was confirmed by operative resection, biopsy, cytology, and/or radiologic findings, the latter of which increased in size over time. Locoregional recurrence was defined as tumor recurrence within the pelvic cavity, and distant metastasis was defined as any recurrence outside the pelvic cavity. Locoregional recurrence was subdivided into central pelvic and LPN recurrences. Central pelvic
Surgery j 2016
recurrence was defined as recurrence in the tumor bed, anastomosis site, anterior pelvic organs (bladder, prostate, vagina, etc), or the pelvic nerve plexus and perineum. LPN recurrence was defined as recurrence in the LPN-bearing areas outside the pelvic nerve plexus, along the obturator and the internal, external, and common iliac vessels. One radiologist (MJK, 9 years of experience) who was blinded to the clinical and pathologic results assessed all pre-CRT and post-CRT MRI images retrospectively. It is difficult to differentiate the other characteristics of LPN, such as a spiculated or indistinct border or a mottled heterogeneic pattern, with the post-CRT changes of LPN seen on MRI.19 Thus, all visible LPNs in the pelvic sidewall were inspected thoroughly, regardless of image findings of primary tumor and perirectal nodes, and the largest long-axis diameter, largest short-axis diameter, and multiplicity of LPN were recorded. Positive LPN involvement was defined as LN $5 mm in the short-axis diameter on MRI,3,20,21 and multiplicity of the LPNs was considered positive when the short-axis diameter of LPNs $5 mm was >2. Of the study’s 580 patients, 157 (27.1%) presented with an LPN with short-axis diameter $5 mm at pre-CRT, and multiple LPNs were detected in 66 patients (11.4%). The median long-axis diameter of the detected LPNs at preand post-CRT were 8 mm (range, 3–27 mm) and 5 mm (range, 2–25 mm), respectively, and the median short-axis diameter of the detected LPNs at pre- and post-CRT were 5 mm (range, 1–19 mm) and 3 mm (range, 2–19 mm), respectively. The LPN responses to preoperative CRT were divided into 3 groups: group I (no suspected LPN), shortaxis diameter of LPNs <5 mm at pre- and post-CRT; group II (responsive LPNs), short-axis diameter of LPNs $5 mm at pre-CRT and shortaxis diameter of LPNs <5 mm at post-CRT; and group III (persistent LPNs), short-axis diameter of LPNs $5 mm at pre- and post-CRT. Statistical analysis. LPN recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival were calculated based on the time interval from the first day of treatment until detection of LPN recurrence, locoregional recurrence, relapse, or death from any cause, respectively, and their probabilities were calculated using the Kaplan–Meier method. The log-rank test was used in univariate analysis to evaluate the effects of pretreatment clinical parameters on LPN recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival. A stepwise procedure was
ARTICLE IN PRESS Surgery Volume j, Number j
performed for multivariate analysis using a Cox proportional hazards model containing all variables that either attained or showed a trend toward statistical significance in a univariate analysis (P < .10). All tests were 2-sided and were performed using STATA software (version 9.0; Stata Corp, College Station, TX). RESULTS Pattern of failure. Disease had recurred in 131 of 580 patients (22.6%) at the time of analysis: locoregional recurrence developed in 41 (7.1%); distant metastasis developed in 119 (20.5%); and both occurred in 29 patients (5%). Locoregional recurrence was pathologically proven in 17 of the 41 patients, and the remaining cases were detected by a combination of radiologic and clinical findings. Of the 41 patients with locoregional recurrence, 14 had a central pelvic recurrence, and 29 had an LPN recurrence, including 2 patients who had both central pelvic and LPN recurrence. At the time of developing LPN recurrence, 13 of 29 patients had no distant metastasis, and 16 had simultaneous distant metastasis. The median times of LPN recurrence, locoregional recurrence, and distant metastasis were 22.7 months (range, 8–72.6 months), 24.4 months (range, 8–89.4 months), and 19.1 months (range, 3.3–97.4 months), respectively. LPN responses to CRT and LPN recurrence, locoregional recurrence, relapse, and survival. The LPN responses to preoperative CRT were 423 patients (72.9%) in group I, 98 patients (16.9%) in group II, and 59 patients (10.2%) in group III. All LPN recurrence and LPN recurrence without distant metastasis, according to the LPN responses to preoperative CRT, were 4 of 423 patients (1.4%) and 3 of 423 patients (0.7%) in group I, 8 of 98 patients (8.2%) and 4 of 98 patients (4.1%) in group II, and 15 of 59 patients (25.4%) and 6 of 59 patients (10.2%) in group III, respectively (P < .05). A comparison of the pre- and post-CRT clinicopathologic parameters according to the LPN response is summarized in Table I. The percentages of patients with tumor size $5 cm and cN+ were higher in groups II and III than in group I (P < .05), but the other preoperative parameters were not significantly different among the 3 groups (Table I). The higher tumor response grade (grades 3–4) was a significantly higher trend according to LPN response to preoperative CRT (group I [no suspected LPN], group II [responsive LPNs], and group III [persistent LPNs]; 32.9%, 24.5%, and 17.0%, P = .024; Table I).
Kim et al 5
Univariate analysis evaluating the associations between clinicopathologic parameters and LPN recurrence-free survival, locoregional recurrencefree survival, relapse-free survival, and overall survival is summarized in Table II. Histologic grade, cT classification, long-axis diameter, short-axis diameter of LPNs at pre- and post-CRT, multiplicity of LPNs at post-CRT, the LPN response, and tumor regression grade were significantly associated with LPN recurrence-free survival (P < .05). Distance from the anal verge, histologic grade, cT classification, clinical circumferential radial margin, long-axis diameter, short-axis diameter, multiplicity of LPNs at pre- and post-CRT, the LPN response, and tumor regression grade were significantly associated with locoregional recurrence-free survival (P < .05; Table II). Distance from the anal verge, histologic grade, CEA level at pre- and post-CRT, short-axis diameter of the LPN at pre- and post-CRT, LPN response, the operation, and tumor regression grade were significantly associated with relapse-free survival (P < .05; Table II). Histologic grade, CEA level at pre- and postCRT, short-axis diameter of the LPN at pre- and post-CRT, multiplicity of the LPNs at post-CRT, LPN response, adjuvant chemotherapy, and tumor regression grade were significantly associated with overall survival (P < .05; Table II). In multivariate analyses, cT classification, the LPN response, and tumor regression grade were significantly associated with LPN recurrence-free survival and locoregional recurrence-free survival (P < .05), whereas distance from the anal verge, the LPN response, and tumor regression grade were significantly associated with relapse-free survival (P < .05). Histologic grade, CEA level at pre-CRT, LPN response, adjuvant chemotherapy, and tumor regression grade were significantly associated with overall survival (P < .05; Table II). The results of univariate and multivariate analyses showed that the LPN response, together with tumor regression grade, was a consistent independent factor associated with LPN recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival (P < .05; Tables II and III). The results regarding LPN response indicated that group I had the best 5-year LPN recurrencefree survival, locoregional recurrence-free survival, relapse-free survival, and overall survival, followed by groups II and III. Group III had significantly poorer LPN recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival than groups I and II (P < .05; Fig).
No. of patients
LPN recurrence-free survival (%) 5-year (95% CI)
5-year (95% CI)
P value*
Relapse-free survival (%) 5-year (95% CI)
P value*
Overall survival (%) 5-year (95% CI)
P value*
(92.4–97.0) (93.8–99.3)
.369
92.3 (89.5–95.0) 95.4 (92.3–98.5)
.171
77.6 (73.4–81.9) 79.8 (73.9–85.8)
.633
84.5 (81.1–87.9) 86.9 (81.8–92.0)
.584
(92.6–97.4) (93.0–98.3)
.745
91.9 (88.9–94.9) 95.3 (92.5–98.0)
.133
77.6 (73.1–82.2) 79.3 (73.9–84.0)
.349
88.7 (85.2–92.2) 84.6 (79.7–89.5)
.166
(91.0–97.6) (93.7–97.9)
.302
90.0 (85.8–94.2) 94.9 (92.6–97.2)
.037
69.8 (63.2–76.3) 83.1 (79.2–87.0)
<.001
83.7 (78.5–89.0) 88.9 (85.6–92.3)
.085
(91.4–97.0) (94.2–98.6)
.344
93.1 (90.1–96.1) 93.4 (90.5–96.4)
.874
78.5 (73.5–83.4) 78.2 (73.3–83.1)
.767
87.5 (83.4–91.6) 86.6 (82.6–90.7)
.444
(94.3–97.7) (71.6–98.6)
.009
93.9 (91.8–95.9) 80.1 (64.2–96.0)
.010
79.6 (76.1–83.0) 55.4 (36.1–74.7)
.001
88.1 (85.2–90.9) 68.2 (51.0–85.5)
.001
(93.3–97.6) (91.5–98.1)
.381
94.1 (91.7–96.5) 91.4 (87.3–95.6)
.058
81.7 (77.8–85.7) 70.9 (64.1–77.8)
<.001
90.3 (87.2–93.4) 80.1 (74.1–86.1)
<.001
(93.3–97.1) (90.1–100)
.722
93.4 (91.2–95.6) 91.6 (83.7–99.5)
.431
79.2 (75.6–82.8) 68.9 (55.8–82.1)
.034
88.4 (85.5–91.3) 74.1 (61.8–86.3)
<.001
(93.9–97.4) (69.7–100)
.029
93.9 (91.8–95.9) 76.2 (58.0–94.4)
.001
78.6 (75.1–82.2) 70.2 (50.2–90.2)
.206
87.1 (84.2–90.0) 85.7 (70.7–100)
.988
(95.9–100) (92.3–96.6)
.065
95.7 (91.9–99.4) 92.6 (90.1–95.1)
.172
80.7 (73.5–88.0) 78.0 (74.1–81.9)
.683
86.1 (79.8–92.5) 87.3 (84.1–90.5)
.980
(93.9–97.4) (70.7–100)
.073
93.9 (91.9–96.0) 77.5 (59.9–95.0)
.006
79.1 (75.6–82.6) 60.9 (40.9–80.8)
.062
87.7 (84.9–90.6) 72.7 (53.6–91.4)
.207
(97.0–99.7) (85.7–94.1)
<.001
96.6 (94.6–98.5) 87.4 (82.8–92.1)
<.001
80.6 (76.4–84.8) 74.4 (68.2–80.5)
.085
89.1 (85.7–92.4) 83.9 (78.5–89.3)
.093
Surgery j 2016
(continued)
ARTICLE IN PRESS
Gender M 398 94.7 F 182 96.5 Age (y) #60 338 95.0 >60 242 95.7 Distance from anal verge (cm) <5 205 94.3 $5 375 95.6 Tumor size (cm) <5 286 94.2 $5 294 96.4 Histologic grade Low 551 96.0 High 29 85.1 CEA level at pre-CRT (ng/mL) #5 396 95.5 >5 184 94.8 CEA level at post-CRT (ng/mL) #5 527 95.2 >5 53 95.8 cT classification cT3 559 95.6 cT4 21 85.2 cN classification cN0 121 98.3 cN+ 459 94.5 cCRM Negative 557 95.7 Positive 23 85.7 LAD of LPN at pre-CRT (mm) <5 367 98.3 $5 213 89.9
P value*
Locoregional recurrence-free survival (%)
6 Kim et al
Table II. Univariate analysis according to clinicopathologic factors for LPN recurrence-free survival, locoregional recurrence-free survival, relapse-free survival, and overall survival
No. of patients
LPN recurrence-free survival (%)
Relapse-free survival (%)
Overall survival (%)
5-year (95% CI)
P value*
5-year (95% CI)
P value*
5-year (95% CI)
(97.4–99.7) (80.6–91.9)
<.001
97.0 (95.4–98.7) 82.9 (76.7–89.0)
<.001
81.7 (77.9–85.5) 69.2 (61.6–76.8)
<.001
89.1 (86.0–92.2) 81.6 (74.9–88.3)
.032
(93.8–97.5) (85.8–98.8)
.089
94.3 (92.2–96.3) 86.9 (78.4–95.5)
.020
78.7 (75.0–82.3) 74.0 (62.8–85.1)
.428
87.5 (84.2–90.2) 85.5 (76.1–95.0)
.813
(96.3–99.1) (80.1–92.6)
<.001
95.8 (93.9–97.7) 83.8 (77.0–90.5)
<.001
80.0 (76.1–83.8) 72.5 (64.5–80.6)
.059
88.3 (85.2–91.4) 82.7 (75.7–89.6)
.121
(96.2–98.9) (62.3–85.9)
<.001
95.6 (93.8–97.4) 71.7 (59.4–84.0)
<.001
80.8 (77.2–84.3) 56.9 (43.8–70.1)
<.001
88.5 (85.6–91.4) 74.9 (63.4–86.3)
.001
(94.1–97.5) (61.4–97.4)
<.001
94.0 (91.9–96.0) 70.6 (47.7–93.4)
<.001
78.7 (75.2–82.2) 62.2 (39.3–85.1)
.116
87.6 (84.7–90.5) 71.6 (50.0–93.1)
.023
(97.4–99.7) (88.3–98.5) (62.3–85.9)
<.001
97.0 (95.4–98.7) 89.4 (83.2–95.6) 71.7 (59.4–84.0)
<.001
81.7 (77.9–85.5) 76.6 (67.8–85.4) 56.9 (43.4–70.4)
<.001
89.1 (86.0–92.2) 85.7 (78.1–93.3) 74.9 (63.4–86.3)
.006
(93.3–97.2) (90.6–99.8)
.904
94.1 (92.0–96.3) 88.2 (81.4–95.1)
.073
80.7 (77.1–84.3) 65.0 (54.6–75.3)
<.001
88.0 (85.0–91.0) 81.7 (73.2–90.1)
.305
(92.7–97.5) (92.9–98.1)
.621
92.4 (89.4–95.4) 94.3 (91.4–97.2)
.236
76.6 (71.8–81.5) 80.4 (75.4–85.4)
.173
86.4 (82.5–90.3) 88.1 (84.0–92.3)
.111
(93.5–97.1) (83.9–100)
.837
93.4 (91.3–95.5) 88.9 (74.4–100)
.435
78.6 (75.1–82.1) 69.2 (46.3–92.2)
.284
87.6 (84.7–90.5) 70.4 (48.2–92.6)
.002
68.6 (58.6–78.7) 86.8 (82.8–90.7) 96.9 (94.2–99.6)
<.001
(95.6–81.3) (92.1–97.2) (98.2–100)
.002
87.8 (73.0–90.5) 93.1 (90.2–95.6) 98.8 (97.2–100)
<.001
55.6 (40.5–62.6) 77.8 (73.0–82.5) 91.6 (87.4–95.8)
<.001
P value*
Kim et al 7
*Log-rank test. LPN, Lateral pelvic node; CI, confidence interval; CEA, carcinoembryonic antigen; CRT, chemoradiotherapy; cCRM, clinical circumferential resection margin; LAD, long-axis diameter; SAD, short-axis diameter.
ARTICLE IN PRESS
P value*
5-year (95% CI)
SAD of LPN at pre-CRT (mm) <5 423 98.6 $5 157 86.2 Multiplicity of LPN at pre-CRT No 514 95.7 Yes 66 92.3 LAD of LPN at post-CRT (mm) <5 454 97.7 $5 126 86.4 SAD of LPN at post-CRT (mm) <5 521 97.6 $5 59 74.1 Multiplicity of LPN at post-CRT No 560 95.8 Yes 20 79.4 LPN response Group I 423 98.6 Group II 98 93.4 Group III 59 74.1 Operation SPS 492 95.3 APR 88 95.2 Preoperative chemotherapy FL 326 95.1 Others 254 95.5 Adjuvant chemotherapy Yes 561 95.3 No 19 94.4 Tumor regression grade Grade 1 87 88.4 Grade 2 320 94.7 Grades 3–4 173 99.4
Locoregional recurrence-free survival (%)
Surgery Volume j, Number j
Table II. (continued)
8 Kim et al
Table III. Multivariate analysis according to clinicopathologic factors for LPN recurrence-free survival, locoregional recurrence-free survival, relapsefree survival, and overall survival LPN recurrence-free survival HR
95% CI
Relapse-free survival
P value*
HR
95% CI
P value*
HR
95% CI
—
— —
— —
—
1.000 0.596
— 0.422–0.843
—
— —
— —
—
— —
— —
—
— —
— —
—
— —
.035
1.000 4.202
— 1.593–11.084
.004
.003 <.001
1.000 3.575 10.327
— 1.612–7.932 4.932–21.624
—
— — 1.000 0.374 0.105
.034 .006
Overall survival
P value*
HR
95% CI
P value*
— —
—
—
—
1.000 2.022
— 1.010–4.048
.047
— —
—
1.000 1.836
— 1.191–2.830
.006
— —
— —
—
— —
— —
.002 <.001
1.000 1.273 2.284
— 0.812–1.996 1.449–3.600
.293 <.001
1.000 1.137 2.280
— 0.628–2.057 1.301–3.996
.672 .004
— —
—
— —
— —
—
1.000 3.620
— 1.634–8.016
.002
— 0.192–0.727 0.030–0.369
.004 <.001
1.000 0.361 0.153
— 0.246–0.529 0.087–0.269
<.001 <.001
1.000 0.406 0.121
— 0.253–0.650 0.052–0.278
<.001 <.001
.003
ARTICLE IN PRESS
Distance from anal verge (cm) <5 — — $5 — — Histologic grade Low — — High — — CEA level at pre-CRT (ng/mL) #5 — — >5 — — cT classification cT3 1.000 — cT4 3.826 1.098–13.334 LPN response Group I 1.000 — Group II 5.181 1.774–15.128 Group III 20.553 7.910–53.407 Adjuvant chemotherapy Yes — — No — — Tumor regression grade Grade 1 1.000 — Grade 2 0.338 0.172–0.875 Grades 3–4 0.110 0.023–0.512
Locoregional recurrence-free survival
—
*Multivariate analysis using Cox proportional hazards model. LPN, Lateral pelvic node; HR, hazard ratio; CI, confidence interval; CEA, carcinoembryonic antigen; CRT, chemoradiotherapy.
Surgery j 2016
ARTICLE IN PRESS Surgery Volume j, Number j
Kim et al 9
Fig. LPN recurrence-free survival (A), locoregional recurrence-free survival (B), relapse-free survival (C), and overall survival curves (D) according to the LPN responses: group I, short-axis diameter of LPN <5 mm at pre- and postCRT; group II, short-axis diameter of LPN $5 mm at pre-CRT and short-axis diameter of LPN <5 mm at post-CRT; and group III, short-axis diameter of LPN $5 mm at pre- and post-CRT. *log-rank test. LPN, Lateral pelvic node; CRT, chemoradiotherapy.
Group II tended to have poorer LPN recurrencefree survival, locoregional recurrence-free survival, relapse-free survival, and overall survival than group I, but the differences were significant only for LPN recurrence-free survival and locoregional recurrence-free survival (P < .05; Fig). DISCUSSION The question of whether LPN metastasis should be considered a sign of systemic disease5,14 or a potentially curable regional disease is
controversial.1,3,13,15,22 Our previous studies and others indicate that LPN metastasis is associated with an increased risk of locoregional recurrence and that about 50% of locoregional recurrences occur within the LPN-bearing pelvic sidewall without evidence of distant metastasis.1,13,15,22 A recent large multicenter study by Akiyoshi et al11 analyzed 11,567 patients with low rectal cancer and showed that patients with LPN metastasis have survival rates similar to those with N2 disease and better survival rates than those with stage IV
ARTICLE IN PRESS 10 Kim et al
disease. Similarly, the present study analyzed 580 patients with locally advanced mid/low rectal cancer treated with preoperative CRT followed by TME and showed that the LPN response to preoperative CRT, together with tumor regression grade, was consistently an independently significant prognostic factor for LPN recurrence, locoregional recurrence, relapse, and survival in these patients. The LPN responses to preoperative CRT in this study included 3 different groups: group I (no suspected LPN), group II (responsive LPNs), and group III (persistent LPNs); these findings imply that LPN involvement and LPN response to preoperative CRT could be among the most important prognostic factors for influencing recurrence and overall survival. In addition, 13 of 29 patients (44.8%) with LPN recurrence had no evidence of distant metastasis at the time of recurrence, and 6 of 13 patients (46.2%) with LPN recurrence without distant metastasis had persistent LPN following preoperative CRT (group III). These findings suggest that LPN recurrence is one of the important potential sites for locoregional recurrence in patients with locally advanced mid/ low rectal cancer treated with preoperative CRT followed by TME and could potentially be cured using strategies to treat LPN, including LPN dissection, in selected patients. The indications and benefits of LPN dissection for patients with locally advanced rectal cancer treated with preoperative CRT followed by TME have remained unclear.6,8,9,16 A randomized study showed that LPN dissection is associated with a high frequency of unnecessary urinary and/or sexual dysfunction without significant differences in locoregional recurrence and overall survival compared with patients receiving preoperative CRT.8 Watanabe et al9 reported no differences in locoregional recurrence or overall survival between patients who underwent preoperative CRT with TME and those who underwent TME with LPN dissection. These findings suggest that routine LPN dissection for all patients with locally advanced mid/low rectal cancer may be overtreatment. Although no conclusions regarding the benefit of LPN dissection for patients with suspected metastatic LPNs who received preoperative CRT followed by TME could be drawn, the LPN dissection indication for patients with suspected metastatic LPNs may be affected by preoperative CRT due to its cytotoxic effects on metastatic LPNs and the primary tumor. A recent retrospective analysis of 66 patients with suspected metastatic LPNs who underwent preoperative CRT followed by TME and LPN dissection
Surgery j 2016
showed that the group with persistent LPNs following preoperative CRT had a significantly higher incidence of residual tumors and poorer oncologic outcomes, ie, higher recurrence and lower survival, than the group with LPNs responsive to preoperative CRT.23 Similarly, we showed here that group III (persistent LPN) had significantly poorer LPN recurrence-free survival, locoregional recurrencefree survival, relapse-free survival, and overall survival than groups II (responsive LPN) and I (no suspected LPN). Furthermore, although group II (responsive LPN) tended to have poorer LPN recurrence-free survival, locoregional recurrencefree survival, relapse-free survival, and overall survival than group I (no suspected LPN), the differences in relapse-free survival and overall survival between the groups were not significant (Fig). These findings suggest that, among patients with suspected metastatic LPN, the patients with LPN responsive to preoperative CRT (group II) may not benefit from LPN dissection, and the patients with persistent LPN following preoperative CRT (group III) may benefit from LPN dissection. Therefore, further large-scale studies are warranted to assess the risks and benefits of LPN dissection in these patients. The present study had some limitations. First, the accuracy of nodal staging using MRI is less reliable than that of local tumor staging, and there is no consensus regarding the size criteria for predicting metastatic lymph nodes.24 In addition, the study has been analyzed by a single radiologist, and the criteria for MRI assessments of LPN response to treatment have not been well validated; thus, further study of how to validate MRI assessments of LPN responses to treatment is warranted. Lymph node size, however, remains the most reliable parameter to diagnose metastatic lymph nodes by MRI, and 5 mm is the most common criterion for the upper limit of a normal lymph node.20,25,26 Second, the study did not have an LPN dissection component and did not evaluate the effects of LPN dissection in patients with persistent LPNs following preoperative CRT. However, because invasive operative procedures, such as LPN dissection, can result in urinary and sexual dysfunction,6,7,10 it is important to use strict selection criteria to identify the subgroup of patients who can benefit from LPN dissection. Third, the study did not examine and compare the effectiveness of strategies to treat LPN. These strategies include operation, additional
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chemotherapy, radiotherapy (including intraoperative radiotherapy), and combinations thereof. Thus, further large-scale and comprehensive studies of various strategies to treat LPN are needed. In conclusion, our data show that the LPN responses to preoperative CRT were significant prognostic factors associated with LPN recurrence and survival in patients with locally advanced mid/ low rectal cancer treated with preoperative CRT followed by TME. These findings suggest that LPN responses to preoperative CRT could be useful therapeutic indicators to identify patients who could benefit from LPN dissection and that LPN dissection might be considered in patients with initially suspected LPN according to the LPN response to preoperative CRT. REFERENCES 1. Ueno M, Oya M, Azekura K, Yamaguchi T, Muto T. Incidence and prognostic significance of lateral lymph node metastasis in patients with advanced low rectal cancer. Br J Surg 2005;92:756-63. 2. Yano H, Moran BJ. The incidence of lateral pelvic side-wall nodal involvement in low rectal cancer may be similar in Japan and the West. Br J Surg 2008;95:33-49. 3. Kim TH, Jeong SY, Choi DH, Kim DY, Jung KH, Moon SH, et al. Lateral lymph node metastasis is a major cause of locoregional recurrence in rectal cancer treated with preoperative chemoradiotherapy and curative resection. Ann Surg Oncol 2008;15:729-37. 4. Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001;345:638-46. 5. Kusters M, Holman FA, Martijn H, Nieuwenhuijzen GA, Creemers GJ, Daniels-Gooszen AW, et al. Patterns of local recurrence in locally advanced rectal cancer after intraoperative radiotherapy containing multimodality treatment. Radiother Oncol 2009;92:221-5. 6. Georgiou P, Tan E, Gouvas N, Antoniou A, Brown G, Nicholls RJ, et al. Extended lymphadenectomy versus conventional surgery for rectal cancer: A meta-analysis. Lancet Oncol 2009;10:1053-62. 7. Lee JW, Lee JH, Kim JG, Oh ST, Chung HJ, Lee MA, et al. Comparison between preoperative and postoperative concurrent chemoradiotherapy for rectal cancer: An institutional analysis. Radiat Oncol J 2013;31:155-61. 8. Nagawa H, Muto T, Sunouchi K, Higuchi Y, Tsurita G, Watanabe T, et al. Randomized, controlled trial of lateral node dissection vs. nerve-preserving resection in patients with rectal cancer after preoperative radiotherapy. Dis Colon Rectum 2001;44:1274-80. 9. Watanabe T, Tsurita G, Muto T, Sawada T, Sunouchi K, Higuchi Y, et al. Extended lymphadenectomy and preoperative radiotherapy for lower rectal cancers. Surgery 2002; 132:27-33. 10. Kim MS, Keum KC, Rhee WJ, Kim H, Kim M, Choi S, et al. The location of locoregional recurrence in pathologic T3N0, non-irradiated lower rectal cancer. Radiat Oncol J 2013;31:97-103.
Kim et al 11
11. Akiyoshi T, Watanabe T, Miyata S, Kotake K, Muto T, Sugihara K, et al. Results of a Japanese nationwide multiinstitutional study on lateral pelvic lymph node metastasis in low rectal cancer: Is it regional or distant disease? Ann Surg 2012;255:1129-34. 12. Liang JT. Technical feasibility of laparoscopic lateral pelvic lymph node dissection for patients with low rectal cancer after concurrent chemoradiation therapy. Ann Surg Oncol 2011;18:153-9. 13. Sugihara K, Kobayashi H, Kato T, Mori T, Mochizuki H, Kameoka S, et al. Indication and benefit of pelvic sidewall dissection for rectal cancer. Dis Colon Rectum 2006;49:1663-72. 14. Syk E, Torkzad MR, Blomqvist L, Ljungqvist O, Glimelius B. Radiological findings do not support lateral residual tumour as a major cause of local recurrence of rectal cancer. Br J Surg 2006;93:113-9. 15. Ueno H, Mochizuki H, Hashiguchi Y, Ishiguro M, Miyoshi M, Kajiwara Y, et al. Potential prognostic benefit of lateral pelvic node dissection for rectal cancer located below the peritoneal reflection. Ann Surg 2007;245:80-7. 16. Kim JC, Takahashi K, Yu CS, Kim HC, Kim TW, Ryu MH, et al. Comparative outcome between chemoradiotherapy and lateral pelvic lymph node dissection following total mesorectal excision in rectal cancer. Ann Surg 2007;246:754-62. 17. Kim YH, Kim DY, Kim TH, Jung KH, Chang HJ, Jeong SY, et al. Usefulness of magnetic resonance volumetric evaluation in predicting response to preoperative concurrent chemoradiotherapy in patients with resectable rectal cancer. Int J Radiat Oncol Biol Phys 2005;62:761-8. 18. Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 1997;12:19-23. 19. Kim DJ, Kim JH, Lim JS, Yu JS, Chung JJ, Kim MJ, et al. Restaging of rectal cancer with MR imaging after concurrent chemotherapy and radiation therapy. Radiographics 2010; 30:503-16. 20. Kim JH, Beets GL, Kim MJ, Kessels AG, Beets-Tan RG. Highresolution MR imaging for nodal staging in rectal cancer: Are there any criteria in addition to the size? Eur J Radiol 2004;52:78-83. 21. Kim MJ, Kim TH, Kim DY, Kim SY, Baek JY, Chang HJ, et al. Can chemoradiation allow for omission of lateral pelvic node dissection for locally advanced rectal cancer? J Surg Oncol 2015;111:459-64. 22. Sato H, Maeda K, Maruta M, Masumori K, Koide Y. Who can get the beneficial effect from lateral lymph node dissection for Dukes C rectal carcinoma below the peritoneal reflection? Dis Colon Rectum 2006;49:S3-12. 23. Oh HK, Kang SB, Lee SM, Lee SY, Ihn MH, Kim DW, et al. Neoadjuvant chemoradiotherapy affects the indications for lateral pelvic node dissection in mid/low rectal cancer with clinically suspected lateral node involvement: A multicenter retrospective cohort study. Ann Surg Oncol 2014;21:2280-7. 24. Bipat S, Glas AS, Slors FJ, Zwinderman AH, Bossuyt PM, Stoker J. Rectal cancer: Local staging and assessment of lymph node involvement with endoluminal US, CT, and MR imaging---A meta-analysis. Radiology 2004;232:773-83. 25. Matsuoka H, Nakamura A, Masaki T, Sugiyama M, Nitatori T, Ohkura Y, et al. Optimal diagnostic criteria for lateral pelvic lymph node metastasis in rectal carcinoma. Anticancer Res 2007;27:3529-33. 26. Blomqvist L, Rubio C, Holm T, Machado M, Hindmarsh T. Rectal adenocarcinoma: Assessment of tumour involvement of the lateral resection margin by MRI of resected specimen. Br J Radiol 1999;72:18-23.