Multimodal preoperative evaluation system in surgical decision making for rectal cancer: a randomized controlled trial.

PURPOSE: Multimodal preoperative evaluation (MPE) is a novel strategy for surgical decision making, incorporating the transrectal ultrasound (TRUS), 64 multi-slice spiral computer tomography (MSCT), and serum amyloid A protein (SAA) for rectal cancer. This trial aims to determine the accuracy of MPE in preoperative staging and its role in surgical decision making for rectal cancer.
METHODS: Two hundred twenty-five participants with histologically proven rectal cancer with tumor height less than 10 cm were randomly assigned into three arms in the ratio 1:1:1. Arm A (MPE) was multimodal staged by the combination of MSCT, TRUS, and SAA. Arm B (MSCT+SAA) was staged by MSCT and SAA. Arm C (MSCT) was staged only by MSCT. The primary endpoints were the accuracy of preoperative staging and expected surgical procedures. This study is registered as an International Standard Randomised Controlled Trial, number ChiCTR-DT-00000409.
RESULTS: The analysis showed statistical difference in the accuracy of T staging between arm A and B (94.6% vs. 77.8%, P=0.003) and arm A and C (94.6% vs. 80.6%, P=0.010). Statistical difference was also observed between the accuracies of preoperative N staging between arm A and C (85.1% vs. 69.4%, P=0.023) and arm A and B (85.1% vs. 84.7%, P=0.029). Surgical decision making in arm A was more accurate than that in arm C (95.9% vs. 80.6%, P=0.001). Pathological T stage (P<0.001), N stage (P<0.001), tumor node metastasis stage (P<0.001), serum level of SAA (P=0.002), and tumor height (P=0.030) were significantly associated with final surgical procedures.
CONCLUSION: MPE is an effective strategy in preoperative staging and more accurate than other available strategies in surgical decision making for rectal cancer.

RCT Entities:   Population Interventions Outcomes

Introduction

Preoperative evaluation of rectal carcinoma is crucial in the decision making of preoperative treatment and surgical procedures. All the choices of surgical procedures, e.g., extended surgery or local excision for rectal cancer, should be tailored on the basis of accurate preoperative staging [1-4]. Recently, the evidence-based move to selective preoperative chemoradiotherapy for selected patients has intensified the need to develop accurate image-based staging systems [5]. Additionally, the use of preoperative therapies may have dramatic effects on the consequential pathological findings. Therefore, accurate details prior to treatment are essential [6].

Various staging modalities for rectal cancer include transrectal ultrasound (TRUS), computed tomography (CT), and MR imaging (MRI) with or without endorectal coil. Current evidence shows that TRUS is the most established and preferred modality for T staging of rectal cancer [7]; however, no ideal imaging technique is available for evaluation of metastatic lymph nodes [8]. The multidetector CT is still the first option for distant metastatic diseases [9].

Serum amyloid A protein (SAA), also termed as acute phase protein, is a major factor in altering high-density lipoproteins metabolism during inflammation [10]. Glojnaric et al. [11] reported a significant increase of SAA level in patients with colorectal cancer. More recent study showed that an increased SAA level was associated with metastatic lymph nodes in rectal cancer, which indicated the potential value for preoperatively noninvasive identification of lymph nodes [12]. Our previous study confirmed that the preoperative evaluation strategy combining 64 multi-slice spiral computer tomography (MSCT) with SAA improved the accuracy of preoperative staging, particularly in N staging. This strategy was more useful in planning the surgical resection than MSCT alone as well [13].

In this prospective, randomized, and controlled study, the multimodal preoperative evaluation (MPE) system was set for surgical decision making in rectal cancer, incorporating TRUS, MSCT, and SAA. The MPE system uses TRUS for T staging, MSCT for M staging, and assesses N stage based on MSCT with SAA for identification. This trial aims to determine the accuracy of MPE in preoperative staging and its role in surgical decision making for rectal cancer. In order to clarify the role of MPE in surgical decision making, this trial is designed as a randomized controlled study.

Materials and methods

All the study subjects were proven to be histologically confirmed colorectal cancer patients. Eligibility criteria included tumor height (proximal from dentate line) less than 10 cm assessed by colonoscopy, tumor which can be passed completely during colonoscopy, and operable diseases. Exclusion criteria included patients with a history of infection within the previous 1 month; immune system disease history; and inflammatory bowel disease, bowel obstruction, or a history of chronic diarrhea; and a neo-adjuvant treatment history.

This was a prospective, single-center, randomized trial conducted between July 2008 and March 2009. Patients were randomly assigned into three arms in the ratio 1:1:1 done by a computer-generated randomization list. Concealment of treatment allocation was achieved with the use of sealed opaque envelops each containing a unique study number and prepared independently by a secretary.

Three arms were compared, each with a different workup of technique for preoperative staging. Arm A (n = 75) was multimodal staged by the combination of MSCT, TRUS, and SAA. Arm B (n = 75) was staged by MSCT and SAA. Arm C (n = 75) was the control group, staged only by MSCT.

MSCT examinations were performed for all patients in three arms by using a Philips Brilliance 64-slice CT scanner (Philips Medical Systems, Best, The Netherlands). Before MSCT examination, all patients were prepared with laxative and enema. Sufflation of approximately 100 ml of air into the rectum was performed, and sequences were obtained with one breath-hold from the level of the diaphragm to the anus in approximately 10 s. The slice interval was adjusted to 5 mm. Imaging of MDCT was obtained using multi-planar reformation technique. Enhancement medium (Omnipaque: GE Healthcare, Buckinghamshire, United Kingdom) was administered intravenously for all patients. Computed tomography was prospectively evaluated prior to surgery by one radiologist (Junhua Wu). The reader was blinded to any patient information. The CT scans were assessed for the depth of tumor invasion and the presence of regional lymph node metastases. CT-tumor node metastasis (TNM) stage was performed according to the Thoeni’s classification (Table 1) [14]. Metastatic lymph nodes were considered to be present if their diameter exceeded 8 mm.

Table 1

The preoperative staging standards of three arms

Preoperative TNM stage	Arm A (MPE)	Arm B (MSCT and SAA)	Arm C (MSCT)
T stage
T1	Submucosa was irregularly thinned by a hypoechoic tumor mass showed by TRUS	Intraluminal polypoid mass without thickening of the bowel wall showed by MSCT	Intraluminal polypoid mass without thickening of the bowel wall showed by MSCT
T2	Complete disruption of submucosa, often with thickening of the muscularis propria showed by TRUS
T3	The border between the muscularis propria and serosa or perirectal fat was irregular or serrated showed by TRUS	Thickening of the bowel wall (>0.5 cm) without invasion of surrounding tissue showed by MSCT	Thickening of the bowel wall (>0.5 cm) without invasion of surrounding tissue showed by MSCT
T4	Extension to the adjacent structures or organs showed by TRUS	Invasion of surrounding tissue walls showed by MSCT	Invasion of surrounding tissue walls showed by MSCT
N stage
N0	No visible lymph node, or a lymph node (diameter <8 mm) showed by MSCT with SAA level <3.30 mg/L	No visible lymph node, or a lymph node (diameter <8 mm) showed by MSCT with SAA level <3.30 mg/L	No visible lymph node, or a lymph node (diameter <8 mm) showed by MSCT
N1	1. A lymph node (diameter <8 mm) showed by MSCT but SAA level ≥3.30 mg/L; 2. serum SAA level ≥8.90 mg/L; and 3. a lymph node (diameter ≥8 mm) was measured by MSCT	1. A lymph node (diameter <8 mm) showed by MSCT but SAA level ≥3.30 mg/L; 2. serum SAA level ≥8.90 mg/L; and 3. a lymph node (diameter ≥8 mm) was measured by MSCT	A lymph node (diameter ≥8 mm) was measured by MSCT
M stage
M0	No distant metastases were found by MSCT	No distant metastases were found by MSCT	No distant metastases were found by MSCT
M1	Distant metastases were found by MSCT	Distant metastases were found by MSCT	Distant metastases were found by MSCT

TRUS was performed for arm A by using a Philips HDI 5000 ultrasound scanner (Philips Medical Systems, Bothell, WA, USA). The rectal probe measures 16 cm in length with a head diameter of 21 mm. During the examination, the frequency can be switched from 7.5 MHz to 5 MHz with a maximum tissue penetration of approximately 7 cm for the latter. The beams can be emitted in line with or transverse to the longitudinal axis of the rectum. TRUS was prospectively evaluated prior to surgery by one ultrasonologist (Yingyu Shi) who have more than 5-year experience on TRUS. The reader was blinded to any patient information. The TRUS scans were assessed for the depth of tumor invasion following Hildenbrandt’s principles (Table 1) [15].

Venous blood specimens in arm A and B were taken on the third day before surgery and sent to Clinical Immunology Laboratory for test. SAA concentration was measured by immunofixed time nephelometry (Dade Behring Diagnostics). The serum SAA level was measured according to the manufacturer’s instructions. In the meantime, venous blood samples were also submitted to Clinical Blood Laboratory for a blood routine test in order to exclude inflammatory cases.

Surgeons collected the information of preoperative evaluation and performed the preoperative staging according to Table 1 [13]. Two senior surgeons developed expected surgical procedures according to preoperative evaluation together and performed the final operative procedures. Surgical procedures were classified as sphincter-preserving radical excision, non-sphincter-preserving radical excision, and palliative colostomy. In nearly all the cases, surgery was performed within a week. Resected specimens were examined by pathologists without knowing the preoperative findings. The pathological findings were assessed according to TNM classification of colorectal cancer, 6th edition, by American Joint Committee on Cancer [16].

The primary endpoints were the accuracy of preoperative staging and concordance rate of expected surgical procedures. The secondary endpoint was association between final surgical procedures and clinicopathological factors. The clinicopathological factors included tumor height, general category, texture of tumor, histology, differentiation, pT stage, pN stage, pM stage, pTNM stage, and preoperative serum levels of SAA.

Statistical analysis was performed by using the SPSS® version 17.0 (SPSS, Chicago, IL, USA). Continuous variables and percentages were compared between groups by using the Mann–Whitney test or chi-square test, respectively. Additionally, the Spearman test for univariate analysis was performed. P = 0.05 (two-sided) was considered as the limit of significance.

This study is registered as an International Standard Randomised Controlled Trial, number ChiCTR-DT-00000409.

Results

From July 2008 to March 2009, 225 patients were randomized. Seven patients were excluded after randomization because of neoadjuvant chemotherapy (n = 5) and hospital infections before surgery (n = 2). The baseline characteristics relating to the remaining 218 patients (71 in Arm A, 72 in Arm B, and 72 in Arm C) are shown in Table 2. The three arms were generally well-matched in all terms. Figure 1 shows the trial profile.

Table 2

Baseline characteristics of three arms

Baseline characteristics	Arm A	Arm B	Arm C	P value
n	74	72	72
Male	51 (68.9)	47 (65.3)	40 (55.6)	0.230
Female	23 (31.1)	25 (34.7)	32 (44.4)
Age (years)	59 (30–80)	60.5 (22–81)	60 (28–80)	0.543
Tumor height (cm)	5 (1–9)	7 (1–10)	6 (1–11)	0.070
Pathological TNM stage
I	11 (14.9)	8 (11.1)	21 (29.2)	0.118
II	20 (27.0)	22 (30.6)	14 (19.4)
III	34 (45.9)	36 (50.0)	31 (43.1)
IV	9 (12.2)	6 (8.3)	6 (8.3)

aData are medians with ranges in parentheses or numbers with percentages in parentheses.

Fig. 1

Trial profile

Tables 3, 4, and 5 present the agreement of preoperative staging and pathological staging in three arms. Regarding depth of tumor invasion (Table 3), the overall accuracy was 94.6% (70/74) in arm A, 77.8% (56/72) in arm B, and 80.6% (58/72) in arm C. The analysis showed that MPE had a significantly higher accuracy of T staging than other preoperative evaluation strategies in arm B (P = 0.003) and C (P = 0.010). With regard to lymph nodes metastasis (Table 4), the accuracy, sensitivity, and specificity were 85.1% (63/74), 90.2% (37/41), and 78.8% (26/33) in arm A, 84.7% (61/72), 85.7% (36/42), and 83.3% (25/30) in arm B, and 69.4% (50/72), 54.3% (19/35), and 83.8% (31/37) in arm C, respectively. The analysis indicated that the accuracy of preoperative N staging was significantly different between arm A and C (P = 0.023) and arm A and B (P = 0.029). Moreover, the incorporation of SAA into MSCT led to significantly higher sensitivity (arm A vs. C, P < 0.001; arm B vs. C, P = 0.002), while lower specificity led to slight sensitivity (arm A vs. C, P = 0.592; arm B vs. C, P = 0.961). All those patients with distant metastasis were diagnosed correctly, and the accuracy of preoperative M staging was 100% in three arms (Table 4). As for overall preoperative TNM staging (Table 5), the accuracy of arm A was 82.4% (61/74), and this did not differ significantly from the figures obtained from arm B and C (81.9% and 70.8%, respectively, P > 0.05).

Table 3

Preoperative vs. pathological T staging in three arms

	Arm A				Arm B			Arm C
T stage	preT1	preT2	preT3	preT4	preT1–2	preT3	preT4	preT1–2	preT3	preT4
pT1	4	0	0	0	1	0	0	4	2	0
pT2	0	8	1	0	5	2	0	13	3	0
pT3	0	1	9	1	1	7	3	0	5	0
pT4	0	0	1	49	0	10	43	0	9	36
n	4	9	11	50	7	19	46	17	19	36

Table 4

Preoperative vs. pathological N and M staging in three arms

	Arm A		Arm B		Arm C
N stage	preN0	preN1	preN0	preN1	preN0	preN1
pN0	26	7	25	5	31	6
pN1–2	4	37	6	36	16	19
n	30	44	31	41	47	25
M stage	preM0	preM1	preM0	preM1	preM0	preM1
pM0	65	0	66	0	66	0
pM1	0	9	0	6	0	6
n	65	9	66	6	66	6

Table 5

Preoperative vs. pathological TNM classification in three arms

	Arm A				Arm B				Arm C
TNM stage	preI	preII	preIII	preIV	preI	preII	preIII	preIV	preI	preII	preIII	preIV
pI	8	1	2	0	4	1	3	0	17	1	3	0
pII	1	14	5	0	1	19	2	0	0	11	3	0
pIII	1	3	30	0	0	6	30	0	0	14	17	0
pIV	0	0	0	9	0	0	0	6	0	0	0	6
n	10	18	37	9	5	26	35	6	17	26	23	6

Table 6 presents the agreement of expected surgical procedures preoperatively and final surgical procedures postoperatively in three arms. The concordance rate with final surgical procedures was 95.9% (71/74) in arm A, 88.9% (64/72) in arm B, and 80.6% (58/72) in arm C. The analysis showed that MPE was significantly superior to preoperative MSCT evaluation strategy in prediction of surgical procedures (P = 0.001). No statistical difference was observed in the prediction of surgical procedures between arm A and B or arm B and C.

Table 6

Expected surgical procedures preoperatively and final surgical procedures postoperatively in three arms

Expected surgical procedures	n	Final surgical procedures
		SPR	NSPR	PC
Arm A
SPR	58	55	2	1
NSPR	6	0	6	0
PE	10	0	0	10
n	74	55	8	11
Arm B
SPR	57	51	3	3
NSPR	4	2	2	0
PE	11	0	0	11
n	72	53	5	14
Arm C
SPR	50	46	2	2
NSPR	14	5	5	4
PE	8	0	1	7
n	72	51	8	13

SPR sphincter-preserving radical excision, NSPR non-sphincter-preserving radical excision, and PC palliative colostomy

Table 7 presents that pathological T stage (P < 0.001), N stage (P < 0.001), TNM stage (P < 0.001), serum level of SAA (P = 0.002), and tumor height (P = 0.030) were significantly associated with final surgical procedures. However, all the correlation coefficient was small. No significant association was found between final surgical procedure and general category, texture of tumor, histology, differentiation, or pM stage (P > 0.05).

Table 7

The relationship between final operative procedures and clinicopathological factors

Clinicopathological factors	SPR	NSPR	PC	Correlation coefficient	P value
n	159	21	38
Tumor height (cm)	6.26 ± 2.62	4.76 ± 2.68	4.54 ± 2.69	−0.147	0.030
General category				−0.070	0.305
Protrude type	51 (32.1)	7 (33.3)	19 (50.0)
Ulcer type	95 (59.7)	12 (57.1)	13 (34.2)
Infiltrating type	10 (6.3)	1 (4.8)	4 (10.5)
Other type	3 (1.9)	1 (4.8)	2 (5.3)
Texture of tumor				0.066	0.329
Rigid	108 (67.9)	12 (57.1)	31(81.6)
Moderate	43 (27.0)	6 (28.6)	7 (18.4)
Soft	8 (5.1)	3 (14.3)	0
Histology				0.086	0.204
Adenocarcinoma	134 (84.3)	19 (90.4)	33 (86.8)
Mucous adenocarcinoma	17 (10.7)	1 (4.8)	2 (5.3)
Signet ring cell carcinoma	2 (1.2)	0	2 (5.3)
Others	6 (3.8)	1 (4.8)	1 (2.6)
Differentiation				−0.034	0.621
Well-differentiated	1 (0.6)	0	0
Moderately differentiated	111 (69.8)	16 (76.2)	29 (76.3)
Poorly differentiated	38 (23.9)	4 (19.0)	4(10.5)
Others	9 (5.7)	1(4.8)	5 (13.2)
pT				0.297	<0.001
pT1	11 (6.9)	0	0
pT2	32 (20.1)	0	0
pT3	20 (12.6)	5 (23.8)	2 (5.3)
pT4	96 (60.4)	16 (76.2)	36 (94.7)
pN				0.234	<0.001
pN0	84 (52.8)	7 (33.3)	9 (23.7)
pN1	75 (47.2)	14 (66.7)	29 (76.3)
pM				0.097	0.152
pM0	146 (91.8)	20 (95.2)	31 (81.6)
pM1	13 (8.2)	1 (4.8)	7 (18.4)
pTNM				0.290	<0.001
I	40 (25.2)	0	0(0)
II	42 (26.4)	7 (33.3)	7 (18.4)
III	64 (40.3)	13 (61.9)	24 (63.2)
IV	13 (8.1)	1 (4.8)	7 (18.4)
Serum levels of SAA(mg/L)b	8.40 ± 13.84	19.37 ± 45.84	51.46 ± 130.34	0.252	0.002

SPR sphincter-preserving radical excision, NSPR non-sphincter-preserving radical excision, PC palliative colostomy

aData are numbers with percentages in parentheses

bOnly the data of MPE and MSCT + SAA groups were pooled into analysis

Discussion

The results of this trial demonstrate that MPE is an effective strategy in preoperative staging and is more accurate than other available strategies in surgical decision making for rectal cancer. TRUS was successfully used to assess local infiltration in MPE system and led to a significantly higher concordance rate of 94.6% than MSCT. The strategy combining MSCT with SAA to identify metastatic lymph nodes in MPE system led to higher accuracy of 85.1%. Although MPE system is reported to have a non-significant increase of overall TNM staging with an accuracy of 82.4%, this multimodal strategy provides the most accurate preoperative staging and effectively guides surgical decision making. However, we should draw this conclusion with a caution, due to the use of MSCT, not MRI, in this study. Many Chinese patients cannot afford the expensive cost of MRI examination, although increasing evidence show MRI is more superior on local invasion [17-19]. Thus, in this study, we use MSCT instead. The result shows MPE system based on MSCT is effective and affordable to patients in developing countries. The role of MRI in MPE system should be warranted in the future.

Our preoperative T staging finding supports the reported studies of TRUS superior to MSCT in local infiltration. TRUS is the most established and preferred modality for T-staging of rectal cancer with an accuracy of 64–96% [20, 21]. In comparison, even when optimized with rectal contrast, glucagon, and prone thin-slice imaging, CT is still limited for local staging because of its inherent low soft tissue contrast. This does not allow for accurate approximation of T stage unless there is gross invasion of adjacent organs [22]. Although no widely accepted protocol has been reached on the role of diagnostic imaging in the preoperative T staging of rectal cancer, an increasing volume of controlled studies [23-26] and two meta-analysis [7, 8] appear that TRUS provides a more accurate information for local invasion. That is the reason why TRUS is adopted for local staging in the MPE system. However, there is still some space for T staging improvements by 3-D TRUS or biopsy, after TRUS [23, 27].

The novel strategy which combined MSCT with SAA serves as a potential approach to improve the assessment of metastatic lymph nodes. Evaluation of lymph node involvement is a difficult task for radiologists. A node measuring more than 8 mm in the short axis is probably malignant [28]. However, enlarged nodes may be benign and reactive, whereas small nodes may be infiltrated. For rectal cancer, in particular, over half of the metastatic nodes are less than 5 mm, which makes sense in the difficulty to evaluate lymph node involvement [29, 30]. There is a wide variation in accuracy for metastatic nodal detection with TRUS (62–87%), CT (22–73%), and MRI (39–75%) [9]. Thus, current imaging techniques are comparably low in accuracy for lymph nodes staging. The main limitations are the use of size criteria, overstaging in inflammatory enlargement, and understaging in nodes beyond the range of image. Recently at the authors’ institution, a novel strategy combining MSCT (or TRUS) with SAA was documented to identify inflammatory enlargement from lymph node involvement or detect the "invisible" metastatic lymph nodes by imaging since the preoperative levels of inflammatory cytokines were considered to associate with metastatic lymph nodes [12, 13, 31]. These previous studies demonstrated that the combination of MSCT with SAA or TRUS with SAA can improve the accuracy of N staging from 62.9-86.5% or 57.7-77.8%, respectively. Similar result was observed in colonic cancer [32]. For the reason that SAA, incorporated into MSCT staging, makes more small metastatic lymph nodes diagnosed correctly, which means MSCT plus SAA leads to higher sensitivity with acceptably decreased specificity. In this study, MSCT combined with SAA is demonstrated to be effective in N staging assessment again. However, we should only draw a cautious conclusion on this innovative method. Since SAA is not considered as a cancer-specific marker and an increased concentration is associated with a broad spectrum of diseases, stricter eligibility should be developed to promote the MPE system stability [33]. Moreover, other acute-phase proteins associated with metastatic lymph nodes, e.g., C-reactive protein and fibrinogen, highlight that future trials may try to compare them with SAA and determine the best one for MPE system [12, 34].

The MPE strategy led to a significantly increased concordance rate of prediction in surgical procedures for rectal cancer as compared with MSCT alone (95.9% vs. 80.6%, P = 0.001). The additional analysis of this study may explain the role of preoperative staging in improving surgical decision making. Firstly, the result indicates that tumor height remains one of the primary factors that influence the choice of surgical management, provided by TRUS accurately in MPE system. With application on the current concept of concise continent resection, combined with total extirpation of the mesorectum, tumors of the upper and middle third of the rectum can be easily resected with preservation of sphincter. In tumors of the lower third, sphincter is preserved in most cases. The only exceptions are patients in whom the sphincter itself is affected or in whom a distal margin of less than 1 cm cannot be achieved [35]. Secondly, the local infiltration and advances, i.e., T stage, are associated with surgical procedures performed. About 15% rectal cancer involves the uterus, adnexa, posterior vaginal wall, and bladder [36, 37], which can be well-evaluated by TRUS in MPE system. En bloc resection is an aggressive surgical method to manage locally advanced, adherent colorectal tumors in order to achieve a complete resection for lesions that are staged T4 clinically and pathologically [38]. Considering the high incidence of complication, low quality of life, and improved adjuvant therapy efficacy, the palliative colostomy followed by postoperative adjuvant therapy was performed instead in the authors’ institution. Other clinicopathological factors, i.e., N stage, TNM stage, and SAA levels, should be indirectly associated with surgical decision making. High grade of these factors always reflects the local advanced rectal cancer. Therefore, those factors mentioned above provided accurately by MPE system allow for tailoring more appropriate surgical decision making in rectal cancer. Besides, it should be noticed that the surgeon’s expertise also plays a crucial role in surgical options [39].

Conclusion

In this study, MPE system is a more effective strategy than a single-imaging technique in preoperative assessment of the depth of infiltration and metastatic lymph nodes of rectal cancers. In the MPE system, TRUS is successfully used to stage local invasion, whilst MSCT combined with SAA are proven to precisely evaluate lymph node involvement. More importantly, it is a useful aid in the surgical decision making of these patients mainly based on improved preoperative staging. MPE strategy could provide reliable information on pathological T, N, TNM stages, SAA levels, and tumor height which allow for appropriate stage-specific preoperative therapy and prediction of surgical procedures.