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INTRODUCTION
Rectal cancer is a common malignancy of the digestive system, and the incidence rate exhibits an increasing trend annually1. Different stages of rectal cancer should be administered with different therapeutic strategies. Local resection is feasible for early-stage rectal cancer, and standard treatment mode, neoadjuvant radiochemotherapy combined with radical surgery, is recommended for locally advanced rectal cancer2. Neoadjuvant radiochemotherapy helps to reduce tumor size, degrade the staging, increase the sphincter preservation rate, reduce local recurrence rate and prolong the survival time of patients 3,4. The “watch-and-wait” strategy can be adopted for rectal cancer patients with clinical complete response after neoadjuvant radiochemotherapy. Hence, tumors should be accurately re-staged after neoadjuvant therapy.
The endorectal ultrasonography (ERUS) offers an important means for preoperative staging of the primary lesion of rectal cancer, characterized by low cost, high efficiency, and accurate rectal wall stratification, and it is far superior to magnetic resonance imaging (MRI) in the differential diagnosis of T1 and T2 stages 5,6. Although stages T3 and T4 rectal cancer will be reduced to T1 or T2 after neoadjuvant radiochemotherapy, there are currently only few reports on the accuracy of ERUS in the post-radiochemotherapy evaluation of low rectal cancer 7. In this study, ERUS was utilized to evaluate the primary lesion of stage T3 and T4 low rectal cancer before and after neoadjuvant radiochemotherapy, aiming to evaluate the accuracy of ERUS after radiochemotherapy and before surgery, and to investigate the correlations between clinical indices and accuracy.
MATERIALS AND METHODS
A total of 114 patients diagnosed as low rectal cancer in our hospital from February 2018 to December 2020 were enrolled, including 69 males and 45 females, aged (57.3±6.2) years old. Digital anal examination showed that the distance between the tumor lower edge and the anal verge was 4-7 cm. The inclusion criteria were as follows: a) patients who were diagnosed with stage II or III low rectal cancer (regional stage T3/T4) by ERUS and MRI for the first time, and ultrasound probe could scan the tumor completely through the intestinal cavity. b) those who had no surgical contraindications, and were administered with surgery at eight weeks after neoadjuvant radiochemotherapy (2 Gy/time, 22 times, for a total radiotherapy dose of 44 Gy, while oral capecitabine 2500 mg/(m2·d), bid for two weeks followed by one week rest as one cycle, for two cycles. And c) those who underwent neoadjuvant radiochemotherapy and total mesorectal excision, with ERUS examination at 4-8 weeks after neoadjuvant therapy and before surgery, and postoperative pathological staging and Wheeler rectal cancer regression grade (RCRG). The exclusion criteria involved: a) patients whose dosage of neoadjuvant radiochemotherapy did not reach the standard, or b) those whose radical excision did not reach the requirement. In the present study, the staging standard met the National Comprehensive Cancer Network (NCCN) guidelines of 2014.
METHODS
Philips iU 22 color Doppler ultrasound system (Netherlands) with C8-4V intracavitary ultrasonic probe was selected. The frequency of ERUS was 5-10 MHz. The probe was inserted into the rectal cavity to complete a “360-degree view” of the tumor. The location, length, diameter, shape, echo, and depth of invasion, followed by the number, size, and echo of the peri-intestinal lymph nodes were observed, and the blood flow distribution in the lesion, the max length of the longitudinal axis of the lesion, the max thickness of the tumor, and T staging (T1: hypoechoic shadow is confined to the first three layers; T2: hypoechoic shadow is present in the fourth layer, but the fifth layer is smooth; T3: hypoechoic shadow is present in the fifth layer; T4: hypoechoic shadow is present in the intestinal lining and partly surrounding tissues or organs) were determined. Color Doppler blood flow imaging grading was performed according to the intensity of blood flow signals: grade 0: no blood flow signal, grade I: blood flow signals of focal region, grade II: multi-point and strip blood flow signals, and grade III: large amounts of dot and strip blood flow signals. ERUS was compared with pathological T staging to evaluate under-stage, over-stage and accuracy, and the correlations of patient’s age, gender, distance between the lower edge of the tumor and the anus, review time of ERUS, nerve invasion, vascular invasion, lymph node metastasis, postoperative T staging and Wheeler rectal cancer regression grade with ERUS re-staging accuracy after neoadjuvant radiochemotherapy were subjected to univariate analysis to identify the factors affecting the accuracy.
STATISTICAL ANALYSIS
SPSS 20.0 software was employed for statistical analysis. Numerical data were expressed as percentage [n (%)] and analyzed using chi-square test. Measurement data were expressed as mean ± standard deviation (χ̄ ± s), and t-test was used for comparison between two groups. The factors affecting the accuracy of post-neoadjuvant radiochemotherapy re-staging examined with ERUS was evaluated by logistic regression analysis. P<0.05 indicated that the difference was statistically significant.
RESULTS
Changes in indices after neoadjuvant radiochemotherapy with ERUS
ERUS showed that the blood flow distribution within the lesion significantly declined (χ2=159.723, p<0.001) after neoadjuvant radiochemotherapy, when compared with the pre-treatment lesion. The max length of the longitudinal axis of the lesion and the max thickness of the tumor were reduced [(5.38±0.34) cm vs. (2.15± 0.14) cm, (3.03±0.24) cm vs. (0.96±0.12) cm] (t=93.792, p<0.001; t=82.368, p<0.001). Compared with before pre-neoadjuvant radiochemotherapy, uT staging had a significant difference after neoadjuvant radiochemotherapy (χ2=58.455, p<0.001) (Table 1).
Table 1 Changes in indices after neoadjuvant radiochemotherapy with ERUS (n=114).
| Group | Pre-neoadjuvant radiochemotherapy | Post-neoadjuvant radiochemotherapy | χ2/t | p |
|---|---|---|---|---|
| Blood flow (n) | χ2=159.723 | <0.001 | ||
| 0 | 0 | 42 | ||
| □ | 0 | 51 | ||
| □ | 51 | 15 | ||
| □ | 63 | 6 | ||
| Max length (cm) | 5.38±0.34 | 2.15±0.14 | t=93.792 | <0.001 |
| Max thickness (cm) | 3.03±0.24 | 0.96±0.12 | t=82.368 | <0.001 |
| uT stage(n) | χ2=58.455 | <0.001 | ||
| T1 | 0 | 12 | ||
| T2 | 0 | 36 | ||
| T3 | 63 | 52 | ||
| T4 | 51 | 24 |
ERUS and pathological T staging after neoadjuvant radiochemotherapy
Compared with postoperative pathological T staging, ERUS showed 88.89% of over-stage in T1 stage, 21.43% of under-stage and 50% of over-stage in T2 stage, 45.45% of under-stage and 27.27% of over-stage in T3 stage, 0 of under-stage and over-stage in T4 stage, and 21.05% of under-stage and 47.37% of over-stage in T stage (overall), and the accuracies of ERUS in T1, T2, T3, T4 and T stages (overall) were 11.11%, 28.57%, 27.27%, 100% and 31.58%, respectively (Table 2).
Table 2 EURS and pathological T staging after neoadjuvant radiochemotherapy.
| EURS stage(n) | Total | EURS stage | ||||||
|---|---|---|---|---|---|---|---|---|
| uT1 | uT2 | uT3 | uT4 | Over staging | Underestimate staging | Accuracy | ||
| ypT1 | 3 | 9 | 15 | 0 | 27 | 0 | 88.89% (24/27) | 11.11% (3/27) |
| ypT2 | 9 | 12 | 18 | 3 | 42 | 21.43% (9/42) | 50.00% (21/42) | 28.57% (12/42) |
| ypT3 | 0 | 15 | 9 | 9 | 33 | 45.45% (15/33) | 27.27% (9/33) | 27.27% (9/33) |
| ypT4 | 0 | 0 | 0 | 12 | 12 | 0 | 0 | 100.00%(12/12) |
| Total | 12 | 36 | 52 | 24 | 114 | 21.05% (24/114) | 47.37%(54/114) | 31.58% (36/114) |
Clinicopathological factors affecting ERUS re-staging accuracy after neoadjuvant radiochemotherapy
Univariate and multivariate logistic analyses indicated that review time of ERUS, post-operative T staging and Wheeler rectal regression stage were factors affecting ERUS re-staging accuracy. ERUS was more accurate in patients with review time of ERUS ≥6 weeks after neoadjuvant radiochemotherapy, ypT4 and RCRG3 (Tables 3 and 4).
Table 3 Univariate analysis results of factors affecting ERUS re-staging accuracy after neoadjuvant radiochemotherapy.
| Item | n | ERUS stage | |||
|---|---|---|---|---|---|
| Accurate (n=36) | Inaccurate (n=78) | χ2 | p | ||
| Age (years) | 1.661 | 0.197 | |||
| ≤60 | 48 | 12 | 36 | ||
| >60 | 66 | 24 | 42 | ||
| Gender | 3.013 | 0.083 | |||
| Male | 69 | 26 | 43 | ||
| Female | 45 | 10 | 35 | ||
| Distance from low margin of tumor to anus (cm) | 2.537 | 0.111 | |||
| <3 | 60 | 15 | 45 | ||
| ≥3 | 54 | 21 | 33 | ||
| Follow up check of ERUS (weeks) | 9.204 | 0.002 | |||
| <6 | 42 | 6 | 36 | ||
| ≥6 | 72 | 30 | 42 | ||
| Nerve invasión | 0.506 | 0.477 | |||
| Negative | 93 | 28 | 65 | ||
| Positive | 21 | 8 | 13 | ||
| Vessel invasión | 0.050 | 0.822 | |||
| Negative | 27 | 9 | 18 | ||
| Positive | 87 | 27 | 60 | ||
| Lymph node metástasis | 0.201 | 0.654 | |||
| Negative | 51 | 15 | 36 | ||
| Positive | 63 | 21 | 42 | ||
| Post-operation stage | 37.948 | <0.001 | |||
| ypT1 | 27 | 3 | 24 | ||
| ypT2 | 42 | 12 | 30 | ||
| ypT3 | 33 | 9 | 24 | ||
| ypT4 | 12 | 12 | 0 | ||
| PCRG | 21.732 | <0.001 | |||
| PCRG1 | 33 | 3 | 30 | ||
| PCRG2 | 39 | 9 | 30 | ||
| PCRG3 | 42 | 24 | 18 | ||
Table 4 Multivariate logistic analysis results of factors affecting ERUS re-staging accuracy after neoadjuvant radiochemotherapy.
| Item | Regression coefficient | Standard error | Wald χ2 | OR | 95% CI | p |
|---|---|---|---|---|---|---|
| Review time of ERUS ≥6 weeks | 2.203 | 0.297 | 5.389 | 1.727 | 1.063~2.804 | 0.004 |
| ypT4 | 2.687 | 0.172 | 6.835 | 2.010 | 1.928~4.400 | 0.000 |
| PCRG3 | 2.236 | 0.238 | 4.623 | 2.581 | 1.689~3.479 | 0.022 |
| Constant term | 1.784 | 0.348 | 76.436 | 6.053 | 0.006 |
DISCUSSION
The incidence rate of low rectal cancer is higher among colorectal tumors. The anatomical structure of the low rectum is different from that of the high rectum, and the effect of radical surgery is poor for low locally advanced rectal cancer in the past, with a poor prognosis. With the extensive development, the role of neoadjuvant radiochemotherapy with the advantages of increasing the radical cure rate of low locally advanced rectal cancer, reducing the recurrence rate, increasing the sphincter preservation rate and prolong the survival time, has been confirmed 7,8. In the NCCN guidelines, it has been definitely proposed to perform neoadjuvant radiochemotherapy for stages II and III low rectal cancer (regional stage T3 and T4). For low rectal cancer within 5 cm from the anus, ERUS has unique advantages 9. In a previous study, it showed that the accuracy of ultrasound is 63-96% in the preoperative staging of low rectal cancer, which is 87-98% in MRI 10. However, there are still few reports on the evaluation value of ERUS after neoadjuvant radiochemotherapy and before surgery.
The accuracy of ultrasound in different locations of rectal cancer differs greatly during the determination of the degree of invasion of the primary rectal cancer. Especially, ultrasound endoscopic scanning is required for middle and upper rectal cancer, which greatly affects the accuracy, but for low rectal cancer, intracavitary ultrasound probes can easily and completely scan the primary lesion to evaluate the length, thickness, depth of invasion, blood flow, and circumferential margins 11,12. Under ERUS, the normal rectal wall is a 5-layer structure with a thickness of 2-3 mm with alternating high and low echoes, containing mucosa, mucosal muscle, submucosa, propria muscle, serous membrane and subserosal layer, surrounding with adipose tissues, mesangial fascia outside the adipose tissues, and the primary lesion is characterized by irregularly shaped masses, with uneven low echoes, some multiple micro-calcifications, different depths of invasion into intestinal wall, disappearance of normal intestinal wall structure, abundant arteriovenous blood flow in the tumor, and high resistance of arterial blood flow 13,14.
After neoadjuvant radiochemotherapy, the primary tumor is prone to pathological features such as necrosis, fibrosis, reduced density, and decreased blood supply, and the original 5-layer structure of the intestinal wall is destroyed, so that MRI or ERUS restaging accuracy is poor 15. Compared with before pre-neoadjuvant radiochemotherapy, ERUS showed that the blood flow distribution within the lesion significantly declined, the max length of the longitudinal axis of the lesion and the max thickness of tumor were significantly reduced, most stage T3 or T4 rectal cancer was reduced to T1 or T2, and the uT staging was decreased after neoadjuvant radiochemotherapy.
These results demonstrated that ERUS is of clinical guiding significance in the evaluation of tumor length, thickness and blood flow after radiochemotherapy, and can effectively evaluate the efficacy of adjuvant therapy. Compared with postoperative pathological T re-staging, the results displayed that ERUS showed 88.89% of overstage in T1 stage, 21.43% of under-stage and 50% of over-stage in T2 stage, 45.45% of under-stage and 27.27% of over-stage in T3 stage, 0 of under-stage and over-stage in T4 stage, and 21.05% of under-stage and 47.37% of over-stage in T stage (overall), and the accuracy of ERUS in T1, T2, T3, T4 and T stage (overall) was 11.11%, 28.57%, 27.27%, 100% and 31.58%, respectively. The above results suggested that ERUS has extensive under-stage in T1 and T2 stages, and the accuracy is extremely poor. The reason may be that neoadjuvant therapy is absolutely effective for the primary lesion of T1 and T2 re-staging, and the 5-layer structure of the intestinal wall is difficult to distinguish. Because of tumor regression, fibrous interstitial tissue proliferation, reduced distribution of tumor cells in the interstitium, and decreased blood flow of the tumor, the accuracy of the stratification of the mucosal layer, mucosal muscle, submucosal layer and muscularis propria is poor, and the fibrous interstitial tissue with incomplete shrinkage may be mistaken for residual tumors, resulting in excessive staging 16. A previous study indicated that the total accuracy of ERUS T staging after neoadjuvant radiochemotherapy is 48%, with 38% of over-staging and 14% of under-staging, tumor regresses notably in the primary tumor that is sensitive to radiochemotherapy, and the accuracy of re-staging is poor 17, similar to the results of this study. The results of this study showed that ERUS was more accurate for T4 re-staging, because T4 re-staging indicates ineffective or extremely poor effect of neoadjuvant radiochemotherapy. Studies have displayed that the accuracy of ERUS and MRI is close to 100% in T4 stage with larger tumor, so the depth of invasion is more accurate, and the evaluation accuracy is higher. Further univariate analysis showed that review time of ERUS, postoperative T staging and Wheeler rectal cancer regression grade are factors affecting ERUS re-staging accuracy in low rectal cancer. The accuracy is higher in patients with review time of ERUS ≥6 weeks. The reason may be that the edema begins to subside 4 weeks after radiotherapy, and the boundary of tumor regression is more obvious, achieving the maximum effect at 6-8 weeks. Hence, ERUS can more accurately distinguish the intestinal wall level after six weeks. Patients with ypT4 and PCRG3 have poor response of tumor to radiochemotherapy, consistent with RCR3 of regression, and higher accuracy of T4 staging mentioned above. ERUS is poorly accurate for regional re-staging of obvious regression after radiochemotherapy, and more accurate for T4 re-staging of unobvious regression after radiochemotherapy. Besides, different operators with experience, different types of probes and fuselages are also factors that affect the results of ERUS.
In conclusion, ERUS can effectively allow the evaluation of the efficacy of low rectal cancer after neoadjuvant radiochemotherapy, including length, volume and blood flow. However, it is poorly accurate for those with prominent effect of neoadjuvant radiochemotherapy and T staging with effective regression, and more accurate for those primary lesions with non-prominent effect of neoadjuvant radiochemotherapy and poor tumor regression. Besides, ERUS has a higher accuracy for the review time at 6 weeks after neoadjuvant radiochemotherapy. Regardless, this study still has limitations. First, the sample size is small, and further verification is needed with a large population. Second, the scan range of ERUS is limited, which cannot display tumors in the upper rectal segment. Third, ERUS does not work well for rectal cancer in the immediate vicinity of the anus or mesorectal lymph nodes. Particularly, patients after receiving neoadjuvant radiotherapy probably cannot tolerate the pain during examination because the mucosa is damaged.
