Effective Study of Preoperative Short-course Radiotherapy for the Advanced Resectable Rectal Cancer

Study Overview
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Brief Summary
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The local recurrence of rectal cancer is one of the main problem that fail the treatment. The preoperative neoadjuvant (chemo)radiotherapy has been confirmed to reduce the local recurrence rate,especially in the advanced rectal cancer. However the local recurrence rate is low about 10-20% totally,and the integrity of the mesorectum after the operation and circumferential resection margin(CRM) are the most critical factor for the local recurrence.So that, the advanced rectal cancer patients with negative CRM and had a complete mesorectum excision,may not benefit from the neoadjuvant radiation.This trial was mainly focus on the resectable advanced rectal cancer patients whose preoperative stage was cT3/N+. These patients will be divided into the lower risk group and higher risk group according the preoperative CT,Endoscopic ultrasound, and MRI,and carrying out randomized trial in the two groups respectively.The purpose of this trial is to confirm whether the preoperative radiotherapy is necessary for all the advanced rectal cancer patients,identify the reason of the local recurrence,and finally help the making of the treatment decision for the advanced resectable rectal cancer.

Detailed Description
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The colorectal cancer is the secondary most common cancer among the population. Every year,it's estimated that there was over 1,200,000 new cases,and in China the data is about 440,000. The local recurrence (LR) and the lung or liver metastasis are the most critical problems that confusing the doctor,which the local recurrence rate is about 3%-50%,with a median rate of 18.8%。 Now, multidisciplinary treatment become a choice treatment for the rectal cancer, and the preoperative neoadjuvant (chemo)radiotherapy is a critical part of the treatment, as various trials have confirmed that the preoperative chemoradiotherapy can reduce the postoperative local recurrence rate. Although the preoperative radiotherapy can decrease the local recurrence, most of the studies show that it can't increase the overall survival. Also the large MRC study shows, the quality of operation is also critical for the local recurrence. and the main reasons of the local recurrence was thought to be the positive circumferential resection margin(CRM) and the remnant of the mesorectum. On the other hand, with the improvement of the TME surgery, the local recurrence of the advanced rectal cancer is lower than 20%, and the preoperative radiation may benefit half of these patients,and reduce the local recurrence rate to 7-10%.over 80% patients may be over treated and simultaneously suffer from the adverse effect of the radiation.The aim of this study was to explore that if the lower risk portion of the advanced rectal cancer patients is not necessary to have preoperative radiation,and the radiation will benefit the higher risk group. In the trial,the operator will divide the resectable advanced rectal cancer patients (cT3/N+) into two subgroups according to the preoperative CT, MRI and EUS.firstly, the criteria of the lower risk group are: the tumor invade into the mesorectum<=5mm in lateral and posterior of the mesorectum, in the anterior wall the tumor had not invaded into the mesorectal fat tissue, there is no enlarged lymph node that larger than 8mm; and the higher risk group are: the tumor invade into the mesorectum >5mm in the lateral or posterior part, or invade into the mesorectum only in the anterior as the anterior mesorectum is relatively thin, or with lymph node larger than 8mm. then these patients were randomized to radiation with surgery or surgery only respectively. In the lower risk group we presume that the local recurrence rate is relatively low and the radiation can not improve LR, and in the higher risk group the radiation is significantly beneficial. Of the preoperative radiation,there are two regimen,the long-term chemoradiotherapy and the short-course radiotherapy. mostly, the long-term regimen is more popular,with a total dose of 50.4 Gy in 25-28 fraction,compare to the short-term one with a dose of 25 Gy in 5 fraction, as the long-term regimen has a better effect of reduce the tumor invasion. For the resectable patients with negative CRM before the surgery,there is no conclusion which is better. so that the short-term radiation was choose as the regimen of this study. Local recurrence after 3 years follow up has been chosen as primary endpoint. Proving a two-sided hypothesis of differences between the arms in higher risk group, the calculation of the sample size was based on expected local recurrence rates of 6% in the radiation group compared with 16% in the surgery group, resulting in altogether 210 patients (Log-Rank-test, with error of the 1st kind: α = 5% two-sided, power = 80%). As the lower risk group may have a very low LR rate, the totally 200 lower risk patients are planning to recruiting to randomization, which was similar to the higher risk group. Patient baseline characteristics and disease factors were summarized using descriptive statistics. The categorical parameters were compared using two-sided Pearson's χ2 test or Fisher's exact test, as appropriate. All summary statistics on time-to-event variables were calculated according to the Kaplan-Meier method and were compared by means of the log-rank test. SPSS software(version 22.0; IBM, Chicago, IL) was used for statistical analyses. A P value<0.05 was considered significant.

Official Title
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the Effect of the Preoperative Short-course Radiotherapy for the cT3/cN+ Mid-lower Rectal Cancer: a Prospective Randomized Study

Conditions
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Rectal Neoplasms

Intervention / Treatment
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* Radiation: preoperative short-course radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: histologically verified adenocarcinoma of the rectum; the lower border of the tumor within 10cm of the anal verge; age between 18 to 80 years; preoperative endosonography,MRI and the abdominopelvic CT diagnosis as advanced rectal cancer (cT3/N+)(the detail of these two subgroup was illustrated in the detailed description of this trial); ECOS ≤ 2 there was no evidence of metastasis with chest and abdominopelvic CT. Exclusion Criteria: with other colorectal cancer, or other cancer,simultaneously; Locally recurrent rectal cancer; had a history of malignant tumor within 5 years(except the skin cancer); Pregnant or lactating women there was contraindication for the preoperative adjuvant radiotherapy or the operation. with antitumor drug or radiation before this trial. discovery of metastasis in the operation worrying about the local recurrence or the adverse effect of the radiation excessively; with mental disorder.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lower risk group with pSRT<br>the patients that was divided into the lower risk group that the mesorectum involvement less than 5mm, and no lymph node larger than 8mm according to the preoperative CT, MRI and Endosonography,and these patients accept the preoperative short-course radiotherapy before the surgery | Radiation: preoperative short-course radiotherapy<br>* preoperative RT received a total dose of 25 Gy in five fractions during five consecutive days. The clinical target volume included the primary tumor and the mesentery with vascular supply containing the perirectal, presacral, and internal iliac nodes(up to the S1/S2 junction).The recommended upper border was at the level of the promontory. Radiation treatment was delivered with a three-portal technique.<br>* Other names: preoperative short term radiotherapy;|
| No Intervention: lower risk group with operation only<br>the patients that was divided into the lower risk group that the mesorectum involvement less than 5mm, and no lymph node larger than 8mm,according to the preoperative CT, MRI and Endosonography,and these patients have a operation directly without preoperative radiotherapy. | |
| Experimental: higher risk group with pSRT<br>the patients that was divided into the higher risk group that the mesorectum involvement more than 5mm, or with lymph node larger than 8mm according to the preoperative CT, MRI and Endosonography,and these patients have a operation directly without preoperative radiotherapy.these patients have the preoperative short-course radiotherapy before the surgery. | Radiation: preoperative short-course radiotherapy<br>* preoperative RT received a total dose of 25 Gy in five fractions during five consecutive days. The clinical target volume included the primary tumor and the mesentery with vascular supply containing the perirectal, presacral, and internal iliac nodes(up to the S1/S2 junction).The recommended upper border was at the level of the promontory. Radiation treatment was delivered with a three-portal technique.<br>* Other names: preoperative short term radiotherapy;|
| No Intervention: higher risk group with operation directly<br>the patients that was divided into the higher risk group that the mesorectum involvement more than 5mm, or with lymph node larger than 8mm according to the preoperative CT, MRI and Endosonography,and these patients have a operation directly without preoperative radiotherapy. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| local recurrence |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| disease free survival | the time from operation to confirmed local recurrence, distant metastases, or death due to disease or treatment, whichever occurred first. | 3 years | 
| metastatic rate | ratio of the patients with metastasis after the operation | 3 years | 
| quality of life |  | 3 years | 
| overall survival | the fraction of the person from the operation the death,no matter the reason of the death. | 3 years | 
| short-term complication of the surgery |  | first 30 day after operation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rectal cancer, Endosonography, preoperative short-course radiotherapy, preoperative adjuvant therapy, neoadjuvant therapy, short-term high-dose preoperative radiotherapy, total mesorectal excision, circumferential resection margin, local recurrence, overall survival, metastasis, complication