Clinical trial NCT01437514: Effective Study of Preoperative Short-course Radiotherapy for the Advanced Resectable Rectal Cancer
Official title: the Effect of the Preoperative Short-course Radiotherapy for the cT3/cN+ Mid-lower Rectal Cancer: a Prospective Randomized Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Rectal Neoplasms
Keywords: 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
Lead sponsor: West China Hospital
Sponsor class: OTHER
First posted: 2011-09-21
Enrollment: 410
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. histologically verified adenocarcinoma of the rectum;
2. the lower border of the tumor within 10cm of the anal verge;
3. age between 18 to 80 years;
4. 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);
5. ECOS ≤ 2
6. there was no evidence of metastasis with chest and abdominopelvic CT.

Exclusion Criteria:

1. with other colorectal cancer, or other cancer,simultaneously;
2. Locally recurrent rectal cancer;
3. had a history of malignant tumor within 5 years(except the skin cancer);
4. Pregnant or lactating women
5. there was contraindication for the preoperative adjuvant radiotherapy or the operation.
6. with antitumor drug or radiation before this trial.
7. discovery of metastasis in the operation
8. worrying about the local recurrence or the adverse effect of the radiation excessively;
9. with mental disorder.

Primary outcomes:
measure: local recurrence
timeFrame: 3 years
Secondary outcomes:
measure: disease free survival
timeFrame: 3 years
measure: metastatic rate
timeFrame: 3 years
measure: quality of life
timeFrame: 3 years
measure: overall survival
timeFrame: 3 years
measure: short-term complication of the surgery
timeFrame: first 30 day after operation
Other outcomes:
Locations:
city: Chengdu
country: China
facility: Sichuan academy of medical science and sichuan provincial people's hospictal
state: Sichuan
city: Chengdu
country: China
facility: the Third People'S Hospital of Chengdu
state: Sichuan
city: Chengdu
country: China
facility: West China hospital, Sichuan University
state: Sichuan
city: Kunming
country: China
facility: The Third Affiliated Hospital of Kunming Medical University
state: Yunnan
Study officials:
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