Lateral Lymph Node Dissection After Neoadjuvant Chemo-radiation in Advanced Low Rectal Cancer

Study Overview
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Brief Summary
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Lateral lymph nodes (LLD) metastasis is a major cause of local recurrence for advanced rectal cancer. As for the treatment strategies on LLN metastasis, there are huge controversies on whether lateral pelvic lymph nodes dissection (LLND) after neoadjuvant chemo-radiotherapy (nCRT) between Western and Eastern countries. Retrospective cohort evidences indicate that LLND following total mesorectal excision (TME) will bring benefit from cT3-4 rectal cancer, not regular predictive LLND, which will bring more side effects on the contrary. Existing reports tend to recommend LLND for specific individual with suspicious LLN metastasis. Moreover, there is a blank strict prospective randomized control study on the comparison of LLND+TME and LLND after nCRT. Therefore, our trial will compare the efficacy and safety of the two strategies for mid/low rectal cancer with suspicious LLN metastasis. The risk factors (such as radiologic factors, pathologic factors, and serum protein) to predict local recurrence and overall survival will be further investigated.

Detailed Description
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Recently, the incidence and mortality of colorectal cancer have increased, leading the second prevalence after lung cancer. Local recurrence of mid/low rectal cancer is not only the poor prognostic factor but also the threat of terrible quality of life. Although universal usage of neoadjuvant chemo-radiotherapy (nCRT) and total mesorectal excision (TME) have decreased local recurrence to 5%-10%, the ratio of local recurrence has occupied almost 30% of total metastasis and recurrence incidences, which limited the therapeutic effect of rectal cancer. Increasing evidences have demonstrated lateral pelvic lymph nodes (LLN) metastasis as one of the prominent causes of local recurrence, accompanied with 10%-25% advanced rectal cancer. Published researches also reminder us preoperative LLN involvement may lead to high local recurrence and poor overall survival. As for the treatment strategies on LLN metastasis, there are huge controversies on whether lateral pelvic lymph nodes dissection (LLND) or LLND+TME after nCRT: Eastern countries especially Japan favors LLND following TME with the reasons: 1) the incidence of LLN metastasis reaches as high as 10%-25% and 27% of rectal patients who undergo TME solely (without LLND) will develop into local recurrence. And the predictive pelvic recurrence rate will decrease 50%; corresponding 5-year overall survival will increase 8%-9%. 2) efficacy of LLND equals to resection of local lymph nodes metastases. A large cohort of 11567 cases from Japan demonstrates resection of iliac lymph nodes metastasis does not show any difference from TME of cTxN2aM0 and resection of obturator and external iliac lymph nodes favors that of liver metastasis. 3) Japanese Guidelines for treatment of colorectal in 2014 also recommends mid/low II/III rectal cancer under peritoneal reflex undergo regular TME+LLND. On the contrary, western countries favor sole TME after nCRT for LLN metastasis, holding that: 1) rate of lymph nodes metastasis is relatively low and LLN metastasis is regarded as systemic metastasis. 2) LLND experiences longer operative time, higher postoperative complications, and poor quality of life. 3) American NCCN and European ESMO guidelines recommend single TME for rectal cancer, if necessary, LLDN is added when LLN is indeed metastasis. However, there is a blank strict prospective randomized control study on the comparison of nCRT and LLND. Present existing retrospective cohort mainly focus on all the mid/low advanced cancer, not the specific individual of suspicious LLN metastasis. In fact, the results almost indicate no differences on local recurrence and overall survival, except for less operation time, blood loss, and perioperative complications in LLND. Although the latest researches start to report their preliminary outcomes, the patients sample sizes are small and they achieve varied recurrence and overall survival. In conclusion, the treatment strategy for colorectal cancer has focused on individual and precision. Massive of retrospective reports have indicated that rectal cancer patients with LLN metastasis will benefit from LLND, however, there is hot controversy on the treatment of whether TME+LLND or TME+nCRT for specific rectal patients with suspicious LLN metastasis. Therefore, our trial will compare the efficacy and safety of the two strategies for mid/low rectal cancer with suspicious LLN metastasis. The risk factors (such as radiologic factors, pathologic factors, and serum protein) to predict local recurrence and overall survival will be further investigated.

Official Title
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Lateral Pelvic Lymph Node Dissection After Neoadjuvant Chemo-radiation for Preoperative Enlarged Lateral Nodes in Advanced Low Rectal Cancer: a Phase III Randomized Controlled Trial

Conditions
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Rectal Cancer

Intervention / Treatment
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* Procedure: LLND
* Device: labeled line


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed rectal cancer (below the peritoneal reflection) Clinical stage I, II, or III No extramesorectal lymph node swelling (shorter diameter is less than 10 mm) No invasion to other organ (s) PS: 0, 1 No past history of chemotherapy, pelvic surgery or radiation Written informed consent operative criteria: Mesorectal excision is performed Operative findings: Main lesion of the tumor is located at the rectum Lower tumor margin is below the peritoneal reflection R0 after resection Exclusion Criteria: High rectal cancer Multiple cancer patients Pregnant patients Psychological disorder Steroid administration Cardiac infarction within six months Severe pulmonary emphysema and pulmonary fibrosis Doctor's decision for exclusion

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: LLND+TME group<br>advanced rectal cancer patients after neoadjuvant chem-radiation with suspicious lateral lymph nodes involvement undergo lateral lymph node dissection and total mesorectal excision(LLND+TME) | Procedure: LLND<br>* advanced rectal cancer patients whose lymph nodes are suspiciously enlarged after neoadjuvant chemoradiation will undergo lateral lymph node dissection (LLND) and total mesorectal excision (TME)<br>* Other names: Lateral Lymph Node Dissection;Device: labeled line<br> <br> |
| No Intervention: TME group<br>advanced rectal cancer patients after neoadjuvant chem-radiation with suspicious lateral lymph nodes involvement undergo total mesorectal excision (TME)solely, without LLND | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year local recurrence |  | until local-recurrence (up to 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival |  | 3 years | 
| disease free survival |  | 3 years | 
| Incidence of sexual and urinary dysfunction |  | 1 year | 
| postoperative complications |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rectal cancer, lateral lymph node dissection, neoadjuvant chemoradiation, total mesorectal excision, surgery, recurrence, metastasis, overall survival