Clinical trial NCT03970694: Neoadjuvant Chemoradiotherapy Versus Neoadjuvant Chemotherapy For Unresectable Locally Advanced Colon Cancer
Official title: Neoadjuvant Chemoradiotherapy Versus Neoadjuvant Chemotherapy For Unresectable Locally Advanced Colon Cancer: An Open, Multi-centered, Randomize Controlled Phase 3 Trial.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Colon Cancer
Keywords: Neoadjuvant chemoradiotherapy
Colon Cancer
Initial Diagnosed Unresectable Locally Advanced Stage
Phase 3 Clinical Trial
Lead sponsor: Sun Yat-sen University
Sponsor class: OTHER
Collaborators: name: First Affiliated Hospital, Sun Yat-Sen University
name: Sixth Affiliated Hospital, Sun Yat-sen University
name: Fujian Medical University Union Hospital
name: Second Affiliated Hospital, School of Medicine, Zhejiang University
name: Nanfang Hospital, Southern Medical University
name: Tongji Hospital
First posted: 2019-05-31
Enrollment: 49
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Research group: Neoadjuvant chemoradiotherapy group Control group: Neoadjuvant chemotherapy group
Primary purpose: TREATMENT

Brief summary: A. Background and purpose:

Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy for unresectable locally advanced colon cancer: an open, multi-centered, randomize controlled phase 3 trial.

Colorectal cancer is one of the most common malignant tumors, the morbidity and mortality rate are both in rising trend. 10-23% newly diagnosed colon cancer is at locally advanced stage and surgically unresectable. For this subgroup, treatment guidelines recommend neoadjuvant chemotherapy with or without targeted therapy. However, less than 50% patients could convert into R0 resectable, therapeutic effect is unsatisfactory, 5-year overall survival rate is only 12.5%-45.7%.\[JCO,2010\] Since 2006, neoadjuvant chemoradiotherapy has been a recommendation as standard treatment for locally advanced rectal cancer, and has been widely applied to clinical use. As for locally advanced colon cancer, it still lacks evidence to support whether neoadjuvant chemoradiotherapy is a beneficial option. There are only several articles about locally advanced colon cancer undertaking neoadjuvant chemoradiotherapy before surgery through Pubmed research, including 3 case reports, 1 abstract and 5 clinical researches with a small sample size, 3 of which are from the investigator's study group.

The investigators recently reported clinical data about therapeutic effect of 60 unresectable locally advanced colon cancer cases and the results were exciting. According to the results, through neoadjuvant chemoradiotherapy, R0 resection rate is 86%, local recurrence rate is 10.2%, 3-year OS and 5-year OS are 76.7% and 66.6%, respectively. \[Onco Targets Ther, 2018\] "Colorectal cancer diagnoses and treatment guidelines" written by Chinses Society of Clinical Oncology (ver. 2017, 2018), suggested that neoadjuvant chemoradiotherapy was an optional treatment strategy or secondary recommended treatment strategy. In a word, the investigators' result was referred as revisory basis of the guideline \[CJC,2016\], with a relatively low level of evidence in evidence-based medicine.

This phase 3 clinical trial mainly aims to acquire a higher level of evidence in evidence-based medicine on the subject about neoadjuvant chemoradiotherapy as a treatment strategy to unresectable locally advanced colon cancer, and the ultimate goal is to rewrite the International treatment guidelines of locally advanced colorectal cancer.

B. Research Content:

1. . Research Object: Patients who newly diagnosed unresectable locally advanced colon cancer. Including: 1. tumor infiltrates through the intestinal wall and adheres to tissues and organs around the colon(T4b), imaging assesses that R0 resection is unachievable. 2. Pericolonic lymph node involvement is closely adjacent to the large abdominal vessels, imaging assesses that lymphadenectomy is difficult. 3. Surgical exploration indicates that R0 resection is not achievable. 4. In initial diagnosis, surgeon evaluates the need for extensive multi-organ combined resection and expected to damage the organs, which would seriously affect the postoperative quality of life.
2. . Main research indicator: 5-year overall survival rate
3. . Secondary research indicators: 1. R0 resection rate 2. 3-year tumor-free survival rate
4. . Research groups assignment: 1. Research group: Neoadjuvant chemoradiotherapy group; 2. Control group: Neoadjuvant chemotherapy group.
5. . Sample calculation: Calculation is based on the main research indicator: 5-year survival rate. Based on α=0.05(bilateral), β=0.20(unilateral), 5-year OS improves from 45% in control group to 65% in research group, 4-year period, 5-year follow-up. Research group and control group should at least enroll 74 and 75 qualified cases, respectively, a total of 149 cases, with an expected delisting rate of 20%, the total sample size is 186, 93 cases for each group.
6. . Research protocols:

1. Research group: Neoadjuvant chemoradiotherapy（XELOX \* 4 + radiotherapy）→ Surgery (if possible) → post-surgery chemotherapy.

2. Control group: Neoadjuvant chemotherapy（XELOX \* 4）→ Surgery (if possible) → post-surgery chemotherapy.

Chemotherapy strategy: XELOX: oxaliplatin 130mg/m2, iv drip, d1, every 3 weeks; capecitabine 1,000mg/m2, bid, d1-d14, every 3 weeks. Concurrent chemotherapy: mXELOX: which oxaliplatin is 100mg/m2.

Radiotherapy strategy: IMRT, 6-8MV X-ray; GTV 45-50Gy/25F, 1.8-2.0Gy/F; CTV 42.5-45Gy/25F, 1.7-1.8Gy/F; Actual delivery dose should be adjusted according to max tolerance dose of organs at risk, but the delivery dose of GTV and CTV must within the required range.

Surgery: Reexamination is performed 5 weeks after radiotherapy for research group and 2 weeks after the fourth period of chemotherapy, surgery is performed in 6-12 weeks after neoadjuvant treatment.


Eligibility criteria: Inclusion Criteria:

* Histology confirms colonic adenocarcinoma.
* The distance from the lower edge of the tumor to the anal edge is greater than or equal to 15cm (from sigmoid colon to ileocecal region)
* Preoperative staging (Satisfying any one out of four conditions below)

  1. Tumor infiltrates through the intestinal wall and adheres to tissues and organs around the colon(T4b), imaging assesses that R0 resection is unachievable.
  2. Pericolonic lymph node involvement is closely adjacent to the large abdominal vessels, imaging assesses that lymphadenectomy is difficult.
  3. Surgical exploration indicates that R0 resection is not achievable.
  4. In initial diagnosis, surgeon evaluates the need for extensive multi-organ combined resection and expected to damage the organs, which would seriously affect the postoperative quality of life.
* No obvious signs of intestinal obstruction, or obstruction has been relieved after proximal enterostomy.
* Preoperative CT/MRI/PET-CT has ruled out distant metastasis.
* Blood and biochemical indexes achieve standard (Satisfying all three conditions below):

  1. Routine blood test: WBC\>4000/mm3; PLT\>100000/mm3; Hb\>6g/dl.
  2. Liver function: SGOT, SGPT and Bilirubin are less than or equal to 1.5 times normal upper limit.
  3. Renal function: Creatinine is less than or equal to 1.5 times normal upper limit.

Exclusion Criteria:

* History: Has colon surgery history; Received chemotherapy or biotherapy in the past 5 years; Received radiotherapy in treatment field.
* Infectious disease: HIV infection history; Active phase chronic hepatitis B or hepatitis C (high copies of virus DNA); Other serious active clinical infection.
* Diagnosed as stage I colon cancer.
* Extraperitoneal distant metastasis is positive in pre-operative stage.
* Dyscrasia or organ decompensation.
* Received radiation therapy in abdominal or pelvic regions.
* Multiple primary cancer.
* Epileptic seizures requiring medical treatment.
* Other malignant tumor history in the past 5 years (except endocervical cancer in situ or skin basal cell carcinoma which had been cured)
* Chronic inflammatory colorectal disease, unrelieved ileus.
* Drug abuse, has medical, psychological or social condition that might affect research results.
* Allergic to research-related drugs.
* Any unstable situation that might endanger patient's safety or compliance.
* Pregnant, lactating woman patient or fertile but lacks adequate contraceptives.
* Refuses to sign informed consent.

Primary outcomes:
measure: 5-year overall survival rate
timeFrame: 5 years after treatment
Secondary outcomes:
measure: R0 resection rate
timeFrame: an average of 6 to 12 weeks after surgery
measure: 3-year progression-free survival rate
timeFrame: 3 years after treatment
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center
state: Guangdong
Study officials:
affiliation: Sun Yat-sen University
name: Yuan-hong Gao, M.D
role: STUDY_CHAIR
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