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All Drugs and Chemicals

Adjuvants, Anesthesia

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Capecitabine

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Cola

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

Arm Type: control. Neoadjuvant chemotherapy（XELOX \* 4）→ Surgery (if possible) → post-surgery chemotherapy.

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.We recently reported clinical data about therapeutic effect of 60 unresectable locally advanced colon cancer cases and it was exciting. According to our 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."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.

Radiotherapy

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 surgical unresectable. For this subgroup, treatment guidelines recommend neoadjuvant chemotherapy with or without targeted therapy.

oxaliplatin+capecitabine

Yuan-hong Gao, M.D

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.

Research group: Neoadjuvant chemoradiotherapy group Control group: Neoadjuvant chemotherapy group

Neoadjuvant Chemoradiotherapy Versus Neoadjuvant Chemotherapy For Unresectable Locally Advanced Colon Cancer

Neoadjuvant Chemoradiotherapy Versus Neoadjuvant Chemotherapy For Unresectable Locally Advanced Colon Cancer: An Open, Multi-centered, Randomize Controlled Phase 3 Trial.

The percentage of patients survive 5 years after treatment.

The percentage of patients whose post-operative pathology indicate negative margin is observed under microscope

The percentage of patients have no tumor progression after treatment.

First Affiliated Hospital, Sun Yat-Sen University

Sixth Affiliated Hospital, Sun Yat-sen University

Fujian Medical University Union Hospital

Second Affiliated Hospital, School of Medicine, Zhejiang University

Nanfang Hospital, Southern Medical University

Tongji Hospital

Sun Yat-sen University

Professor

Symptoms and General Pathology

Neoplasm Metastasis

Liver Neoplasms

Rectal Diseases

Neoplastic Processes

Liver Diseases

Hematinics

Bevacizumab

Liver Extracts

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

postoperatively oxaliplatin 130 mg/m2 i.v. day 1 plus capecitabine 1000 mg/m2 b.i.d. on day 1-14, q3w

postoperatively oxaliplatin 130 mg/m2 i.v. day 1 plus bevacizumab 7.5 mg/kg on day 1 plus capecitabine 1000 mg/m2 b.i.d. on day 1-14, q3w

Oxaliplatin+capecitabine+bevacizumab

Richard van Hillegersberg, MD PhD

The primary aim of this study is to investigate whether the addition of the new anti-cancer drug bevacizumab (Avastin) to the combination of the chemotherapeutic agents capecitabine (Xeloda) and oxaliplatin (Eloxatin) reduces (slows down) the recurrence of metastatic disease after a radical resection of liver metastases in patients with colorectal cancer.

The primary therapy of colorectal cancer is surgical resection, but more than half of all colorectal cancer patients eventually die of metastatic disease. Although the introduction of new anticancer agents with efficacy in metastatic colorectal cancer, e.g.: oxaliplatin and irinotecan, and the targeted agents cetuximab and bevacizumab has changed therapeutic nihilism, chemotherapy alone has failed to cure these patients.

It is estimated that 15-20 % of colorectal cancer patients present with synchronous liver metastases and approximately 50% of the patients with colorectal tumors will develop liver metastases at some point during the course of their disease. In almost one third of the cases, the liver was shown at autopsy to be the only site of cancer spread. This is in accordance with the 20% - 45 % five-year survival obtained with surgical resection of hepatic metastases.

Previous studies have not shown a clear benefit of adjuvant chemotherapy after metastasectomy of liver metastases. However, most of these studies have been performed with 5-fluorouracil with or without other older cytostatic drugs. Since new effective agents have been developed (e.g.: capecitabine, oxaliplatin and bevacizumab), adjuvant combination treatment with these agents might be more effective. These drugs have proven activity as first line palliative treatment of recurrent metastases. This raises the question if this new effective treatment is of value as an adjuvant treatment after metastasectomy.

As mentioned before, a two-arm EORTC study: neoadjuvant and adjuvant FOLFOX vs no chemotherapy in resectable liver metastases of colorectal cancer is almost completed (Nordlinger et al). It is expected that this study will show a 10% 3 year DFS benefit in favour of th treatment arm. Definitive data of this trial will be released at the end of 2006, and will most probably lead to adjuvant treatment post metastasectomy as a standard of care. In the HEPATCIA trial we anticipate on this by using adjuvant XELOX as the control arm.

As mentioned earlier, the 3-year disease free survival in patients post metastasectomy of liver metastases is approximately 25%. There is no data available on the effectivity of the XELOX regimen as adjuvant treatment after metastasectomy of colorectal cancer metastases. The EORTC study was designed to demonstrate a 10% improvement in 3y DFS. Assuming that this study is positive, 3 year DFS would be 35% in the control arm (XELOX post liver resection).

Since bevacizumab inhibits angiogenesis, which is required for growth of metastases, this drug may be valuable in the adjuvant setting. Several studies investigate the value of this drug in combination with fluoropyrimidines as an adjuvant regimen after resection of primary colorectal cancers. However, at this moment there is no mature data available of these studies. Therefore, we assume an increase in 3-year disease free survival of 10%, to 45% in the XELOX and bevacizumab treatment arm.

This study will therefore evaluate patients with resectable liver metastasis without extra-hepatic disease, investigating whether the capecitabine, oxaliplatin and bevacizumab regimen is superior to capecitabine and oxaliplatin alone applied as adjuvant treatment, in order to extent disease free and overall survival.

Adjuvant Xeloda Plus Eloxatin +/- Avastin After Radical Resection of Liver Metastasis of Colorectal Cancer

Randomized Phase III Study Post Radical Resection of Liver Metastasis of Colorectal Cancer: Bevacizumab in Combination With XELOX as Adjuvant Chemotherapy vs XELOX Alone

Sanofi

Roche Pharma AG

Dutch Colorectal Cancer Group

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Neoadjuvant Chemoradiotherapy Versus Neoadjuvant Chemotherapy For Unresectable Locally Advanced Colon Cancer	NCT03970694	Colon Cancer	Radiotherapy oxaliplatin+cap...	18 Years - 70 Years	Sun Yat-sen University
Adjuvant Xeloda Plus Eloxatin +/- Avastin After Radical Resection of Liver Metastasis of Colorectal Cancer	NCT00394992	Colorectal Canc... Liver Metastase...	oxaliplatin+cap... Oxaliplatin+cap...	18 Years -	Dutch Colorectal Cancer Group
Neoadjuvant Chemoradiotherapy Versus Neoadjuvant Chemotherapy For Unresectable Locally Advanced Colon Cancer	NCT03970694	Colon Cancer	Radiotherapy oxaliplatin+cap...	18 Years - 70 Years	Sun Yat-sen University
Adjuvant Xeloda Plus Eloxatin +/- Avastin After Radical Resection of Liver Metastasis of Colorectal Cancer	NCT00394992	Colorectal Canc... Liver Metastase...	oxaliplatin+cap... Oxaliplatin+cap...	18 Years -	Dutch Colorectal Cancer Group

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