Oxaliplatin, Capecitabine, and Radiation Therapy With or Without Cetuximab in Treating Patients Undergoing Surgery for High-Risk Rectal Cancer

A Multicentre Randomised Phase II Clinical Trial Comparing Oxaliplatin (Eloxatin), Capecitabine (Xeloda) and Pre-Operative Radiotherapy With or Without Cetuximab Followed by Total Mesorectal Excision for the Treatment of Patients With Magnetic Resonance Imaging (MRI) Defined High Risk Rectal Cancer

RATIONALE: Drugs used in chemotherapy, such as oxaliplatin and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving chemotherapy and radiation therapy with or without cetuximab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known whether giving oxaliplatin, capecitabine, and radiation therapy is more effective with or without cetuximab when given before surgery in treating rectal cancer.

PURPOSE: This randomized phase II trial is studying oxaliplatin, capecitabine, and radiation therapy to compare how well they work with or without cetuximab in treating patients undergoing surgery for high-risk rectal cancer.

OBJECTIVES:

• Compare the pathological complete response rate at total mesorectal excision in patients with high-risk rectal cancer treated with neoadjuvant therapy comprising oxaliplatin, capecitabine, and radiotherapy with or without cetuximab.

OUTLINE: This is a multicenter, open-label, randomized, controlled study. Patients are stratified according to participating center and presence of T4 disease (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I:

  • Neoadjuvant chemotherapy: Patients receive oxaliplatin IV over 2 hours on days 1, 22, 43, and 64 and oral capecitabine twice daily on days 1-14, 22-35, 43-56, and 64-77.
  • Neoadjuvant chemoradiotherapy: Patients undergo radiotherapy once daily on days 85-89, 92-96, 99-103, 106-110, 113-117, and 120-124 and receive oral capecitabine twice daily on days 85-126.
  • Surgery: Four to six weeks after completion of chemoradiotherapy, patients undergo total mesorectal excision (TME).
  • Adjuvant therapy: Beginning 6-8 weeks after surgery, patients receive oxaliplatin IV over 2 hours on days 1, 22, 43, and 64 and oral capecitabine twice daily on days 1-14, 22-35, 43-56, and 64-77.

• Arm II:

  • Neoadjuvant therapy: Patients receive oxaliplatin and capecitabine as in arm I neoadjuvant chemotherapy and cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.
  • Neoadjuvant chemoradiotherapy: Patients undergo radiotherapy and receive capecitabine as in arm I neoadjuvant chemoradiotherapy and cetuximab IV over 1 hour on days 85, 92, 99, 106, 113, and 120.
  • Surgery: Four to six weeks after completion of chemoradiotherapy patients undergo TME as in arm I.
  • Adjuvant therapy: Beginning 6-8 weeks after surgery, patients receive oxaliplatin and capecitabine as in arm I adjuvant chemotherapy and cetuximab IV over 1 hour on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

In both arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed periodically.

After completion of study treatment, patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually for 2 years.

PROJECTED ACCRUAL: A total of 164 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma or undifferentiated non-small cell carcinoma of the rectum

• MRI-defined high-risk, operable disease, defined by ≥ 1 of the following:

  • Tumors within 1 mm of mesorectal fascia (i.e., circumferential resection margin threatened or involved)
  • T3 tumors at or below levators
  • Tumors extending ≥ 5 mm into perirectal fat
  • T4 tumors
  • Presence of extramural venous invasion (primary tumor is therefore at least T3)

• No evidence of metastatic disease by CT scan of the chest and abdomen or, if required, by positron emission tomography scan or biopsy

• No rectal cancer that is unlikely to be operable even after neoadjuvant treatment (i.e., tumor involving the internal iliac vessels)

• No T1-2 rectal cancer, in the absence of other high-risk factors

  • T2 tumors within 1 mm of mesorectal fascia allowed

• No recurrent disease

PATIENT CHARACTERISTICS:

• WHO performance status 0-2

• Life expectancy > 3 months

• WBC > 3,000/mm³

• Absolute neutrophil count > 1,500/mm³

• Platelet count > 100,000/mm³

• Bilirubin < 1.5 times upper limit of normal (ULN)

• Transaminases < 2.5 times ULN

• Creatinine normal OR creatinine clearance > 50 mL/min

• Not pregnant or nursing

• Fertile patients must use effective contraception

• No concurrent uncontrolled medical condition

• No other active malignant disease within the past 10 years except nonmelanoma skin cancer or carcinoma in situ of the cervix

• No contraindications to MRI (e.g., pacemaker)

• No medical or psychiatric conditions that would preclude informed consent

• No known malabsorption syndrome or lack of physical integrity of the upper gastrointestinal tract

• No clinically significant (i.e., active) cardiac disease, including any of the following:

  • Congestive heart failure
  • Symptomatic coronary artery disease
  • Cardiac dysrhythmia (e.g., atrial fibrillation, even if controlled with medication)
  • Myocardial infarction within the past 12 months

• No symptoms or history of peripheral neuropathy

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy, radiotherapy, or investigational treatment for rectal cancer
• No other concurrent cytotoxic agents or investigational drugs
• No concurrent sorivudine or sorivudine analogues (e.g., brivudine)