Study of Radiation Therapy in Combination With Xeloda, for Initially Metastatic, Low and Middle Rectal Cancer

Study Overview
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Brief Summary
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In initially metastatic rectal carcinoma, a neo-adjuvant multi-drug chemotherapy is usually performed, followed by a pelvic chemoradiation. The surgical indications on both metastases and the pelvic site are then discussed: in the case where a complete (or near-complete) response (CR) of the rectal tumor is observed (10 to 40%), the local surgery may be omitted or poned (wait-and-see) in a sphincter-sparing strategy, in order to minimize or avoid the surgical morbidity, to focus on metastatic disease by the continuation of chemotherapy, and to preserve a better quality of life. After 8 weeks of induction chemotherapy (mFolfox6 regimen, 4 cycles), the aim of our study is to optimize the chemoradiation step on the distal rectal tumor, thanks to Intensity-Modulated Radiotherapy (IMRT) with simultaneous integrated boost (SIB) (Phase-1 part of the study), concomitantly with oral capecitabine. According to a Fibonacci dose-escalation scheme, 3 radiation dose-levels are defined, up to the definition of the maximal tolerated dose (MTD), requiring the inclusion of a maximum of 20 patients. Further patients will be included at the recommended dose for phase-2 (RDP2) in a two-step phase-2 study, considering simultaneously as principal objective at 12 months, both the efficacy (local CR rate in the range of 10 to 25%) and the tolerance (pelvic radiation disease: grade 3-4 toxicities in the range of 30 to 10%). Overall 65 patients will be included in the phase-2 study at the RDP2 dose.

Detailed Description
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The study population has metastatic rectal cancer. After obtaining informed consent and if they fulfil all of the criteria for inclusion, patients will be included. After 8 weeks of induction chemotherapy with FOLFOX, patients perform an imaging assessment. Then they are treated by radiotherapy with an oral Xeloda At the end of irradiation, patients realize on other Imaging assessment. Patients are then followed for 2 years

Official Title
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Phase-1 Study of Escalated-dose Pelvic Radiation Therapy Using Intensity-Modulated Radiotherapy (IMRT) With Simultaneous Integrated Boost (SIB), in Combination With Xeloda, for Initially Metastatic, Low and Middle Rectal Cancer

Conditions
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Rectal Cancer, Metastasis, Radiotherapy

Intervention / Treatment
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* Combination Product: IMRT + oral chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Metastatic distal rectal carcinoma (low and middle); age >18 years Estimated life expectancy greater than 3 months PS: ECOG<2 Normal hematologic, renal and hepatic functions Normal or only partially decreased DPD activity Effective contraception in women and men of childbearing age Social insurance. Signed informed consent Exclusion Criteria: No previous treatment with pelvic radiotherapy or chemotherapy Disorder precluding understanding of trial information or informed consent No severe or uncontrolled disease (infection, VIH, HBs, diabetes mellitus) No peripheral neuropathy > grade 2 No inflammatory disease or fructosemia Diarrhea of grade > 2 Pregnancy, breastfeeding women Patients already included in another therapeutic within a period of 30 days Other malignancy treated within the last 5 years (except non-melanoma skin cancer) Bilateral total hip prosthesis Patient is willing and able to comply with the protocol for the duration of the study including all scheduled treatment, visits and examinations

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Interventional Model Description: Phase-1 study of escalade dose of radiation
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMRT + oral chemotherapy<br>Radiotherapy = IMRT with SIB. The overall duration of irradiation is 5 to 7 weeks Chemotherapy = oral capecitabine. Chemotherapy is taken in concomitance as radiotherapy days | Combination Product: IMRT + oral chemotherapy<br>* It's a dose escalation of radiation (IMRT), during 5 to 7 weeks, 5 days per week. Concomitantly, patient have oral chemotherapy (capecitabin)<br>* Other names: Intensity-Modulated Radiotherapy + capecitabine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| maximum tolerated radiation dose (MTD) delivered by IMRT with SIB, in combination with oral capecitabine, for initially metastatic, low and middle rectal cancer after 4 induction cycles of mFolfox6 regimen. | MTD = dose level -1 after at least 2 patients with DLT to upper level | 84 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Progression-free survival at 12 months, | % patient with Local Progression at CT scan, 12 months after inclusion | 12 months after inclusion | 
| Toxicity profile of the chemoradiation step for NCI.CTC grade 3-4 local toxicities due to Pelvic Radiation Disease | % patient with >= grade 3 toxicity (NCI.CTC AE) | 84 months | 
| To evaluate quality of Life | EORTC-QLQC-30 | 84 months | 
| To evaluate quality of Life | QLQ-CR29 | 84 months | 
| Overall survival at 2 years | Overall survival is defined as the delay between the date of inclusion and the date of end of study | 24 months after inclusion | 
| The usefulness of surgery | The surgical decision within 12 months after the end of radiochemotherapy will be recovered | 12 months after the end of radiochemotherapy | 
| The prognostic value of PET | The interest of PET to define the volume in radiotherapy | 108 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intensity Modulated Radiotherapy, Simultaneous Integrated Boost, Low and middle Rectal carcinoma