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

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

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.

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

Inclusion Criteria:

1. Metastatic distal rectal carcinoma (low and middle);
2. age >18 years
3. Estimated life expectancy greater than 3 months
4. PS: ECOG<2
5. Normal hematologic, renal and hepatic functions
6. Normal or only partially decreased DPD activity
7. Effective contraception in women and men of childbearing age
8. Social insurance.
9. Signed informed consent

Exclusion Criteria:

1. No previous treatment with pelvic radiotherapy or chemotherapy
2. Disorder precluding understanding of trial information or informed consent
3. No severe or uncontrolled disease (infection, VIH, HBs, diabetes mellitus)
4. No peripheral neuropathy > grade 2
5. No inflammatory disease or fructosemia
6. Diarrhea of grade > 2
7. Pregnancy, breastfeeding women
8. Patients already included in another therapeutic within a period of 30 days
9. Other malignancy treated within the last 5 years (except non-melanoma skin cancer)
10. Bilateral total hip prosthesis
11. Patient is willing and able to comply with the protocol for the duration of the study including all scheduled treatment, visits and examinations