Phase III Study Evaluating Induction Chemotherapy Followed by Chemoradiotherapy Compared to Standard Chemoradiotherapy for Locally Advanced SCCA

• induction chemotherapy (mDCF) (Drug): Induction chemotherapy consists of mDCF administered every 2 weeks: * Docetaxel (40 mg/m², day 1), * Cisplatin (40 mg/m², day 1) * 5-FU (1200 mg/m²/day IV for 2 days)
• Concomitant chemotherapy (Capecitabin + Mitomycin-C) (Drug): Concomitant Chemotherapy consists of Mitomycin-C (10 mg/m2 intravenous infusion at D1 and D29) and Capecitabine (1650 mg/m²/day divided in two oral intakes 825 mg/m² twice a day, five days a week). Patients should be counseled to only take capecitabine on the days when radiotherapy is being given
• radiotherapy (Radiation): Radiotherapy consists of conformational intensity-modulated external irradiation with simultaneous integrated boost (IMRT-SIB) with 2 level of dose (30 sessions) * 49.5 Gy (5 x 1.65 Gy/week) to the pelvis * 60 Gy (5 x 2 Gy /week) to the primary tumor and initially involved nodes

Primary outcomes

• Disease-related event free survival (DREFS) at 2 years [2 years after last patient completed treatment]: DREFS will be compared between the two arms . An event is defined as :progression, residual tumor at 6 months requiring APR, recurrence (local or metastatic) or death

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Anal Squamous cell carcinoma histologically proven
2. Locally advanced tumors without metastases

   * Stage T3 or T4
   * Stage N1 (a, b or c) - any T (T1 to T4)
3. Age ≥18 and ≤ 75 or > 75 in case of score G8 > 14 or favourable oncogeriatric assessment
4. Measurable tumor on MRI
5. Able to receive chemotherapy and radiotherapy
6. No major comorbidity that may preclude the delivery of treatment
7. Adequate hematologic function: absolute neutrophil count ≥ 1500/mm3, platelet count ≥ 100 000/mm3, Hb ≥ 9g/dl
8. Adequate renal function: creatinine clearance (according to MDRD formula) ≥ 60 ml/min
9. Adequate hepatic function: AST and ALT ≤ 2.5 × Upper Limit of Normal and total bilirubin ≤ 1.5 × ULN
10. WHO performance status < 2
11. Signature of informed consent
12. A negative pregnancy test for inclusion in the study for all female patients of child-bearing potential. In case of a "urine pregnancy test", it must be a highly sensitive urine pregnancy test, in accordance with the recommendations of the CTFG regarding pregnancy risk management (Recommendations related to contraception and pregnancy testing in clinical trials)
13. Female patients postmenopausal for at least one year or surgically infertile for at least 6 weeks, or effective contraception for male (until 6 months after the end of the investigational treatments) and female patients of childbearing potential (until 7.5 months after the end of treatment with cisplatine)
14. Patient to be covered by a regimen of French Social Security system.

Exclusion Criteria:

1. Presence of metastases
2. Stage T1N0 or T2N0
3. History of pelvic radiotherapy
4. Complete or partial Dihydropyrimidine dehydrogenase (DPD) deficiency (uracilemia ≥ 16 ng/mL)
5. Positive HIV serology with CD4 < 400 / mm3
6. Presence of neuropathy > grade 2 according to NCIC-CTC 4.0
7. Contraindication for chemotherapy and/or radiotherapy
8. Concomitant treatment with CYP3A4 inhibitors or inducers
9. Symptomatic cardiac or coronary insufficiency
10. Progressive active infection or any unbalanced progressive severe condition in the last 6 months
11. No contraindication to MRI imaging
12. Other cancer treated within the last 3 years except in situ cervical carcinoma or basocellular/ spinocellular carcinoma or any other carcinoma in situ considered as cured
13. breastfeeding woman.
14. Persons deprived of liberty or under guardianship or incapable of giving consent
15. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol or follow-up schedule.
16. Live attenuated vaccines within 4 weeks before randomization 17. In case of hearing problem 18. In case of combination with phenytoin with prophylactic aim 19. In case of recent or concomitant treatment brivudine

14 more sites not listed.

• Veronique Vendrely, Md-pHD, Principal investigator, University Hospital, Bordeaux