Radiochemotherapy With Panitumumab in the Localised Epidermoid Carcinoma of the Anus

• Phase I = determination the maximum tolerated dose 5FU and panitumumab in combination with radiotherapy and mitomycin, and thereby to deduce the maximum tolerated dose in patient with localised epidermoid carcinoma of the anus [ Time Frame: 9 weeks after the beginning of treatment ] [ Designated as safety issue: No ]
  Phase I = determine the dose limiting toxicity of 5FU and panitumumab in combination with radiotherapy and mitomycin, and thereby to deduce the maximum tolerated dose in patient with localised epidermoid carcinoma of the anus
• Phase II = Complete response of the tumor rectal examination and morphological exams [ Time Frame: 8 weeks evaluations after the end of the treatment by radiochemotherapy ] [ Designated as safety issue: No ]
  phase II = Response criteria: complete desappearance of the tumor upon rectal examination and morphological exams (MRI, endoscopic ultrasonography) and non appearance of secondary lesions, response validated by an independant committee.

• Phase II = Partial response rate, stable disease and progression [ Time Frame: 6 weeks and 17 weeks after the beginning of treatment ] [ Designated as safety issue: No ]
  • Intermediate objective response rate (complete and partial) at 6 weeks (before the additional radiotherapy). The 80% reduction rate in the largest tumour diameter will also be recorded.
  • Partial response rate, stable disease and progression 8 weeks after the end of treatment
• Phase II = Colostomy-free survival [ Time Frame: At 3 years after randomization ] [ Designated as safety issue: No ]
• Phase II = Recurrence-free survival at 3 years [ Time Frame: At 3 years after randomization ] [ Designated as safety issue: No ]
• Phase II = Overall survival [ Time Frame: At 3 years after randomization ] [ Designated as safety issue: No ]
• Phase II = Quality of life (EORTC QLQ-C30 + Wexner questionnaire) [ Time Frame: At 3 years after randomization ] [ Designated as safety issue: No ]
  -

Treatment is based on radiochemotherapy for locally advanced tumours. The objective of treatment is to provide a cure without resorting to abdominoperineal amputation, while preserving sphincter function.

The prognosis is mainly related to tumour size and lymph node invasion. The large majority of patients do not show any spread remote from the tumour at the time of diagnosis (2).

Recurrences are mainly of a local/regional nature and require abdominoperineal amputation. This type of intervention is not always possible or complete, which then gives rise to the particularly distressing risk of local progression, with survival at 3 years of approximately 30% (3).

It is therefore very important to achieve a complete and permanent tumour response from initial treatment with radiochemotherapy.

Furthermore, the use of an anti-EGFR antibody in combination with exclusive radiotherapy in ENT cancer was able to increase recurrence-free survival and overall survival in these patients. These data are in favour of the use of a combination of chemotherapy and anti-EGFR antibodies in epidermoid cancer of the anus.

• Epidermoid Carcinoma
• Anus

• Drug: radiochemotherapy
  Radiotherapy : PTV1 45 Gy 5 weeks PTV2 20 Gy 2 weeks Chemotherapy : 5Fu (400 to 1000 mg/m²) mitomycin : 10 mg/m²
• Drug: Panitumumab
  3 or 6 mg/kg (according to dose level)

Inclusion Criteria:

• Histologically proven epidermoid carcinoma of the anus
• Locally advanced tumour without metastases
• Stage T2>3 cm or T3 or T4, irrespective of N
• Stage N1-N3 irrespective of T stage (T1 to T4)
• General condition WHO 0-1
• Life expectancy > 3 months
• Signed informed consent form
• Age > 18 years
• Effective contraception in female and/or male patients having reached sexual maturity during treatment and up to 6 months after the end of treatment
• CD4 > 400 / mm3
• Measureable tumor on at least one of the following exams : MRI, endoscopic ultrasonography, clinical exam

Exclusion Criteria:

• Presence of metastases
• Previous anti-EGFR therapy
• Stage T1N0 or T2 < 3 cm N0
• History of pelvic radiotherapy
• At least one of the following laboratory test results: Neutrophils < 1500 /mm3, platelets < 100 000 /mm3, Hb < 9 g/dl, leukocytes < 3000/mm3, blood bilirubin > 1.5 times the upper limit of the normal range, transaminase (ASAT and ALAT) > 2.5 times the upper limit of the normal range, creatinine clearance < 50 mL/min (Cockcroft's formula Appendix x), Mg2+ < the lower limit of the normal range, Ca2+ < the lower limit of the normal range
• Significant coronary artery disease or myocardial infarction in the past year
• Follow-up not possible due to psychological or geographic reasons
• History of interstitial pneumonitis or pulmonary fibrosis
• History of malignant disease in the past five years apart from basocellular skin carcinoma or in situ cervical carcinoma having received adequate treatment
• Pregnant or breast-feeding women, women of child-bearing potential not having taken a pregnancy test.