title: Phase I study of cetuximab in combination with 5-fluorouracil, mitomycin C and radiotherapy in patients with locally advanced anal cancer.
abstract: BACKGROUND
  5-fluorouracil (5FU) and mitomycin C (MMC)-based chemoradiotherapy (CRT) is standard treatment for anal squamous cell carcinoma. In this phase I study cetuximab was added and the primary aim was to determine the maximum tolerated dose (MTD) of 5FU and MMC in this combination.
  
  
  METHODS
  Patients with locally advanced anal cancer, T2 (≥4 cm)-4N0-3M0, received weekly standard doses of cetuximab starting 1 week before CRT. Intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) with simultaneous integrated boost (SIB) was given to 57.5/54.0/48.6 Gy in 27 fractions to primary tumour/lymph node metastases/adjuvant lymph node regions. 5FU/MMC was given concomitantly on RT weeks 1 and 5 according to a predefined dose escalation schedule.
  
  
  RESULTS
  Thirteen patients were enrolled. Two patients discontinued cetuximab due to hypersensitivity reaction. The median age was 65 years (range 46-70), nine were females, and 85% had stage IIIB disease. Dose-limiting toxicity events (diarrheoa, febrile neutropenia and thrombocytopenia) occurred in 3 of 11 patients. The most common grade 3-4 side-effects were radiation dermatitis (63%), haematologic toxicity (54%), and diarrheoa (36%). No treatment-related deaths occurred. Three months following completion of treatment, ten patients (91%) had a local complete remission (CR), but two patients had developed liver metastases, yielding a total CR rate of 73%.
  
  
  CONCLUSIONS
  The MTDs were determined as 5FU 800 mg/m(2) on RT days 1-4 and 29-32 and MMC 8 mg/m(2) on days 1 and 29 when combined with IMRT/VMAT with SIB and cetuximab in locally advanced anal cancer.
authors.affiliation: Department of Oncology, Skåne University Hospital, Lund, Sweden. Electronic address: otilia.leon@skane.se.
authors.forename: Otilia
authors.initials: O
authors.lastname: Leon
authors.affiliation: Department of Oncology, Oslo University Hospital, Oslo, Norway; K.G.Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.
authors.forename: Marianne G
authors.initials: MG
authors.lastname: Guren
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Calin
authors.initials: C
authors.lastname: Radu
authors.affiliation: Department of Oncology, Skåne University Hospital, Lund, Sweden.
authors.forename: Adalsteinn
authors.initials: A
authors.lastname: Gunnlaugsson
authors.affiliation: Department of Oncology, Skåne University Hospital, Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Johnsson
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001005:Anus Neoplasms / Q000473:pathology / Q000628:therapy*; D002294:Carcinoma, Squamous Cell / Q000556:secondary / Q000628:therapy*; D000068818:Cetuximab / Q000009:adverse effects / Q000627:therapeutic use*; D059248:Chemoradiotherapy / Q000009:adverse effects; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016685:Mitomycin / Q000009:adverse effects / Q000627:therapeutic use*; D009367:Neoplasm Staging; D009664:Norway; D011446:Prospective Studies; D050397:Radiotherapy, Intensity-Modulated / Q000009:adverse effects; D012074:Remission Induction; D013548:Sweden; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D016685:Mitomycin; D000068818:Cetuximab; D005472:Fluorouracil
keywords: 5-Fluorouracil; Anal cancer; Cetuximab; Mitomycin C; Phase I; Radiotherapy