Phase I study of cetuximab in combination with 5-fluorouracil, mitomycin C and radiotherapy in patients with locally advanced anal cancer

Eur J Cancer. 2015 Dec;51(18):2740-6. doi: 10.1016/j.ejca.2015.08.029. Epub 2015 Nov 18.


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 and materials: 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%.

Conclusion: 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.

Trial registration: NCT01621217.

Keywords: 5-Fluorouracil; Anal cancer; Cetuximab; Mitomycin C; Phase I; Radiotherapy.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Anus Neoplasms / pathology
  • Anus Neoplasms / therapy*
  • Carcinoma, Squamous Cell / secondary
  • Carcinoma, Squamous Cell / therapy*
  • Cetuximab / adverse effects
  • Cetuximab / therapeutic use*
  • Chemoradiotherapy* / adverse effects
  • Disease Progression
  • Disease-Free Survival
  • Female
  • Fluorouracil / adverse effects
  • Fluorouracil / therapeutic use*
  • Humans
  • Kaplan-Meier Estimate
  • Liver Neoplasms / secondary
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Mitomycin / adverse effects
  • Mitomycin / therapeutic use*
  • Neoplasm Staging
  • Norway
  • Prospective Studies
  • Radiotherapy, Intensity-Modulated* / adverse effects
  • Remission Induction
  • Sweden
  • Time Factors
  • Treatment Outcome


  • Mitomycin
  • Cetuximab
  • Fluorouracil

Associated data

  • EudraCT/EUDRACT2010-023829-38