Reply to phase 1 study of cetuximab in combination with 5-fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma


Feliu et al believe that local factors related to the central venous catheters (CVC) played a major role in the high incidence of venous thromboembolism (VTE) reported in our phase 1 trial.[1] Moreover, they claim that the inclusion of patients with concomitant severe illness favored the increased rates of VTE. They bring to light their own phase 2 experience in treating patients with locally advanced anal canal carcinoma with pelvic chemoradiation based on the use of mitomycin-C plus panitumumab, in which no cases of VTE were reported to have occurred. In addition, they refer to the results of two phase 2 trials that have been published only in abstract form.

Our reasons for disagreeing with Feliu et al are manifold. First, comparison across the trials they refer to is not trivial because different treatment strategies and agents were administered. Full reports of these trials are required to draw any conclusion. We believe the type of catheter used in our study did not influence the rate of VTE. The alteration of peripherally inserted central catheters to implanted CVCs in 12 patients treated with the recommended phase 2 dose did not appear to have any impact on the VTE rate, which continued to occur in 25%, or 3 of 12 patients. Conversely, the use of agents with potential risk for VTE (cisplatin and cetuximab) in combination may be an issue. In our experience with the use of only cisplatin-based chemoradiation in 86 patients with locally advanced anal canal carcinoma, no patient developed VTE.[2]

Cumulative toxicities may be relevant. In our trial, the majority of patients received full treatment and developed severe toxicities, and the majority of the cases of VTE occurred after the second cycle of chemotherapy. Conversely, in the ACCORD 16 trial,[3] which is more similar to ours, no VTE occurred, but only 8 of the 16 enrolled patients completed treatment. In fact, a constellation of factors such as diarrhea, infection, neutropenia, and hospitalization may have played a role.

Secondly, severe comorbidities or cardiovascular disease were exclusion criteria in our trial. The Khorana et al predictive model for chemotherapy-associated thrombosis was applied in all patients.[4] Only 3 of 23 patients were found to have an intermediated risk for VTE, and the remaining 20 patients were found to be at low risk for developing VTE. In conclusion, local factors and comorbidities do not appear to have played a major role in the high VTE rate found in our study.[1]


The authors made no disclosures.

  • Luis Olivatto, MD, MSc

  • Division of Clinical Oncology National Cancer Institute Rio de Janeiro, Brazil

  • Carlos Gil Ferreira, MD, PhD

  • Coordination of Clinical Research National Cancer Institute Rio de Janeiro, Brazil