Clinical Investigation
Could the Addition of Cetuximab to Conventional Radiation Therapy Improve Organ Preservation in Those Patients With Locally Advanced Larynx Cancer Who Respond to Induction Chemotherapy? An Organ Preservation Spanish Head and Neck Cancer Cooperative Group Phase 2 Study

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Purpose

To evaluate the efficacy and safety of induction chemotherapy (IC) followed by bioradiotherapy (BRT) to achieve functional larynx preservation in the setting of locally advanced head and neck tumors.

Methods and Materials

This was a phase 2, open-label, multicenter study of patients with stage III and IVA laryngeal carcinoma who were candidates for total laryngectomy. The primary endpoint was the rate of survival with functional larynx (SFL) at 3 years, with a critical value to consider the study positive of SFL >59%. Patients received 3 cycles of IC with TPF (docetaxel, cisplatin, and 5-fluorouracil), and those who responded received conventional BRT with cetuximab. In patients with residual nodal disease after BRT, neck dissection was planned 2 months after BRT. Patients who did not respond to IC underwent total laryngectomy plus neck dissection and radiation therapy.

Results

A total of 93 patients started TPF. Responses to IC on larynx target lesion were as follows: 37 patients (40%) showed a complete response; 38 patients (41%) showed a partial response; 8 patients (9%) showed stabilization; 2 patients (2%) showed progressive disease, and 8 patients (9%) were not evaluated (2 deaths, 5 adverse events, and 1 lost to follow-up). Seventy-three patients (78%) received BRT: 72 as per protocol, but 1 with only stable disease. Median follow-up was 53.7 months. Three-year actuarial rates were as follows: SFL: 70% (95% confidence interval [CI] 60%-79%); laryngectomy-free survival: 72% (95% CI 61%-81%); overall survival: 78% (95% CI: 63%-82%). The acute toxicity observed during both IC and BRT was as expected, with only 1 toxicity-related death (local bleeding) during BRT.

Conclusions

According to this protocol, the SFL rate was clearly higher than the critical value, with acceptable levels of toxicity. The use of cetuximab added to radiation therapy in patients with stage III and IVA laryngeal cancer who respond to TPF could improve functional larynx preservation. A phase 3 trial is warranted.

Introduction

The first study evaluating the possibility of avoiding total laryngectomy (TL) in patients with locally advanced laryngeal cancer was published 25 years ago (1). Induction chemotherapy (IC) followed by conventional radiation therapy (RT), in those patients who had responded, demonstrated organ preservation without significantly affecting overall survival.

A decade later, the usefulness of IC was questioned when a published article reported the first results of the Radiation Therapy Oncology Group (RTOG) 91-11 study (2), claiming that concomitant treatment with RT and cisplatin was superior in locoregional control and larynx preservation. These data were consistent with the results of the meta-analysis on the use of chemotherapy published a few years earlier (3), and as a result, most institutions changed their approach to larynx preservation from IC to concomitant chemotherapy.

Optimization of IC produced by introducing docetaxel (Taxotere, T) to the classic platinum plus fluorouracil (PF) scheme 4, 5 enabled its use in organ preservation protocols, and the GORTEC (Groupe d'Oncologie Radiothérapie Tête Et Cou) group demonstrated that the 3-drug schedule with TPF was clearly superior to PF for larynx preservation (6).

Cetuximab is a chimeric monoclonal antibody that binds with high affinity to the extracellular domain of the epidermal growth factor receptor and induces antibody-dependent cellular cytotoxicity (7). The combination of cetuximab plus RT has demonstrated superior efficacy and has only slightly increased toxicity as compared with RT alone (8).

Cetuximab combined with RT seems to be as effective as cisplatin in organ preservation, with a different pattern of acute toxicity after induction with TPF (9), which could result in higher rates of larynx preservation. The aim of our study was to evaluate survival with functional larynx (SFL) after RT plus cetuximab in patients who respond to IC with TPF.

Section snippets

Study patients

From October 2008 to February 2011, previously untreated patients between 18 and 70 years of age with stage III and IVA squamous cell carcinoma of the larynx, and candidates for TL according to each local multidisciplinary committee, were included in this trial. Patients were followed up until May 2015. The protocol was approved by all institutional review boards at the participating institutions, and all the patients provided written, informed consent.

Study design and treatment

This was a prospective, multicenter, phase

Patient characteristics

A final total of 94 patients were enrolled in the study (see Fig. 1 for intent-to-treat population), and 1 patient was excluded because he did not fulfill 1 of the inclusion criteria (renal insufficiency) and therefore did not start IC. Demographic, clinical, and pathologic characteristics of the modified intent-to-treat population (n=93) are represented in Table 1. The following factors are also worth mentioning: the limited inclusion of women (8%), the high proportion of supraglottic

Discussion

All trials investigating organ preservation that have used an IC arm have also used RT alone as the local treatment in patients who demonstrated an almost PR 1, 2, 6, 13. Our study was designed to evaluate the role of cetuximab added to RT in maintaining locoregional control and reducing chronic toxicity (pharyngo-larynx functionality). We found that BRT with cetuximab was superior to the use of RT alone in locoregional control (8), and possibly also in larynx preservation (14). Controversy

Acknowledgments

The authors thank Eva Uson, statistician from TFS, and Juan Carlos Adansa from the TTCC: Spanish Head and Neck Cancer Cooperative Group, for their continuous support during the development of this clinical trial; Crystal Freeman for her support in reviewing the English; and the patients and families who participated in this trial.

References (20)

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