Post RT Adjuvant Cetuximab for Locally Advanced Oropharyngeal Cancer

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In a randomized, Phase 2 trial, weekly maintenance cetuximab for 12 weeks after concomitant definitive radiation therapy/cetuximab induction was associated with better disease-free survival at 1 year. However, by year 2, the local recurrence rate was the same for both treatment groups and overall survival was also no different. Toxicity was transiently and only mildly worse for those treated with the additional 3 months of cetuximab.

Source: Mesia R, et al. Adjuvant therapy with cetuximab for locally advanced squamous cell carcinoma of the oropharynx: Results from a randomized, phase II prospective trial. Ann Oncol 2013;24:448-453.

Although there has been improvement in the management of squamous cell cancer of the head and neck (SCCHN), overall survival for those who present with locally advanced disease remains only slightly better than what it was 2 decades ago. To improve outcomes for such patients, effective new treatments with less toxicity are currently under investigation.

Cetuximab is a chimeric monoclonal antibody that binds to the extracellular domain of epidermal growth factor receptor (EGFR).1 Concomitant cetuximab and radiotherapy (RT) has proven superior to RT alone in producing local control, and preclinical studies2,3 would suggest that extending cetuximab after RT would enhance local control and possibly overall survival.

To this end, Mesia and colleagues throughout Spain conducted a randomized, Phase 2 trial to evaluate the efficacy and safety of cetuximab maintenance therapy following definitive RT with concomitant cetuximab in patients with oropharyngeal cancer.

For this, ninety-one patients with stage III–IV M0 oropharyngeal tumors were randomly assigned to treatment with accelerated concomitant boost RT (69.9 Gy) plus cetuximab (400 mg/m2 as initial dose followed by 250 m/m2 weekly for the duration of RT) or the same treatment with an additional 12 consecutive weeks of cetuximab (250 mg/m2) maintenance therapy. Study enrollment occurred from November 2005 to July 2007. The primary endpoint was locoregional control (LRC) at 1 year. Secondary endpoints included LRC rates at 2 and 3 years, specific disease-free survival (SDFS), event-free survival (EFS), overall survival (OS), and the safety and toxicity of concomitant RT plus cetuximab followed by 12 additional weeks of cetuximab.

The treatment arms were evenly matched for all important prognostic indicators including age, sex, performance score, stage, and site of primary tumor. Treatment compliance during the concomitant phase was high and similar in both groups. More than 85% of the patients received the planned dose of RT and cetuximab. Further, compliance during the adjuvant phase was also high, with 79% completing 10 or more weeks of weekly adjuvant treatments.

Adverse events during concomitant treatment were comparable between both treatment groups. Only one patient discontinued cetuximab because of a hypersensitivity reaction after the first infusion. Cetuximab was generally well tolerated; most adverse events were grade 1-2 and mainly included skin rash, mucositis, odynophagia, and asthenia. There were few episodes of grade 4 toxic effect: n = 4 with mucositis, n = 1 with toxic skin rash, and n = 1 with radiation dermatitis. Notably, the toxicity due to RT recovered similarly in patients receiving adjuvant cetuximab when compared to the non-adjuvant group. Only the recovery from mucositis (grade 1–2) was slower in the adjuvant treatment group. However, skin toxicity was increased during the adjuvant treatment, but was mild in the majority of cases with a clear tendency toward improvement with time.

LRC at 1 year was superior among patients in the experimental arm treated with cetuximab maintenance (59% vs 47%). However, LRC was similar between both arms after 2 years of follow-up as a result of increased locoregional recurrences after the first year in the maintenance group.

Commentary

Twelve weeks of cetuximab maintenance therapy after concomitant cetuximab + RT in locally advanced oropharyngeal carcinoma is feasible and improves clinical outcomes measured at 1 year. However, the improvement is not maintained beyond that, with comparable survival at year 2. Thus, it appears that epidermal growth factor receptor blockade is insufficient to completely eliminate minimal residual disease.

Accordingly, novel strategies need to be developed incorporating agents such as cetuximab or other targeted therapies with cytotoxic chemotherapy administered either combined or in sequence with RT to eliminate resistant local residual as well as disseminated microscopic disease. Although maintenance therapy in the current study was not associated with greater toxicity, the addition of chemotherapy may prove challenging in this regard.

References

1. Goldstein NI, et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1995;1:1311-1318.

2. Milas L, et al. Importance of maintenance therapy in C225-induced enhancement of tumor control by fractionated radiation. Int J Radiat Oncol Biol Phys 2007;67:568-572.

3. Pueyo G, et al. Cetuximab may inhibit tumor growth and angiogenesis induced by ionizing radiation: A preclinical rationale for maintenance treatment after radiotherapy. Oncologist 2010;15:976-986.