Efficacy of cetuximab in the treatment of Menetrier's disease

Abstract

Ménétrier's disease is a rare premalignant disorder of the stomach with no proven effective medical therapy. Increased epidermal growth factor receptor signaling has been implicated in the pathogenesis of Ménétrier's disease. We conducted a single-arm clinical trial with cetuximab, a monoclonal antibody that blocks epidermal growth factor receptor signaling, in nine individuals with clinically and histologically documented severe Ménétrier's disease that impaired quality of life to the extent that gastrectomy was being considered. Of the seven patients who completed the 1-month course of treatment, all showed statistically significant improvement both clinically (quality-of-life indices) and biochemically (increased parietal cell mass and gastric acidity). Furthermore, all seven patients who completed the 1-month trial elected to continue treatment, and four subsequently showed near-complete histological remission. Cetuximab should be considered as first-line therapy for Ménétrier's disease.

Fig. 1

Response to one-month course of cetuximab in patient 4. (A) Patient 4 showed a marked reduction in stomach wall thickness by CT scan. An equivalent amount of VoLumen (an oral contrast agent) was administered prior to the scans. Arrows, thickness of gastric wall. (B) Biopsies before and 1 month after treatment show regression of foveolar hyperplasia and restoration of glandular mucosa with return to normal pit to gland ratio of 1:4. Surface mucous cells are strongly positive and mucous neck cells are weakly positive by diastase-resistant periodic acid-Schiff staining. Gastric pH decreased from 7 to 2 after 4 weekly infusions of cetuximab. Scale bar is 250 microns.

Fig. 2

Recovery of parietal cells and decrease in proliferation one day after initiation of cetuximab treatment. (A) Patients 1 and 3 demonstrated rapid (one day) and sustained (one month) increases in H⁺/K⁺⁻ATPase α-subunit immunoreactivity. Scale bar is 250 microns. (B) Patient 7 had a dramatic decrease in Ki-67 staining one day after first dose of cetuximab. Scale bar is 250 microns.

Fig. 3

Progressive improvement in gastric histology during cetuximab treatment. Foveolar hyperplasia [with characteristic cysts (arrow in top left panel) and tortuous glands (arrow in middle left panel)] and glandular atrophy are evident the day before treatment by hematoxylin-eosin staining. At last follow-up, patients 1, 2 and 3 showed reduced thickness of gastric mucosa, regression of foveolar hyperplasia and restoration of glandular mucosa and gastric acidity. Cetuximab has been discontinued in patients 1 and 2. Patient 3 had the most distorted architecture at presentation. Progressive histological improvement was noted beginning at 31 months (Fig. S2) and last follow-up at 38 months. Scale bar is 250 microns.