PPI Use May Reduce Capecitabine Efficacy For Gastro-oesophageal Cancer

Gastro-oesophageal cancer patients who take proton pump inhibitors during oral chemotherapy may have shorter survival than those who do not

medwireNews: Secondary analysis of the TRIO-013/LOGiC trial adds evidence for a link between overlapping use of acid-suppressing medication and reduced efficacy of oral capecitabine chemotherapy in patients with metastatic gastro-oesophageal cancer.

“Oncologists treating patients with capecitabine should be aware of the potential negative interaction with gastric acid suppressants such as PPIs [proton pump inhibitors] and possibly histamine antagonists”, the authors caution in JAMA Oncology.

In the phase III randomised trial of capecitabine plus oxaliplatin (CapeOx) with or without oral lapatinib for patients with ERBB2/HER2-positive disease, PPIs were used by 42% of the 545 participants, say Michael Sawyer, from the Cross Cancer Institute in Edmonton, Alberta, Canada, and co-workers.

Among the 119 patients who received CapeOx plus placebo, those who did not use PPIs had significantly longer median progression-free survival (PFS, 5.7 vs 4.2, hazard ratio [HR]=1.55) and overall survival (OS, 11.3 vs 9.2, HR=1.34).

The HRs for PFS and OS were also demonstrated to be significant in multivariate analysis, at 1.68 and 1.41, respectively, after adjusting for markers of poor prognosis, including age over 60 years, male gender, non-Asian race/ethnicity, a diffuse subtype and metastatic disease at presentation.

Nonusers of PPIs who were treated with CapeOx plus placebo also had a significantly higher disease control rate than PPI users (82.5 vs 71.2%).

By contrast, PPI use did not initially seem to influence PFS or OS for the 110 patients who were assigned to receive CapeOx plus lapatinib, although multivariate analysis gave a significant HR for OS of 1.38 for nonusers of PPIs versus users.

“Drawing conclusions from these patients is difficult given that they received 2 oral therapeutics of which both may have been affected by coadministration of gastric acid suppression therapy”, the authors comment on the lapatinib treated-patients.

“Further, though the primary outcomes of TRIO-013 were negative, preplanned subgroup analyses found younger patients and Asian patients benefited from adding lapatinib to CapeOx. Consequently, in light of a PPI-related effect on outcomes in the control arm, the lack of poorer outcomes in lapatinib-treated patients suggests that PPIs impair capecitabine absorption”, they continue.

“Whether or not there is a substantial interaction with lapatinib cannot be answered from this analysis due to these patients receiving 2 oral therapeutics.”

The authors admit that “this trial did not examine for pharmacokinetics and circulating drug levels so a direct link with potential reduced capecitabine absorption cannot be made in this analysis.”

But noting the increasing use of oral agents, they hypothesize that other such drugs, such as erlotinib or sunitinib , may also be affected by PPI use.

“While stopping gastric acid suppressants may prove difficult, it may be possible to temporarily counteract a lowered absorption by using an acidic beverage for drug administration”, they suggest.

“Overall, more food-effect studies are warranted in the development of oral therapeutics, and our study draws light to the possibility that such an interaction may also affect more commonly used cytotoxic chemotherapeutics, such as capecitabine, used across tumor subtypes.”

Reference

Chu MP, Hecht JR, Slamon D, et al. Association of proton pump inhibitors and capecitabine efficacy in advanced gastroesophageal cancer. Secondary analysis of the TRIO-013/LOGiC randomized clinical trial. JAMA Oncol; Advance online publication 13 October 2016. doi:10.1001/jamaoncol.2016.3358

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