Capecitabine after gastrectomy for advanced gastric cancer: have we got the patient right?

Abstract

We have read with great interest the meta-analysis reported by Okines et al. [1.Okines A.F.C. Norman A.R. McCloud P. et al.Meta-analysis of the REAL-2 and ML17032 trials: evaluating capecitabine-based combination chemotherapy and infused 5-fluorouracil-based combination chemotherapy for the treatment of advanced oesophago-gastric cancer.Ann Oncol. 2009; 20: 1529-1534Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar] comparing capecitabine-based and 5-fluorouracil-based combination chemotherapy in advanced gastric cancer (AGC) and we completely agree with the authors’ conclusion that capecitabine can substitute 5-fluorouracil in this setting. Moreover, as the analysis demonstrates a significant (despite limited) survival advantage for capecitabine combinations and considering the possibility of avoiding the central venous catheter, the oral fluoropyrimidine could be even preferable over 5-fluorouracil. Unfortunately, authors did not compare the results reported with the two agents in terms of toxic effects. Both REAL-2 [2.Cunningham D. Starling N. Rao S. et al.Capecitabine and oxaliplatin for advanced esophagogastric cancer.N Engl J Med. 2008; 358: 36-46Crossref PubMed Scopus (1851) Google Scholar] and ML17032 [3.Kang Y.K. Kang W.K. Shin D.B. et al.Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial.Ann Oncol. 2009; 20: 666-673Abstract Full Text Full Text PDF PubMed Scopus (665) Google Scholar] demonstrated that capecitabine is well tolerated, but neither these nor other published experiences evaluating capecitabine in AGC examined its safety profile after total gastrectomy. Only a small number of subjects in the capecitabine arms of the REAL-2 and ML17032 studies had undergone previous surgery (39 of 480 and 40 of 160, respectively), but no data regarding this specific subset are presented in the articles. A large amount of trials are now evaluating capecitabine combinations or capecitabine plus radiotherapy as adjuvant treatment of resected gastric cancer patients. In our opinion, lack of a clear definition of the safety profile of capecitabine after gastrectomy represents a call for caution. After gastric surgery, patient recovery is usually difficult and often impaired by nutritional deficiency and surgery-related sequelae: all these factors contribute to the poor tolerance to treatments frequently reported in adjuvant trials. Moreover, the modified gastrointestinal transit determined by gastrectomy could affect capecitabine pharmacokinetics, a complex phenomenon that may be influenced by different somatic factors and by a variety of genetic determinants yet to be clarified [4.Midgley R. Kerr D.J. Capecitabine: have we got the dose right?.Nat Clin Pract Oncol. 2009; 6: 17-24Crossref PubMed Scopus (59) Google Scholar]. Our personal experience indicates that tolerability of capecitabine after total gastrectomy could be significantly impaired. In fact, in the last months, we have treated seven previously gastrectomized patients with capecitabine (1000 mg/m2/b.i.d. days 1–14) in combination with oxaliplatin (130 mg/m2 day 1) every 3 weeks. Four of these seven patients reported grade 3–4 gastrointestinal toxicity (diarrhea, stomatitis, and/or nausea and vomiting) during the first two cycles of treatment and required capecitabine dose reductions or delays; in two cases, capecitabine was substituted with infusional 5-fluorouracil due to persistent toxicity with an improvement in the tolerability of the chemotherapy. Obviously, no conclusions can be drawn from this limited series. However, these results prompt the need for a better definition of the safety profile of such an effective drug in this specific patient subgroup. It could be of great interest to analyze data from REAL-2 and ML17032 trials comparing toxic effects for capecitabine-based versus 5-fluorouracil-based combinations in patients previously submitted to gastrectomy. With many ongoing postoperative trials with capecitabine-containing regimen, this information could be of great interest and can be effectively derived from an individual patient data meta-analysis of two large randomized trials. Since adequate dose intensity is essential to retain the efficacy of adjuvant treatment, the need for frequent dose reductions and delays could have negative impact on patients’ outcome in this setting.