Safety of Chronic Low-Dose Capecitabine as Maintenance Therapy in Gastrointestinal Cancers

摘要

Background: Maintenance chemotherapy is not routinely used in gastrointestinal (GI) cancers. Capecitabine is an oral formulation that is enzymatically converted to 5-fluorouracil preferentially in tumor tissue. We hypothesize that capecitabine could be used as a long-term maintenance therapy to improve outcomes in patients with high-risk GI cancers following standard chemotherapy regimens. Methods: We conducted a retrospective study to assess the toxicity of maintenance capecitabine in 28 patients with a variety of advanced GI malignancies. Capecitabine 1,000 mg twice daily without interruption was used for the first 11 patients. The dose was reduced to 1,000 mg twice daily 5 days per week in 8 patients who developed hand-foot syndrome. The remaining patients began treatment on the same abbreviated schedule. All documented clinical adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (v3.0, 2003). Results: Main toxicities were grade 1/2 fatigue and hand-foot syndrome. Only one grade 3 toxicity was observed and no grade 4 toxicities were seen. We also observed a significant increase in red blood cell mean corpuscular volume in participants, which may have potential use as a biomarker to monitor therapeutic response. Conclusions: Fixed therapeutic doses of oral capecitabine 1,000 mg twice daily, 5 days on, 2 days off, can be administered chronically with a high level of safety and should be explored in larger prospective studies to demonstrate efficacy in GI malignancies, especially pancreatic and metastatic colorectal cancers. While an accepted modality in other cancer types, maintenance therapy in gastrointestinal (GI) cancers is not routinely delivered. Current standards are to administer a set number of chemotherapy cycles in the adjuvant setting followed by observation until disease progression. In the setting of metastatic colon cancer, combination therapy incorporating newer cytotoxic and biologic agents has changed practice in the past several years, extending the median survival of patients with metastatic disease to beyond 20 months. Advancements in neoadjuvant and adjuvant chemotherapy regimens and improvements in surgical techniques for liver and lung metastasectomy have offered patients with metastatic colon cancer the possibility of cure. Yet, to date, no therapeutic approaches have been defined for these patients after potentially curative surgeries and adjuvant chemotherapy. Given patient preferences for more tolerable regimens and improved quality of life, treatment approaches have changed from continuous high-dose aggressive therapy until disease progression to either chemotherapy-free intervals or reduced-dose, less-toxic maintenance regimens. 1 , 2 The concept of maintenance therapy in gastrointestinal cancers has been explored using infusional 5-fluorouracil (5-FU), gemcitabine, erlotinib, marimastat, and oral S-1 in small clinical trials with positive results. 3 – 8 Substantial evidence suggests that chronically administered intravenous 5-FU is safe and has antitumor activity against epithelial malignancies involved in gastrointestinal, breast, and head and neck malignancies. 9 In the OPTIMOX2 study, it was shown that in terms of progression-free survival, maintenance therapy with leucovorin/5-FU was superior to a chemotherapy-free interval after FOLFOX7 administration. 10 While continuous-infusion 5-FU is cumbersome when used as a maintenance agent, oral 5-FU derivatives are certainly more feasible options. Long-term maintenance therapy with 2 years of the oral 5-FU derivative UFT (uracil and tegafur) has been studied in stage I adenocarcinoma of the lung and shown overall survival benefits with only 2% of patients developing grade 3 toxic effects. 11 In another study, UFT was used as adjuvant therapy for 12 months in serosa-positive gastric cancer. 12 Though the study failed to show any survival benefit, only 2% of patients studied experienced grade 4 toxicity. Compared to other oral 5-FU derivatives such as S-1 and UFT, capecitabine is approved by the US Food and Drug Administration (FDA) and has been extensively studied in GI and breast malignancies. Capecitabine has been shown to be a safe and efficacious alternative to bolus 5-FU for metastatic colorectal cancer in phase III clinical trials. 13 , 14 However, the safety profile and efficacy of capecitabine as a long-term maintenance therapy in GI malignancies has yet to be evaluated. 15 Capecitabine is an oral 5-FU prodrug that is modified via a different metabolic pathway compared to other oral 5-FU derivatives. Capecitabine is absorbed intact through the gastrointestinal mucosa and is metabolized in the liver to 5′-deoxy-5-fluorocytidine (5′-DFCR), then to 5′-deoxy-5-fluorouridine (5′-DFUR). Subseque