Capecitabine in the Treatment of Advanced Gastric Cancer

DPD = Dihydropyrimidine dehydrogenase; FU = Fluorouracil.

*Study included six patients who had prior history of systemic chemotherapy.
^{‡Study included patients who had recurrent disease after curative resection and adjuvant fluoropyrimidine-based chemotherapy.}
§In total, 57% of patients had gastroesophageal junction adenocarcinoma.
^¶Randomized Phase II trial; patients with gastroesophageal junction adenocarcinoma comprised 15% of the irinotecan-containing arm and 37% of the cisplatin-containing arm.
CR = Complete response; HFS = Hand-foot syndrome; NR = Not reached; n.r. = Not reported; OS = Overall survival; PR = Partial response; TTP = Time-to-progression.

*Study included six patients who had prior history of systemic chemotherapy.
^{‡Study included patients who had recurrent disease after curative resection and adjuvant fluoropyrimidine-based chemotherapy.}
§In total, 57% of patients had gastroesophageal junction adenocarcinoma.
^¶Randomized Phase II trial; patients with gastroesophageal junction adenocarcinoma comprised 15% of the irinotecan-containing arm and 37% of the cisplatin-containing arm.
CR = Complete response; HFS = Hand-foot syndrome; NR = Not reached; n.r. = Not reported; OS = Overall survival; PR = Partial response; TTP = Time-to-progression.

*Study included six patients who had prior history of systemic chemotherapy.
^{‡Study included patients who had recurrent disease after curative resection and adjuvant fluoropyrimidine-based chemotherapy.}
§In total, 57% of patients had gastroesophageal junction adenocarcinoma.
^¶Randomized Phase II trial; patients with gastroesophageal junction adenocarcinoma comprised 15% of the irinotecan-containing arm and 37% of the cisplatin-containing arm.
CR = Complete response; HFS = Hand-foot syndrome; NR = Not reached; n.r. = Not reported; OS = Overall survival; PR = Partial response; TTP = Time-to-progression.

*Study included six patients who had prior history of systemic chemotherapy.
^{‡Study included patients who had recurrent disease after curative resection and adjuvant fluoropyrimidine-based chemotherapy.}
§In total, 57% of patients had gastroesophageal junction adenocarcinoma.
^¶Randomized Phase II trial; patients with gastroesophageal junction adenocarcinoma comprised 15% of the irinotecan-containing arm and 37% of the cisplatin-containing arm.
CR = Complete response; HFS = Hand-foot syndrome; NR = Not reached; n.r. = Not reported; OS = Overall survival; PR = Partial response; TTP = Time-to-progression.

*Tumor response was evaluated every 3 months, compared with 1.5 months in ML17302 and 2 months in V325.
ANC = Absolute neutrophil count; C = Cisplatin; E = Epirubicin; F = 5-fluorouracil; N/V = Nausea and vomiting; O = Oxaliplatin; OS = Overall survival; PFS = Progression-free survival; PVI = Protracted venous infusion; RR = Response rate; X = Capecitabine.

DPD = Dihydropyrimidine dehydrogenase; FU = Fluorouracil.

*Study included six patients who had prior history of systemic chemotherapy.
^{‡Study included patients who had recurrent disease after curative resection and adjuvant fluoropyrimidine-based chemotherapy.}
§In total, 57% of patients had gastroesophageal junction adenocarcinoma.
^¶Randomized Phase II trial; patients with gastroesophageal junction adenocarcinoma comprised 15% of the irinotecan-containing arm and 37% of the cisplatin-containing arm.
CR = Complete response; HFS = Hand-foot syndrome; NR = Not reached; n.r. = Not reported; OS = Overall survival; PR = Partial response; TTP = Time-to-progression.

*Tumor response was evaluated every 3 months, compared with 1.5 months in ML17302 and 2 months in V325.
ANC = Absolute neutrophil count; C = Cisplatin; E = Epirubicin; F = 5-fluorouracil; N/V = Nausea and vomiting; O = Oxaliplatin; OS = Overall survival; PFS = Progression-free survival; PVI = Protracted venous infusion; RR = Response rate; X = Capecitabine.

*Japanese-approved dose according to BSA category: BSA <1.25 m², 40 mg twice-daily; BSA 1.25-1.5, 50 mg twice-daily; and BSA ≥1.5 m², 60 mg twice-daily.
^‡Strict dosing based on BSA (m²).
BSA = Body surface area; CR = Complete response; n.r. = Not reported; OS = Overall survival; PR = Partial response; TTP = Time to progression.

DPD = Dihydropyrimidine dehydrogenase; FU = Fluorouracil.

*Japanese-approved dose according to BSA category: BSA <1.25 m², 40 mg twice-daily; BSA 1.25-1.5, 50 mg twice-daily; and BSA ≥1.5 m², 60 mg twice-daily.
^‡Strict dosing based on BSA (m²).
BSA = Body surface area; CR = Complete response; n.r. = Not reported; OS = Overall survival; PR = Partial response; TTP = Time to progression.

DPD = Dihydropyrimidine dehydrogenase; FU = Fluorouracil.

Authors and Disclosures

Jae-Lyun Lee, Yoon-Koo Kang, University of Ulsan College of Medicine, Division of Oncology, Department of Internal Medicine, Asan Medical Center, 388-1 Poongnap-dong, Songpa-gu, Seoul, 138-736, Korea

Disclosure: Y-K Kang had an advisory role for Roche and received honoraria. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Sidebar: Information Resources

• Recent reviews on gastric cancer: Richards DA, Boehm KA, Anthony SP: Systemic therapy for gastric cancer and adenocarcinoma of the gastroesophageal junction: present status and future directions. Expert Opin. Investig. Drugs 16, 1059-1068 (2007). Ajani JA: Evolving chemotherapy for advanced gastric cancer. Oncologist 10(Suppl. 3), 49-58 (2005).
  
  

• Recent review regarding capecitabine in gastric cancer: Ajani J: Review of capecitabine as oral treatment of gastric, gastroesophageal, and esophageal cancers. Cancer 107, 221-231 (2006).

Sidebar: Executive Summary

• Gastric cancer is the fourth most common cancer and the second most common cause of cancer deaths worldwide.
  
  

• Adjuvant treatments differ geographically: in North America, adjuvant chemoradiotherapy is standard; in the UK, perioperative chemotherapy is standard; and in Asia, postoperative chemotherapy has become integrated into standard practice.

Overview of the market

• The reference regimens for palliative chemotherapy consist of 5-fluorouracil (5-FU) plus cisplatin (FP), with or without anthracycline.
  
  

• Although addition of docetaxel to FP (DCF) resulted in superior response rates and survival when compared with FP, DCF was associated with significant toxicities, and the survival benefit was not clinically significant.
  
  

• Oral 5-FU, such as capecitabine or S-1, can avoid the inconvenience and drawbacks of infusional 5-FU.
  
  

• S-1 showed promising efficacy when used as monotherapy or in combination with cisplatin.
  
  

• Owing to the genetic polymorphism of CYP2A6, additional dose-finding and comparative efficacy studies are needed to confirm the role of S-1 in the treatment of advanced gastric cancer (AGC).

Pharmacodynamics & pharmacokinetics of capecitabine

• Capecitabine is metabolized preferentially in tumor tissue to the cytotoxic moiety 5-FU by the enzyme thymidine phosphorylase, which is upregulated by other cytotoxic agents and by x-rays.
  
  

• Pharmacokinetic parameters of capecitabine are not affected by prior gastrectomy.
  
  

• Capecitabine and warfarin show clinically significant drug interactions.
  
  

Clinical efficacy

• Non-comparative Phase II studies revealed:

  • Capecitabine monotherapy induces response rates of 26-34% in chemotherapy-naive AGC patients.
    
    

  • The combination of capecitabine plus cisplatin is active and well tolerated in patients with or without a history of prior 5-FU-based adjuvant chemotherapy.
    
    

  • The combination of capecitabine and oxaliplatin is effective, with lower rates of nausea/vomiting and neutropenia, but with higher rates of neurotoxicity and thrombocytopenia than capecitabine plus cisplatin.
    
    

  • The combination of capecitabine plus docetaxel is effective and convenient, but has high rates of neutropenic fever.
    
    

  • The combination of capecitabine and irinotecan is comparable in efficacy to the combination of capecitabine plus cisplatin.
    
    

  • The triple combination of docetaxel plus capecitabine plus cisplatin (DXP) is highly active, with acceptable toxicity. DXP has been found to downstage tumors, which, in selected patients, could change a patient's disease status from incurable to curable.
    
    

  • Two randomized Phase III studies demonstrated the noninferiority of capecitabine in progression-free and overall survival.

Regulatory affairs

• In Europe, South America, Korea and East Asia, capecitabine, in combination with a platinum-based regimen, has been approved as first-line chemotherapy for AGC patients. An application to the US FDA for its use in the USA is pending.