H. Lee Moffitt Cancer Center & Research Institute

Quirin Brekelenkam, 1662. The Tailor's Workshop. From the collection of Dr. Gordon and Adele Gilbert of St. Petersburg, Florida.

 

Chemotherapy for Advanced Gastric Cancer: Focus on New Agents and Combinations

André M. Murad, MD, PhD


Chemotherapy provides limited benefits for patients with advanced gastric cancer.
New drugs and combinations are needed to improve overall survival.

Background: Although many treatments for advanced gastric cancer have been developed, systemic therapy remains elusive.
Methods:  The author reviewed data on recent phase II and III trials of the main new agents and combinations.
Results:  Chemotherapy appears to improve survival of patients with advanced disease, albeit slightly. New drugs that might improve response rates and survival include the taxanes.
Conclusions:  New combinations, including the taxanes, must be designed and evaluated to further improve the outcome for patients with advanced gastric cancer.

Introduction

Worldwide, gastric cancer is the second most common cancer, following lung cancer.1 According to 1997 World Health Organization statistics, 765,000 deaths worldwide were due to gastric cancer.1 For several decades, this disease was most prevalent in Japan, Chile, and Scandinavia.2 In the United States in 1999, approximately 21,900 new cases will be diagnosed and 13,500 deaths will be caused by gastric cancer.3

In Brazil, the recent incidence and mortality rates of gastric cancer are alarming. According to the Brazilian Ministry of Health, the estimated number of new cases of gastric cancer for 1997 reached 20,665, and 269,000 new cases of cancer were predicted for 1998. In Brazil, the incidence of gastric cancer is surpassed only by breast and cervical cancer, and it is the leading cause of cancer death, with 13,200 deaths estimated in 1998.4

According to several studies, 75% of patients with gastric cancer are considered incurable at diagnosis due to advanced disease. Even among patients with clinically resectable tumors, the relapse rate is high — for 70% to 80% of patients, local residual disease is present following surgery or develops later.5 However, gastric cancer responds to efforts directed at prevention, early detection, and intensive therapy.

Single-Agent Chemotherapy

Despite being considered resistant to chemotherapy, gastric cancer can respond to chemotherapy. However, the role of medical treatment in advanced gastric cancer remains strictly palliative. While several chemotherapeutic agents have been tested, only a limited number of agents (5-fluorouracil [5-FU], doxorubicin, mitomycin C, and cisplatin) have demonstrated response rates of more than 20%.6 Furthermore, the responses generally are incomplete and brief, with few lasting longer than four months.7

Combination Chemotherapy

The low therapeutic activity of single agents led to interest in using these same drugs in combination. The most widely used regimen is the combination of 5-FU, doxorubicin, and mitomycin C (FAM),8 but this regimen provides a questionable survival benefit. In a phase III trial by Cullinan et al,9 153 patients with advanced gastric cancer were randomized to receive either 5-FU alone, 5-FU plus doxorubicin, or FAM. The major endpoint of this study was survival, although a substantial proportion of the patients had no measurable disease, and the extent of tumor was not measurable in regard to response. Neither FAM nor 5-FU plus doxorubicin provided a benefit over 5-FU alone in terms of improvement of disease-free or overall survival; the median survival was 35 weeks in all groups. In terms of survival of combination chemotherapy based on the FAM regimen or even 5-FU alone, real benefit remains questionable.

In the last few years, several other chemotherapeutic regimens have been tested,6-18 including EAP (cisplatin, etoposide, doxorubicin), FAMTX (5-FU, doxorubicin, methotrexate), ELF (etoposide, leucovorin, 5-FU), ECF (epirubicin, cisplatin, 5-FU), and PELF (epirubicin, cisplatin, 5-FU) (Table 1). These "second-generation" regimens have similar objective response rates — approximately 50%, including 10% to 12% of complete responders. Despite better response rates, the overall survival does not appear to be substantially improved when compared to that obtained with previous regimens. The median overall survival reaches 7 to 11 months, but the two-year survival is inferior at 10%.10 Also, toxicity is more pronounced.

Table 1. — Chemotherapeutic Regimens Most Often Utilized in Advanced Gastric Cancer

Regimen
Drug
Dose

Day(s)

OR (%) / CR (%)
Median Overall Survival (mos)
2-Year
Survival (%)
FAMTX14 Methotrexate 1,500 mg/m2 1a 59 / 12 8 6
  5-Fluorouracil 1,500 mg/m2 1      
Doxorubicin 30 mg/m2 15
M-FAMTX11 Methotrexate 1,000 mg/m2 1a 50 / 10 10 3
5-Fluorouracil 1,500 mg/m2 1      
Doxorubicin 30 mg/m2 15      
EAP15 Cisplatin 40 mg/m2 2, 8 49 / 8 8.5 NI
  Etoposide 125 mg/m2 4, 5, 6      
  Doxorubicin 20 mg/m2 1, 7      
ELF17 Etoposide 120 mg/m2 1, 2, 3 53 / 12 11 NI
Leucovorin 300 mg/m2 1, 2, 3b
5-Fluorouracil 500 mg/m2 1, 2, 3
 
CDDP/5-FU17 Cisplatin 100 mg/m2 2 49 / 4 8.5 NI