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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.

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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
	5-Fluorouracil	100 mg/m2/day	1-5c
ECF16	Epirubicin	50 mg/m2	1	71 / 12	8.2	10
	Cisplatin	60 mg/m2	1
	5-Fluorouracil	200 mg/m2/day	1-147c
PELF (weekly)18	Epirubicin	35 mg/m2	1d	62 / 17	11	5
	Cisplatin	40 mg/m2	1d
	5-Fluorouracil	500 mg/m2	1d
NI = not informed OR = objective responses CR = complete responses a 5-FU administered 1 hour after methotrexate and 15 mg/m2 of leucovorin every 6 hours orally for 8 doses initiated 24 hours after methotrexate. b Leucovorin administered in 1 hour. c Continuous infusion. d Weekly plus glutathione and filgrastim.

Combination Chemotherapy vs Best Supportive Care

In 1988, our institute conducted a randomized trial using a modified FAMTX regimen (M-FAMTX).¹¹ In this new regimen, the methotrexate dose was reduced from 1,500 mg/m² to 1,000 mg/m² to reduce toxic effects and to avoid laboratory measurements of serum methotrexate. Patients with advanced gastric cancer were randomly assigned to receive either supportive care only or treatment with M-FAMTX. The inclusion of a control group was justified by the lack of data supporting any improvement in survival with chemotherapy for patients with advanced gastric cancer. In the middle of the study, the randomization was interrupted due to strong evidence of benefit in terms of tumor reduction and projected survival in the chemotherapy-treated arm. By the end of study, 30 assessable patients had received chemotherapy, and 10 had received supportive treatment. The overall response rate was 50%. Twelve patients (40%) had partial responses, and 3 (10%) had complete responses. The median overall survival was 10 months in the treated group compared with only 3 months in the control group (P=0.001). One toxic death was due to neutropenia and sepsis.

In an attempt to improve the M-FAMTX results, a phase II trial was designed at our center that added etoposide to the regimen.¹² Etoposide was included because of its preclinical and clinical activity in gastric cancer. Etoposide (150 mg/m²) was given via intravenous (IV) infusion on day 1 and day 15 of the cycle. Thirty-two patients received treatment and were evaluable. The results were similar to those obtained with M-FAMTX — objective responses of 59%, including complete responses of 12.5%. The overall median survival was 10 months, which suggests that the inclusion of additional drugs to the standard regimen does not necessarily result in survival improvement.

In a controlled phase III trial, Pyrhonen et al¹³ compared FEMTX (in which epirubicin replaced doxorubicin) with supportive care only. Seventeen patients were included in the FEMTX arm and 19 in the supportive care arm. The median survival was 12 months in the FEMTX arm compared with 3 months in the supportive care arm (P<0.001), also suggesting survival benefit of chemotherapy over supportive care for patients with advanced gastric cancer.

Chemotherapy Regimens: Comparative Trials

Unfortunately, part of the clinical experience with these combinations comes from phase II trials involving a limited number of patients who are selected and treated at the same institution. Few controlled studies were conducted using these regimens. In general, results from multicenter phase III trials have had lower response rates than single-institution phase II studies for the same drug regimens. One of these studies, conducted by the European Organization for Research on Treatment of Cancer (EORTC),¹⁴ suggested that FAMTX is superior to FAM in terms of response rates and overall survival (42 weeks compared with 29 weeks for FAM; P=0.004). The toxic death rate of the two combinations was similar (4% for FAMTX, 3% for FAM). At one year, 41% of patients in the FAMTX arm were alive vs 22% of those in the FAM regimen. There were no survivors at the two-year mark in the FAM arm, whereas 9% of the patients on the FAMTX arm were alive. Severe hematologic toxicity was seen in more patients on the FAM regimen than on the FAMTX regimen.

Kelsen et al¹⁵ reported the results of a random-assignment trial comparing EAP and FAMTX in patients with advanced gastric cancer. The response rates were similar for both regimens. Complete remissions were obtained in 3 patients (10%) on the FAMTX arm compared with none on the EAP arm. Although there were no significant differences in the response rate, EAP was significantly more toxic than FAMTX for neutropenia, anemia, and thrombocytopenia. More importantly, 4 patients (13%) died of treatment-related complications on the EAP arm vs none on the FAMTX arm (P=0.04). The study was closed due to the significant toxicity difference. The median duration of survival of all patients was similar (7 months for the FAMTX arm and 6 months for the EAP arm). The authors concluded that FAMTX was at least as active as EAP but was significantly less toxic.

More recently, in a comparison of FAMTX and ECF, Webb et al¹⁶ reported that ECF was superior in response rate, median survival, and quality of life. However, the overall survival and response rates obtained with ECF in this trial were inferior to those described in other phase II single-institution studies.

A recent EORTC randomized trial¹⁷ compared three combinations: FAMTX vs ELF vs cisplatin plus 5-FU. Response rates were approximately 25% for each combination, and none had a statistically significant impact on survival. No combination has emerged as a standard treatment for advanced gastric cancer. Thus, new drugs and therapeutic interventions need to be tested to improve response rates and survival in patients with advanced gastric cancer.

Taxanes in Gastric Cancer

Paclitaxel

Paclitaxel is one of the most promising cytotoxic agents in clinical use. It is an antitubulin agent that inhibits microtubules and is derived from the Pacific yew, Taxus brevifolia. While the vinca alkaloids prevent microtubule assembly, submicromolar concentrations of paclitaxel can be easily achieved in patients, thus decreasing the lag time and shifting the dynamic equilibrium between tubulin dimers and microtubules toward polymerization. Submicromolar concentrations of paclitaxel also stabilize microtubules against depolymerization. In essence, paclitaxel decreases the critical concentration of tubulin required for microtubule assembly.¹⁹ The stabilization results in cell-cycle arrest and apoptosis. Paclitaxel demonstrates good antitumor activity, particularly in adenocarcinomas such as breast and ovarian cancers.^20,21

Paclitaxel has not been extensively explored in the treatment of gastric cancer. A phase II multicenter trial conducted by the Eastern Cooperative Oncology Group (ECOG) studied 250 mg/m² of paclitaxel given in 21-day cycles for the treatment of 20 patients with advanced esophageal and gastric carcinoma.²² After a median of five cycles, a partial response was observed in one patient with extensive hepatic involvement and in five patients with stable disease. The nonhematologic toxicity was not important. Fourteen patients developed significant leukopenia, and one patient had sepsis. In another phase II trial at The University of Texas M.D. Anderson Cancer Center,²³ 250 to 280 mg/m² of paclitaxel was given to 43 patients with esophageal carcinoma, including 33 patients with adenocarcinoma of the lower third and gastroesophageal junction. There were 16 responses (32%), including 22% of objective responses in patients with adenocarcinomas. The median duration of responses was 16.5 weeks.

Two recent studies^24,25 confirmed the efficacy and safety of paclitaxel as a single agent in the treatment of gastric cancer. In a report by Ajani et al,²⁴ 30 patients received 200 mg/m² of paclitaxel in either 3-hour or 24-hour infusions. The objective response rates were 17% and 23%, respectively. The median response duration was 6.5 months (range = 2.3 to 11.3+ months) with mainly hematologic toxicity. Tamura et al²⁵ reported on paclitaxel at 210 mg/m² in 13 patients with advanced gastric cancer who were previously treated with other regimens of chemotherapy. Three patients (21.4%) had objective responses, with response durations of 67, 104, and 125 days, respectively. The toxicity was mild and mainly hematologic.

Docetaxel

Docetaxel, a paclitaxel analogue, also appears to be effective in gastric cancer. A phase II trial conducted by EORTC²⁶ included 37 patients with advanced, untreated, measurable gastric cancer. They were given 100 mg/m² of docetaxel IV over 60 minutes without premedication once every 3 weeks. The median age was 59 years (range = 37 to 72 years) with a median performance status of 1 (0 to 2). Metastatic sites included the liver in 12 patients and retroperitoneal lymph nodes in 16. Eight of the 33 evaluable patients (24%) achieved a partial remission for a median of 7.5 months (range = 3 to 11+ months). An additional 11 patients had stabilization of disease. The patients received a median of four cycles of docetaxel (range = 1 to 8 cycles) for a total of 156 courses. Dose reduction was necessary in 30 cycles, and 14 cycles were delayed a mean of 3 days. Hematologic toxicity consisted mainly of noncumulative neutropenia, with a median nadir count of 0.35 x 10⁹ l-1 (0.04-1.64) and 8 episodes (5%) of leukopenic fever. Nonhematologic toxicities included alopecia, mild nausea and vomiting, and allergic manifestations such as skin rash and pruritus.

More recently, Furue and Taguchi²⁷ administered 60 mg/m² of docetaxel IV over 60 to 120 minutes at three- or four-week intervals to 59 evaluable patients with advanced or recurrent gastric cancer. Prior chemotherapy included mainly the pyrimidine fluoride in 30 patients and cisplatin in 14. The antitumor effects produced a complete response in one patient and partial responses in 13, with an overall response rate of 23.7% in 14 patients. The response rate was 9.5% in the primary tumor (2 of 21 patients), 31.3% in the liver (5 of 16), 50% in the abdominal tumor (3 of 6), 24.1% in the lymph nodes (7 of 29), and 50% in the lungs (1 of 2). Grade 3 to 4 leukocytopenia and neutropenia were the most frequent dose-limiting factors in 41 patients (68.3%) and 54 patients (90%), respectively.

The combination of docetaxel with other agents has also been investigated. Roth et al²⁸ conducted a phase I-II trial investigating the activity and tolerance of docetaxel in combination with cisplatin. Patients with advanced gastric cancer who were not pretreated palliatively by chemotherapy received up to 8 cycles of 85 mg/m² of docetaxel and 75 mg/m² of cisplatin every three weeks. Dose escalation of docetaxel to 100 mg/m² in 5 patients was discontinued due to toxicity. Forty-seven patients were evaluable for toxicity, and 45 for response. The authors reported 2 complete responses and 22 partial responses (response rate = 53%; 95% confidence interval: 38% to 68%). Median time to progression and overall survival was 7 months and 8.6 months, respectively. Three patients died (two of pulmonary embolisms and one suicide). Grade 3 or higher toxicity was neutropenia (68%), thrombocytopenia (6%), alopecia (36%), fatigue (9%), mucositis (4%), neurologic (2%), nausea/vomiting (2%), and one episode of hypersensitivity reaction precluding treatment administration.

Other New Agents

CPT-11 (irinotecan), a new topoisomerase-I inhibitor, has also shown promising activity in patients with advanced gastric cancer. Köhne et al²⁹ administered 350 mg/m² of CPT-11 every three weeks to 18 evaluable patients until disease progression occurred, toxicities were unacceptable, or consent was withdrawn. Metastatic sites were as follows: liver, 67%; lymph nodes, 56%; abdominal mass, 39%; and lung, 11%. The authors observed three complete responses and one partial response, with minor responses in two patients. Grade 3 to 4 toxicity was neutropenia in six patients and diarrhea in six patients.

S-1, a novel oral fluoropyrimidine derivative, has also been tested recently in advanced gastric cancer. S-1 is composed of tegafur (a 5-FU prodrug), 5-chloro-2,4-dihydroxypyridine (an inhibitor of 5-FU degradation), and potassium oxonate (an inhibitor of gastrointestinal toxicities by 5-FU) in a molar ratio of 1:0.4:1. In a early phase II study, the response rate of S-1 for patients with advanced gastric cancer was 53.6%, which is striking.³⁰

Paclitaxel Plus Fluorouracil

Standard treatment for advanced gastric cancer with 5-FU as a single agent or in combination with other agents offers low response rates and short survival and has only palliative goals. Based on the studies that showed activity of this new compound in gastric cancer, a trial was conducted at our institute combining standard 5-FU with paclitaxel to treat patients with advanced gastric cancer.^31-33 These two drugs act by different mechanisms of action and with almost no overlapping toxicity. The same dose of 5-FU used in the FAMTX and M-FAMTX regimens —1,500 mg/m² — was also used in this regimen.

Table 2. — Regimen Schedule for Paclitaxel and 5-FU in Advanced Gastric Cancer
	Day	Dosage
Premedication	1	Dexamethasone (4 mg PO at 12 hrs and 4 mg IV at 15 min before paclitaxel administration)
		Metoclopramide IV (0.5 mg/kg)
		Dimenhydrinate IV (Dramamine, 100 mg)
		Promethazine IM (50 mg)
		Ranitidine IV (50 mg)
Paclitaxel	1	175 mg/m2 as 3-hr infusion with premedication
5-FU	2	1,500 mg/m2 as 3-hr infusion

Patients eligible for the trial had histologically proven gastric cancer with measurable disease, were between 18 and 70 years of age, had a Karnofsky Performance Status (KPS) between 60% and 100%, and had a life expectancy of at least 3 months. All patients signed the informed consent and had hematologic, hepatic, and renal function tests within normal limits. No patient had central nervous system disease or other cancers except uterine cervix or basal cell carcinoma.

Regimen and Clinical Benefit Assessment

The paclitaxel and 5-FU regimen (Table 2) was administered according to the following schedule: Day 1 consisted of 175 mg/m² of paclitaxel IV in a three-hour infusion diluted in 500 mL of 0.9% normal saline. Premedication included dexamethasone (4 mg PO at 12 hours and 4 mg IV at 15 minutes before paclitaxel administration) and metoclopramide IV (0.5 mg/kg), dimenhydrinate IV (Dramamine, 100 mg), promethazine (50 mg, intramuscularly), and ranitidine IV (50 mg), all given immediately before paclitaxel infusion. Day 2 consisted of 1,500 mg/m² of 5-FU in a 3-hour infusion diluted in 500 mL of 0.9% normal saline.

Clinical benefit of the regimen was assessed by using a modified version of the system developed to assess clinical benefit for advanced pancreatic adenocarcinoma.³⁴ Response assessment consisted of three components: KPS, weight gain, and pain (based on analgesic consumption and pain intensity measured by an analog nonvisual scale). Each parameter was measured at baseline as well as regularly during the study. Clinical benefit response was defined as a sustained improvement (longer than four weeks) in at least one parameter without a worsening in any other.

Patient Enrollment and Toxicity

Thirty-one patients signed the informed consent and were initially enrolled in the study. Patient characteristics are shown in Table 3. Of the 31 patients, 29 were considered eligible for response and toxicity assessment. Two patients were excluded from the analysis because they abandoned treatment after the first cycle for personal reasons.

Table 3. — Paclitaxel and 5-FU in Advanced Gastric Cancer: Patient and Tumor Characteristics in 31 Patients
Characteristic		Number of Patients (%)
Sex:
Men		19	(61.3%)
Women		12	(38.7%)
Race:
White		20	(64.5%)
Other		6	(19.4%)
Black		5	(16.1%)
Age (yrs):
Range		31-70
Median		61
Karnofsky Index:
60		14	(45.2%)
70		16	(51.6%)
80		1	(3.2%)
Median		70
Histopathologic Differentiation:
Adenocarcinoma -
	GI	2	(6.5%)
	GII	9	(29.0%)
	GIII	20	(64.5%)
Lauren's Classification:
Diffuse		8	(25.8%)
Intestinal		10	(32.2%)
Not classified		13	(42.0%)
Staging:
IIIB		9	(29.0%)
V		22	(71.0%)
Previous Surgical Treatment:
Total gastrectomy		3	(9.7%)
Partial gastrectomy		2	(6.4%)
Gastrojejunoanastomosis		2	(6.4%)
Jejunostomy		3	(9.7%)
Unresectable/no surgery		21	(67.8%)
Analgesic Consumption:
Weak opioids		8	(25.8%)
Strong opioids		22	(71.0%)
Anti-inflammatories		1	(4.2%)

A total of 147 cycles of chemotherapy were administered, with no WHO grade 4 toxicity or death due to chemotherapy. The main toxicities consisted of complete but reversible alopecia, nausea, peripheral neuropathy, and mild myalgia. Grade 2 neutropenia was observed in 8.2% of the cycles and grade 3 in 6.8%. Grade 1 infection was observed in 6% of cycles and grade 2 in 3.4% of cycles. The upper respiratory tract was the most common site of infection. All patients had good response to oral antibiotics. One case of mild bradycardia occurred, which was reversible at the end of paclitaxel infusion and not observed in subsequent cycles. A total of 137 cycles of chemotherapy were administered with no delays and with the intended doses of both drugs. Delays occurred in four patients and in seven cycles; dose reductions due to neutropenia and neuropathy occurred in three cycles.

Responses

Objective responses occurred in 19 (65.5%) patients, including 7 (24.1%) complete responses. Two patients (6.8%) had disease stabilization, and 7 patients (24.1%) had disease progression. In 3 (10.3%) patients, complete remission was documented histopathologically with biopsies obtained by laparoscopy and endoscopy.

A second-look laparotomy was performed in 6 patients with tumor response (partial or complete) assessed by physical examination and imaging studies. In 2 patients, partial response was surgically confirmed, although the tumor was still considered unresectable. In 3 patients, the second procedure was successful in allowing a potentially curative esophagogastrectomy. These patients are alive and in remission at 10, 11, and 15 months after surgery.

Clinical Benefit and Survival

Fifteen (51.7%) patients showed improvement in at least one of the parameters: clinical outcome (KPS), weight gain, and analgesic consumption. Quality of life measured by clinical benefit response showed that 15 (51.7%) patients improved in at least one of the parameters. Nine patients showed improvement in all three parameters, while 3 patients showed improvement in two parameters, and 3 patients improved in only one parameter. There was agreement between clinical benefit and tumor response in 14 patients.

The median overall survival was 12 months (range = 2 to 30+ months). The 30-month survival was 20%, which is impressive. Nonparametric analysis of survival between the two histopathologic groups from Lauren’s classification, diffuse and intestinal, did not reach statistical significance. The comparison between the survival curves of the studied regimen and the formerly studied M-FAMTX, our "historical control," is depicted in the Figure. However, although the difference favoring paclitaxel plus 5-FU combinations is statistically significant, it is not a prospective, randomized comparison.

This study suggests that the combination of 5-FU plus paclitaxel is effective and safe for the treatment of advanced gastric cancer. However, controlled trials need to be designed to confirm the merit of this novel regimen.

Conclusions and Future Directions

No post-FAM combination chemotherapy for advanced gastric cancer has emerged as a standard treatment, although FAMTX variations appear to slightly improve survival in small phase III trials. Regimens employing cisplatin such as ECF and PELF are also effective, although they produce significant toxicity. New drugs and therapeutic interventions need to be tested to improve response rates and survival in patients with advanced gastric cancer.

More recently, the taxanes and other new compounds (eg, CPT-11 and S-1) have demonstrated good activity in gastric cancer. Combined paclitaxel and 5-FU, which produced a 20% two-year overall survival in a phase study trial conducted at our institution, deserves further evaluation.

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