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 |
| |
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 studies24,25
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.
References
1. World Health Report 1998:
A Vision for All. Geneva, Switzerland: World Health Organization; 1998.
2. Parker SL, Tong T, Bolden
T, et al. Cancer statistics, 1997. CA Cancer J Clin. 1997;47:5-27.
3. Cancer Facts & Figures
1999. Atlanta, Ga: American Cancer Society; 1999.
4. Ministério da Saúde,
Brasil. Secretaria Nacional de Assistência à Saúde. Instituto
Nacional de Câncer. Coordenação de Programas de Controle
de Câncer - Pro-Onco. Estimativas da Incidência e Mortalidade por
Câncer no Brasil 1998: Rio de Janeiro, Pro-Onco.
5. Clarke JS, Cruze K, El Farra
S, et al. The natural history and results of surgical therapy for carcinoma
of the stomach: an analysis of 250 cases. Am J Surg. 1961;102:143-149.
6. Katz A. Câncer gástrico.
In: Murad AM, Katz A, eds. Oncologia. Bases Clínicas do Tratamento.
Rio de Janeiro, Brazil: Guanabara Koogan; 1996:163-167.
7. Kelsen D. Chemotherapy of
gastric cancer: a review. Isr J Med Sci. 1988;24:557-561.
8. Macdonald JS, Schein PS,
Woolley PV, et al. 5-Fluorouracil, doxorubicin and mitomycin (FAM) combination
chemotherapy for advanced gastric cancer. Ann Intern Med. 1980;93:533-536.
9. Cullinan SA, Moertel CG,
Fleming TR, et al. A comparison of three chemotherapeutic regimens in the treatment
of advanced pancreatic and gastric carcinoma: fluorouracil vs fluorouracil and
doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA. 1985;253:2061-2067.
10. Leichman L. Gastric cancer
therapy: a translational research paradigm. In: ASCO Educational Book.
Alexandria, Va: American Society of Clinical Oncology; 1997:262-271.
11. Murad AM, Santiago FF, Petroianu
A, et al. Modified therapy with 5-fluorouracil, doxorubicin and methotrexate
in advanced gastric cancer. Cancer. 1993;72:37-41.
12. Murad AM. Uso do esquema
EFAMTX: etoposide, 5-fluorouracil, adriamicina, metotrexate e leucovorin no
tratamento do cancer gástrico avançado. Rev Med Minas Gerais.
1993;3(suppl 2):32.
13. Pyrhonen S, Kuitumen T,
Kouri M. A randomized, phase III trial comparing fluorouracil, epidoxorubicin
and methotrexate (FEMTX) with best supportive care in non-resectable gastric
cancer. Ann Oncol. 1992;3(suppl 5):12. Abstract.
14. Wils JA, Klein HO, Wagener
DJ, et al. Sequential high-dose methotrexate and fluorouracil combined with
doxorubicin: a step ahead in the treatment of advanced gastric cancer. A trial
of the European Organization for Research and Treatment of Cancer Gastrointestinal
Tract Cooperative Group. J Clin Oncol. 1991;9:827-831.
15. Kelsen D, Atiq O, Saltz
L, et al. FAMTX (fluorouracil, methotrexate, adriamycin) is as effective and
less toxic than EAP (etoposide, adriamycin, cisplatin): a random assignment
trial in gastric cancer. Proc Annu Meet Am Soc Clin Oncol. 1991;10:137.
Abstract.
16. Webb A, Cunningham D, Scarffe
JH, et al. A randomized trial comparing ECF with FAMTX in advanced oesophago-gastric
cancer. Ann Oncol. 1996;7(suppl):50.
17. Wilke H, Wils J, Rougier
P, et al. Preliminary analysis of a randomized phase III trial of FAMTX versus
ELF versus cisplatin/FU in advanced gastric cancer (gastric cancer): a trial
of the EORTC Gastrointestinal Tract Cancer Cooperative Group and the AIO (Arbeitsgemeinschaft
Internistische Onkologie). Proc Annu Meet Am Soc Clin Oncol. 1995;14:206.
Abstract.
18. Cascinu S, Labianca R, Alessandroni
P, et al. Intensive weekly chemotherapy for advanced gastric cancer using fluorouracil,
cisplatin, epi-doxorubicin, 6S-leucovorin, glutathione, and filgrastim: a report
from the Italian Group for the Study of Digestive Tract Cancer. J Clin Oncol.
1997;15:3313-3319.
19. Kingston DG, Samaranayake
G, Ivey CA. The chemistry of Taxol, a clinically useful anticancer agent. J
Nat Prod. 1990;53:1-12.
20. McGuire WP, Rowinsky EK,
Rosenshein NB, et al. Taxol: a unique antineoplastic agent with significant
activity in advanced ovarian epithelial neoplasms. Ann Intern Med.
1989;111:273-279.
21. Thigpen J, Blessing J, Ball
H. Phase II trial of Taxol as a second-line therapy for ovarian carcinoma: a
Gynecologic Oncology Group study. Proc Annu Meet Am Soc Clin Oncol. 1990;9:A604.
Abstract.
22. Einzig AI, Wiernik PH, Lipsitz
S, et al. Phase II trial of Taxol in patients with adenocarcinoma of upper gastrointestinal
tract (UGIT): the Eastern Cooperative Oncology Group (ECOG) results. Proc
Annu Meet Am Soc Clin Oncol. 1993;12:A566. Abstract.
23. Ajani JA, Ilson DH, Daugherty
K, et al. Activity of Taxol in patients with squamous cell carcinoma and adenocarcinoma
of the esophagus. J Natl Cancer Inst. 1994;86:1086-1091.
24. Ajani JA, Fairweather J,
Dumas P, et al. A phase II study of Taxol in patients with advanced untreated
gastric carcinoma. Proc Annu Meet Am Soc Clin Oncol. 1997;16:A933. Abstract.
25. Tamura F, Ohtsu A, Boku
N, et al. Three-hour infusion of paclitaxel for advanced gastric cancer. Proc
Annu Meet Am Soc Clin Oncol. 1997;16:A1091. Abstract.
26. Sulkes A, Smyth J, Sessa
C, et al. Docetaxel (Taxotere) in advanced gastric cancer: results of a phase
II clinical trial. EORTC Early Clinical Trials Group. Br J Cancer. 1994;70:380-383.
27. Furue H, Taguchi T. A late
phase II study of RP56976 (docetaxel) in advanced or recurrent gastric cancer.
Ann Oncol. 1998(suppl 4);9:49. Abstract.
28. Roth AD, Maibach R, Martinelli
N, et al. Taxotere-cisplatin in advanced gastric carcinoma (Agastric cancer):
an active drug combination. Proc Annu Meet Am Soc Clin Oncol. 1998;17:283.
Abstract.
29. Köhne CH, Thusspatience
P, Catane R, et al. A phase II trial of CPT-11 in patients (pts) with advanced
gastric carcinoma (Agastric cancer). Ann Oncol. 1998;9(suppl 4):46.
30. Horikoshi N, Mitachi Y,
Sakata Y, et al. S-1, new oral fluoropyrimidine is very active in patients with
advanced gastric cancer (early phase II study). Proc Annu Meet Am Soc Clin
Oncol. 1996;15:206.
31. Murad AM, Tinoco LA, Guimares
RC, et al. Paclitaxel (T) plus 5-fluorouracil (5-FU): a novel and very active
regimen for advanced gastric cancer (Agastric cancer). A phase II trial. Proc
Annu Meet Am Soc Clin Oncol. 1997;16:A1063. Abstract.
32. Murad AM. Estudo prospectivo
do uso da associação de paclitaxel e 5-fluorouracil no tratamento
do câncer gástrico avançado. Tese (Doutorado). Faculdade
de Medicina da UFMG. Belo Horizonte, 1997.
33. Murad AM. Phase II trial
of combination of paclitaxel and 5-fluorouracil in the treatment of advanced
gastric cancer. South Am J Cancer. 1998;2:35-43.
34. Andersen JS, Burris HA,
Casper E, et al. Development of a new system for assessing clinical benefit
for patients with advanced pancreatic cancer. Proc Annu Meet Am Soc Clin
Oncol. 1994;13:A1600. Abstract.
From the Universidade
Federal de Minas Gerais, Belo Horizonte, Brazil.
Address reprint requests
to André M. Murad, MD, PhD, Oncology Section Chief, Hospital das Cl’nicas,
Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
No significant relationship
exists between the author and the companies/organizations whose products
or services may be referenced in this article.
Back to Cancer Control Journal Volume 6 Number 4