1 Department of Internal Medicine I, Division of Oncology and 2 Center of Excellence in Clinical and Experimental Oncology (CLEXO), University of Vienna, Vienna, Austria
* Correspondence to: Dr M. Hejna, Department of Internal Medicine I, Division of Oncology, Waehringer Guertel 1820, A-1090 Vienna, University of Vienna, Austria. Email: michael.hejna{at}meduniwien.ac.at
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Abstract |
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Methods: A computerized (Medline) search was carried out to identify papers published on this topic between 1966 and 2003. Only articles with an English abstract were reviewed, and studies only presented in abstract form were not included in the analysis.
Results: A total of 101 trials were subsequently identified. Four randomized trials compared palliative chemotherapy with best supportive care in 174 patients with advanced gastric cancer. Effectiveness and side-effects were evaluated in 73 phase II studies and 24 randomized phase III trials.
Conclusion: Analysis of results shows chemotherapy to be superior to best supportive care alone. Combination chemotherapy compared with monochemotherapy is associated with significantly higher overall (complete plus partial) response rates but nevertheless results in similar survival. ECF (epirubicin, cisplatin and 5-fluorouracil) currently represents one of the most effective regimens for advanced gastric cancer, whereas among the newer combinations, irinotecan- or taxane-based regimens have also given promising results. In patients with a poor performance status, consideration could be given to leucovorin-modulated 5-fluorouracil alone. Prognosis for the majority of patients, however, remains poor, as increases in survival were moderate at best.
Key words: chemotherapy, gastric cancer, palliative treatment, review
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Introduction |
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In the absence of curative treatment modalities, chemotherapy and radiation, but also surgery, have been used in an attempt to both control cancer-related symptoms and improve survival. Previous studies, however, have shown that cytotoxic chemotherapy is the most effective therapy in order to prolong median survival and increase quality of life [36
]. Although various chemotherapeutic agents, either alone or in combination, have been studied since 1970, the median survival of patients with metastatic disease remains between 6 and 9 months. Similar figures, however, have also been reported by Moertel in a cohort of untreated patients with advanced gastric cancer [7
]. Some of the newer combination chemotherapies nevertheless have shown high overall response rates and increased survival times. The objective of this article is to review briefly the clinical trials available in the current literature utilizing cytotoxic chemotherapy either in patients with advanced, i.e. locally inoperable or metastatic gastric cancer.
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Materials and methods |
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Results |
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Doxorubicin, an anthracycline antibiotic, produced overall responses in 17% of patients with gastric cancer [14] when given as monotherapy. In contrast to this, mitoxantrone, a structurally related anthracenedione, produced no objective responses in 15 patients with advanced gastric cancer [17
] Table 3.
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Both taxanes, i.e. paclitaxel (see notes) and docetaxel, have been tested as single agents in the treatment of gastric cancer. Paclitaxel was well tolerated in all trials [2022
] and the reported overall response rate ranged between 17% and 23%. Docetaxel was also found to be active in advanced gastric cancer, with overall response rates between 17% and 29% [23
29
]. As a result of their unique mode of action, both taxanes appear to be a valuable alternative treatment option in cases of resistance to other agents commonly used for gastric cancer, rendering them promising potential combination partners for inclusion in polychemotherapy regimens.
In four reports involving 161 patients, irinotecan was associated with overall response rates between 14% and 23% [3033
]. Topotecan, another camptothecin analog, showed only minimal activity when given as single agent in phase II trials [34
36
].
Trimetrexate showed modest activity and was tolerated poorly in 33 patients with unresectable or metastatic gastric adenocarcinoma [37].
Oral cytotoxic drugs
Because of the convenient route of administration, oral chemotherapy has received increased consideration in recent years. In particular, 5-FU prodrugs including capecitabine, UFT and S-1 have been evaluated in advanced gastric cancer.
UFT, a combination of uracil and ftorafur (FT), has yielded an overall response rate of about 28% in three phase II trials [3840
]. Toxic effects were tolerable and consisted mostly of anorexia, nausea/vomiting, diarrhea and oral mucositis. It was suggested that orally administered low-dose leucovorin could probably increase the efficacy of UFT [41
].
S-1 is a novel oral anticancer drug, composed of the 5-FU prodrug FT, gimestat (CDHP) and otastat potassium (Oxo). CDHP inhibits dihydropyrimidine dehydrogenase, an enzyme that degrades 5-FU, and maintains prolonged 5-FU concentration in the blood and within the tumor. Oxo distributes throughout the gastrointestinal tract and alleviates gastrointestinal toxicity caused by 5-FU. In a phase II clinical study with 51 patients with advanced gastric cancer, an unusually high overall response rate of 49% was achieved [42]. It was concluded that S-1 is effective and well tolerated in patients with advanced gastric cancer.
An overall response rate of 19.4% and median overall survival of 8.8 months was achieved with capecitabine [43] in a pilot phase II study including 32 patients. Handfoot syndrome, anorexia, nausea and diarrhea were the most common adverse events. Thus, capecitabine seems to be safe and effective in patients with advanced gastric carcinoma.
Oral etoposide produced an overall response rate of 17% and was well tolerated in previously untreated gastric cancer patients [44].
Combination chemotherapy
The relatively low activity observed with single agents provided the rationale for the development of combination regimens. Tables 2 and 3 give an overview of the most prominent studies of combination chemotherapy in advanced gastric cancer. Randomized trials comparing monotherapy with combination regimens have consistently shown increased response rates in favor of combination regimens, whereas similar survival rates were usually found [45]. When compared with best supportive care, a consistent survival benefit (39 months) of combination chemotherapy has been demonstrated in advanced gastric cancer [3
, 4
, 6
].
5-FU, doxorubicin- or epirubicin-based combinations (FAM, FAB, FAMTX, ECF)
One of the first multidrug regimens in advanced gastric cancer was the combination of 5-FU, doxorubicin and mitomycin (FAM), which achieved a response rate of more than 40% [46], and several combinations based on 5-FU and doxorubicin were subsequently compared in a randomized fashion in the 1980s [46
50
]. These studies were in favor of FAM, which was shown to be the most active regimen. In addition, it was also well tolerated, producing only moderate bone marrow suppression [47
]. However, a randomized three-arm trial conducted by the NCCTG including 305 patients with advanced gastric and pancreatic cancer, demonstrated soberingly equivalent response rates and overall survival times for patients treated either with FAM, FA (5-FU and doxorubicin), or 5-FU alone [51
].
In a study from Korea, 5-FU plus cisplatin was compared either with 5-FU alone or with FAM. The objective response rate in the 5-FU/cisplatin arm was superior to the other two regimens (51% versus 26% versus 25%), but survival was not statistically different (37 versus 31 versus 29 weeks) [52].
Similarly, a trial of 187 patients who were randomly assigned to receive a three-drug combination of 5-FU, doxorubicin, and BCNU (FAB) or doxorubicin alone failed to detect an improved survival in the combination group despite a significantly higher overall response rate (40% versus 13%) [53].
Comparison of high-dose methotrexate, 5-FU and doxorubicin (FAMTX) with FAM in a prospective randomized study including 213 patients revealed a significantly higher overall response rate (41% versus 9%) and median survival (42 versus 29 weeks) for FAMTX. There were no major differences in the toxicity [54], and subsequent studies with FAMTX confirmed overall response rates of 30% to 40% [54
56
]. The comparison of a modified form of FAMTX (with a lower dose of methotrexate) with best supportive care demonstrated a significantly better median survival in the chemotherapy arm (9 versus 3 months), which led to premature closure of the study before completion of accrual [3
]. Another modification of FAMTX substituting epirubicin for doxorubicin (FEMTX) showed an overall response rate of 29% and a significantly better median survival compared with best supportive care alone (12 versus 3 months) [4
].
The combination of epirubicin, cisplatin and continuous ambulatory infusion of 5-FU (ECF) was associated with an overall response rate of 71% (15 complete and 76 partial responses) and a median overall survival of 8.2 months in a phase II study of 128 patients with advanced disease [58]. The toxicity was moderate with a grade 3 or 4 emesis in 13%, stomatitis in 7%, diarrhea in 4%, infection in 6%, leucopenia in 21% and thrombocytopenia in 8% of patients. In addition, this regimen enabled resection of previously inoperable tumors in some cases. The activity of ECF was confirmed in a study from Italy in which 22 of 37 evaluable patients responded [59
]. A direct comparison of this regimen with FAMTX revealed a somewhat lower overall response rate than in the phase II trials. ECF was superior over FAMTX in terms of both response rate (45% versus 21%) and median survival (8.9 versus 5.7 months) [60
]. There was no measurable reduction in quality of life, and the main toxic effects consisted of emesis, oral mucositis and infection during treatment with ECF. Complications with the central venous line mandatory for continuous 5-FU infusion occurred in 15% of ECF-treated patients.
Similar overall response rates and median survival but a reduced quality of life were observed with the combination of mitomycin, cisplatin and 5-FU (MCF) in a randomized study that compared ECF with MCF in 580 patients with advanced gastric cancer [61].
Etoposide-based combinations (EAP, EEP, ELF)
The combination of etoposide, doxorubicin and cisplatin (EAP) was associated with an overall response rate of 64% in 67 patients with locally advanced or metastatic disease including eight pathologically documented complete responses. The median survival of all patients was 9 months in this early phase II trial [62]. A follow-up study, however, suggested a much lower overall response rate of 33% [63
], and direct comparison conducted by the Memorial Sloan-Kettering Cancer Institute of this regimen with FAMTX [55
] showed a significantly lower overall response rate (20% versus 33%), similar median survival (6.1 versus 7.3 months) and four toxic deaths in the EAP arm. In view of these data, EAP does not appear a suitable regimen for routine treatment, and it was stated that the EAP regimen should not be applied for the treatment of gastric cancer [64
].
In a Spanish trial, EEP has been compared with FEM (substituting epirubicin in EAP and FAM for doxorubicin). In 98 fully evaluable patients, the overall response to FEM was 13% and 30% to EEP (P=0.05). The latter nevertheless was significantly more toxic, resulting in three treatment-related deaths and the survival in the EEP arm was significantly inferior to that in the FEM arm (4.2 versus 7.9 months) [65] in spite of the higher overall response rate.
ELF, which consists of etoposide, 5-FU and leucovorin, was initially developed for patients older than 65 years or with cardiac risk unsuitable for treatment with an anthracycline or cisplatin. It yielded an overall response rate of 53% in 51 patients, including 12% complete responses. In locally advanced disease, the overall response rate was 70% (seven of 10 patients), whereas in peritoneal carcinomatosis, the overall response rate was only 26%. According to the investigators, this protocol was well tolerated, even in elderly patients. The median survival was 11 months, which was also confirmed by other investigators [6668
]. Raderer et al. [68
]. investigated the clinical effectiveness and tolerance of an oral modification of the ELF regimen in patients with advanced gastric cancer. An objective response was seen in only 16% and stable disease was documented in 22%. The median time to progression was only 2.8 months (range 0.712) and the median overall survival was short at 6 months (range 118+). It was concluded that this oral combination regimen cannot be recommended for the treatment of advanced disease [69
].
The European Organization for Research and Treatment of Cancer compared the efficacy and tolerability of ELF with infusional 5-FU plus cisplatin (FUP) or FAMTX in 399 patients with advanced gastric cancer [70]. No regimen proved superior either in terms of overall response rate (9% with ELF, 20% with FUP and 12% with FAMTX) or median survival (7.2 months with ELF, 7.2 months with FUP and 6.7 months with FAMTX). The incidence or severity of toxic effects, however, surprisingly also did not differ significantly among the three groups. It was concluded that all three regimens demonstrated modest clinical efficacy and should not be regarded as standard treatment of advanced gastric cancer or as reference arms in future trials.
Platinum-based combinations (FP, PELF)
Based on in vitro data, it is supposed that the combination of cisplatin plus 5-fluorouracil (FP) is synergic or has at least additive antitumor activity. This combination achieved an overall response rate of 40% and a median overall survival of 9 months in two phase II studies [71, 72
]. Hematological toxic effects were mild, nausea and vomiting were common and a cumulative nephro- and neurotoxicity represented the dose-limiting toxicity of this regimen. The comparison of ELF, FP and FAMTX in a randomized phase III trial showed neither a significant difference in the overall response rate nor a significant difference in median survival between these groups [70
].
The interim results of a phase III trial with 200 patients presented at ASCO 2001 indicated that the combination of cisplatin, epirubicin, leucovorin and 5-FU (PELF) is more active than FAMTX. PELF was associated with a significantly higher overall response rate (38% versus 21%) and higher 12-month survival rate (31% versus 22%) compared with FAMTX.
Mitomycin-based combinations
Two Japanese studies showed that the combination of MMC and UFT is an effective regimen for advanced gastric cancer [72, 73
]. An overall response rate of 24% and a median survival of 5.3 months in patients with unresectable or recurrent gastric cancer was achieved. It was concluded that MMC/UFT is at least as effective as MMC/5-FU. Moreover, it was shown that MMC/UFT was superior to MMC/5-FU in terms of quality of life.
Capecitabine-based combinations
Administration of oral capecitabine and intravenous cisplatin in 38 patients with advanced gastric cancer in a phase II trial resulted in an overall response rate of 54.8%. The median time to progression was 6.3 months and the median overall survival was 10.1 months. The therapy was well tolerated and the principal adverse events were neutropenia and handfoot syndrome [75].
Taxane-based combinations
Based on the promising results of taxane monochemotherapy, taxane-containing combination regimens are currently under evaluation. In one report, the combination of paclitaxel, cisplatin and continuously infused 5-FU/folinic acid appears to be a highly active regimen with acceptable toxicity (mainly neutropenia) [76]. An overall response rate of 51% and a median survival of 14 months were achieved in 45 patients with advanced gastric adenocarcinoma.
Murad and colleagues investigated the combination of paclitaxel and 5-FU in 31 patients with advanced gastric cancer [77]. The overall response rate was 65% and the overall median survival was 12 months. The toxicity of this combination was considered low, predictable, and manageable and was characterized mainly by reversible alopecia, peripheral neuropathy, myalgia and mild neutropenia.
Promising results were also achieved with a regimen of paclitaxel and cisplatin [78]. The overall and complete response rates were 44% and 11%, respectively, and the median time to progression and overall survival were 7 and 11.2 months. The main toxicities of this regimen were neutropenia, peripheral neuropathy and anaphylaxic reactions.
The combination of paclitaxel with carboplatin is a highly tolerable but only moderately active regimen (overall response rate 33%). The median response duration was 4.9 months, and median survival was 7.5 months. Grade III/IV neutropenia occurred in 33%, and grade III peripheral neuropathy in 7.4% of patients [79].
An overall response rate of 37.2% [80] to 56% [80
] and a median overall survival of 9 months [81
] to 11.5 [82
] months were achieved when combining docetaxel and cisplatin. The regimen was well tolerated and the main toxicity was uncomplicated neutropenia. The interim results of a phase III trial that compared docetaxel, cisplatin, 5-FU (DCF) to cisplatin and 5-FU (CF) showed a significantly longer time to progression (5.2 versus 3.7 months) and higher overall response rates (39% versus 22%) after treatment with DCF. The median survival was 10.2 months for DCF, and 8.5 months for CF [34
].
A phase II multicenter trial showed that protracted continuous intravenous 5-FU infusion can be safely added to the docetaxelcisplatin (TC) combination if docetaxel is dose reduced [83]. An overall response rate of 51% and a median overall survival of 9.3 months were achieved. A randomized trial is ongoing to compare the efficacy of TCF with TC and ECF.
Amazing results (OR 67%, median overall survival 17.2 months) with the combination of capecitabine and docetaxel were reported at ASCO 2003 by Hee et al. [84]. However, there is a remarkable discrepancy between the median time to progression (4.8 months) and median overall survival (17.2 months) in this study. The major toxic effects were handfoot syndrome and leucopenia. Grade 3 handfoot syndrome was common (52%), resulting in premature termination of therapy in these patients.
Irinotecan-based combinations
The combination of irinotecan and cisplatin in the treatment of advanced gastric cancer was investigated in three studies [8587
]. Overall response rates were between 41.7% [86
] and 58% [85
] and the median survival was about 9 months. The major toxic effects included diarrhea, neutropenia and fatigue. Acceptable toxicity was seen with irinotecan 70 mg/m2 on days 1 and 15 and cisplatin 80 mg/m2 on day 1 every 4 weeks [86
]. No randomized trials of this promising combination, however, have been carried out so far in advanced gastric cancer.
A highly tolerable alternative to the above-mentioned regimen is the combination of irinotecan (60 mg/m2) with low-dose cisplatin (6 mg/m2). This regimen resulted in a remarkable effectiveness (overall response rate 52%) and positive impact on quality of life in 21 patients with metastatic gastric cancer resistant to 5-FU [88].
An overall response rate of 22% and a median survival of 7.6 months were seen with the combination of irinotecan, 5-FU and leucovorin in a phase II study including 36 patients. Toxicity was high with severe neutropenia in 36% and diarrhea in 28% of patients. Neutropenic infection was observed in 14% of patients, with three (8%) dying of neutropenic sepsis [89].
Oxaliplatin-based combinations
A phase II study of oxaliplatin, 5-FU and folinic acid (FOLFOX) in 49 patients with locally advanced or metastatic gastric cancer showed an overall response rate of 44.9% and a median survival of 8.6 months [90]. Treatment was complicated by grade 3/4 neutropenia, febrile neutropenia, and peripheral neuropathy in 38%, 12% and 21%, respectively.
In contrast to this, treatment with oxaliplatin plus raltitrexed has demonstrated no substantial antitumor activity, albeit in patients with progressive, chemotherapeutically pretreated metastatic gastric cancer [91].
Randomized trials
Some important conclusions can be drawn from the randomized trials using polychemotherapy in advanced gastric cancer. Despite higher overall response rates, most combination regimens showed neither a survival advantage nor a palliation benefit over 5-FU monochemotherapy [10, 45
, 51
, 52
, 92
, 93
]. Therefore, FAMTX can be considered a milestone because it was one of the first regimens showing not only a significantly superior overall response rate, but also an increased median survival [54
]. However, a randomized study showed no significant survival difference between ELF, FUP and FAMTX [70
]. The sobering conclusion was that all three combinations investigated demonstrated only modest clinical efficacy and should not be regarded as standard treatment of advanced gastric cancer.
In comparison with FAMTX, ECF showed a survival and response advantage with a tolerable toxicity, better quality of life and cost-effectiveness [60, 94
]. Replacing 5-FU by capecitabine may eliminate the need for a central venous line for continuous 5-FU infusion (REAL 2 trial).
The direct comparison between PELF and FAMTX, abstracted at ASCO 2001 showed a significantly higher overall response rate in the PELF group but again there were no differences in time to progression, duration of response or survival [95]. The combination of docetaxel, cisplatin and 5-FU (DCF) showed promising results (overall response rate of 39%, median overall survival of 10.2 months) when compared with CF at interim analysis of 232 patients with advanced gastric cancer. It was suggested that DCF may emerge as the new standard for treatment of advanced gastric cancer. Final results of this study are awaited [34
].
Chemotherapy versus best supportive care
In view of the minimal impact of chemotherapy on patient survival, a considerable debate occurred whether chemotherapy for patients with advanced gastric cancer had any advantages over best supportive care. Four randomized trials have addressed this issue and have evaluated the impact of chemotherapy on survival [35
] and quality of life [6
], compared with best supportive care.
Although these studies have relatively small numbers of patients, the data are fairly consistent (Table 4). Nevertheless, certain caveats have to be kept in mind when interpreting the data. For instance, in spite of the claim to have randomized 40 patients, only 20 patients were correctly randomized in one trial [3], while a further 20 patients were simply added to the active treatment arm. The median survival of patients undergoing chemotherapy was 911 months, whereas the median survival of patients with best supportive care was only 34 months. In addition to the significant survival advantage obtained with chemotherapy, a stabilization in quality of life was also seen in the treated patients [6
].
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Discussion |
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Therefore, a descriptive approach was used to compare the different chemotherapy regimens. In general, results from multicenter phase III trials have had lower overall response rates than single-institution phase II studies for the same drug regimens [4750
, 53
, 96
100
]. This finding, however, has also been seen in other tumor types such as colorectal cancer, where phase III studies have consistently yielded lower overall response rates than phase II studies with identical chemotherapies. Several combination chemotherapy regimens have shown overall response rates in the range of 30% to 50%, usually in phase II studies. Based upon the results of randomized trials, ECF currently represents a standard regimen for advanced gastric cancer. For patients who do not wish to receive therapy using a portable infusion pump for a prolonged time, one of the new irinotecan or taxane-based regimens is a reasonable alternative. In elderly patients, or individuals with a poor performance status, consideration could be given to leucovorin-modulated 5-FU alone, which remains the standard single agent chemotherapy in advanced gastric cancer. Despite the fact that median survival has not changed significantly with the use of modern therapies, some progress has been achieved in the treatment of advanced gastric cancer. First of all, it has been shown clearly that chemotherapy is better than best supportive care alone, with respect to both median survival and quality of life. Secondly, combination therapy appears to be associated with significantly higher overall response rates than monochemotherapy, but leads to similar survival [45
]. The low incidence of gastric cancer in the western world implies that future studies must be undertaken on a broad multicenter or even international basis in order to accrue a sufficient number of patients within a reasonable time.
When assessing the value of anticancer treatment, it is important to consider the impact on both survival and quality of life. This is particularly so for patients with advanced gastric cancer, whose life expectancy is short. ECF seems to be one of the most effective regimens at the moment and should be considered as the reference regimen in phase III trials.
Received for publication March 14, 2004. Revision received May 14, 2004. Accepted for publication May 18, 2004.
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