Pemetrexed in Gastric Cancer
Pemetrexed in Gastric Cancer
Gastric cancer continues to be a
major challenge to clinical oncologists
because of its poor
overall prognosis. In addition, the life
span of patients with advanced disease
is very limited, and their quality
of life often leaves much to be desired.
Palliation is often difficult, even
when employing aggressive modalities
such as surgery.
In 2001, Macdonald and colleagues
of the US Intergroup study 116 apparently
revolutionized this field with
a randomized trial (n = 556 with resected
adenocarcinoma of the stomach
or gastroesophageal junction)
showing that combined chemoradiation
reduced the risk of recurrence
and death by almost 40% . Nevertheless,
some have critiqued these
findings, and it was realized that the
combined treatment regimen was associated
with the risk of severe toxicity-
difficult for a large proportion
of these patients who are fragile after
There is a strong need for better
treatment strategies, but targeted therapies
that have reported limited but
objective success in breast, colon, renal,
and lung cancer, as well as the
rare gastrointestinal stromal tumors
(GISTs), have thus far failed to
achieve significant activity. Along
with the development of innovative
treatment modalities, classical chemotherapeutic
agents continue to be investigated
in this disease. Thus,
advances in more conventional therapy
approaches are the focus of this
Figure 1 illustrates the generalized
overall prognosis of gastric cancer.
Out of 100 consecutive, unselected
patients who present clinically (and
undergo medical and/or surgical intervention),
approximately 15 are
cured. This figure derives from the
generalized clinical observation that
30 patients will present with uncurable
stage IV disease; 20 will have
unresectable tumors (either due to their
locally advanced nature or associated
comorbid conditions). Of the 50 who
will undergo surgery, 5 will generally
die from postoperative complications,
and 10 will have positive surgical
margins, which lack curative treatment.
The standard recommendations
of management for each condition are
also illustrated in Table 1.
Stage IV patients benefit from chemotherapy
either at presentation or
relapse; in fact, there are three randomized
trials comparing chemotherapy
vs best supportive care (BSC)
that demonstrate doubling of median
survival. Patients who undergo an R1
or R2 resection (for microscopically
and macroscopically positive margins,
respectively) appear to benefit substantially
chemoradiation therapy, as demonstrated
by a randomized trial of Moertel
et al that accrued 62 patients
with resectable but poor-prognosis
Finally, patients who undergo an
R0 resection (complete) benefit from
adjuvant, combined chemoradiation
therapy as well. Thus, aggressive
medical intervention with this combined-
modality approach impacts the
natural history of the disease, regardless
of disease stage. Despite these
therapeutic advances, what are termed
the "absolute figures" are dismal (ie,
percent of cure rates and median survival
times of the various disease stages)
so that, although the absolute
benefit of treatment expressed as percent
of improvement vs no treatment
is high, the absolute number itself remains
Evolution of Chemotherapy
for Advanced-Stage Patients
The clinical research and drug development
during the past 20 years
have produced a series of incremental
improvements in the median survival
of these patients. In general,
one may state that progress has been
achieved even in the most prohibitive
disease settings. Figure 2 illustrates
this concept. From the median
survival of 3 to 4 months reported
with no treatment, the combinations
of fluorouracil (5-FU)/doxorubicin
5-FU/cisplatin (Platinol) (FUP),
(ELF)[7,8] progressively increased
median survival rates. Comparable
improvements were obtained with
epirubicin/cisplatin/5-FU (ECF) with
increases in survival ranging from 8.7
to 8.9 months, with improved safety
profile and quality of life.[9,10]
Finally, the recent use of the taxane
docetaxel (Taxotere) in combination
with cisplatin and 5-FU (TCF)
produced one of the greatest durations
of median survival reported in
randomized trials in advanced gastric
In a large international ongoing (n
= 232; target accrual of 460) phase III
randomized trial (V325) in advanced
gastric cancer, Ajani et al reported
significantly greater survival duration
of 10.2 months (P = .064), with 38.7%
response vs the standard FUP that
achieved 8.5 months, with a significantly
lower response of 23.2% (P =
.012). Interestingly, substitution
of the oral fluoropyrimidine capecitabine
for 5-FU resulted in a median
survival of 11.9 months, with a 53%
response rate, as reported recently by
Kang et al who employed a docetaxel/
combination in first-line therapy in a
phase I/II trial (n = 35).
Despite the trend of progressive
improvements illustrated by Figure 2,
the overall number remains small. This
is in part why no worldwide consen-sus exists for a standard chemotherapy
regimen in gastric cancer. In general,
ECF is considered standard
therapy in the United Kingdom. Cisplatin/
(PELF) is also common in Italy.
FUP is a standard therapy in the United
States and France, whereas clinicians
in Germany use both FUP and
ELF, as espoused by Vanhoefer et al
in their phase III trial (n = 399; median
survial = 7.2 months).
A relevant piece of information that
is generally not available in reports
published in the literature is the percentage
of patients with advanced disease
who do not receive chemotherapy.
This may be due to a lack of
ability to tolerate aggressive therapy
based on low performance status, deteriorating
medical characteristics, or
a referral pattern that leads them away
from specialized treatment centers. It
is likely, though, that this percentage
of untreated patients is substantial.
Contradictions of Chemotherapy
for Advanced Gastric Cancer
An observation gleaned from Figure
2 is the relatively large number of
agents (and combinations) that possess
objective activity in gastric cancer.
Notably, as with other gastrointestinal
neoplasms, standard therapy
is dominated by 5-FU. Even more
intriguing is the response rate in clinical
trials of gastric cancer. For untreated
patients, the response rates
ranged between 25% and 60%. Thus,
one would conclude on the basis of
response alone that there are at least
eight active chemotherapeutic agents
in this disease. However, this parameter
alone may not reflect major clinical
impact by this avenue of medical
intervention. Hence, this contradiction
typifies a clinical aspect of gastric
cancer (also seen in other
malignancies). Several active agents
exist and achieve relatively high response
rates, but these are generally
of short duration. Moreover, a very
short interval from disease progression
to death occurs, with a relative
short overall survival duration or percentage-
60% to 80% of the patients
in randomized trials die from this disease
within 12 months.
Activity of New
The development of oral fluoropyrimidines,
the taxanes, camptothecins,
platinum analogs, and antifolates have
been major avenues of clinical research
thus far. Generally, the goal of
the first class of agents is to simplify
the treatment, and thus, no increased
efficacy may reasonably be expected;
rather, convenience and a more favorable
toxicity profile than the standard.
Although the taxanes and
camptothecins are new entries into
the armametarium for treatment of
gastric cancer, given their high rates
of toxicity, they either will add substantial
efficacy or the therapeutic
margin will limit their clinical use.
The novel platinum analog oxaliplatin
and the antifolates possess a
favorable toxicity profile, but similarity
with their parental compounds
might only allow for similar efficacy.
Thus, it appears that the overall benefit
from the above approaches utilizing
conventional chemotherapy may
be limited, and a plateau in terms of
efficacy may be near.
A combination of the fluorouracil prodrug tegafur and the dihydropyrimidine dehydrogenase inhibitor uracil (UFT), capecitabine, and S1 (a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine) have all been investigated in several phase II studies of advanced gastric cancer, yielding an approximate response rate of 30%.[15,16] Three trials that each accrued between 36 and 45 patients employed single-agent UFT. Similarly, two small studies (n = 32 and n = 35, respectively) were conducted with capecitabine alone or in combination with docetaxel and cisplatin. Capecitabine alone had a response of 19.4%, with median survival of 247.5 days.[12,17] S1, the compound that contains both a dihydropyrimidine dehydrogenase inhibitor and an orotate phosphoribosyl transferase inhibitor, is available in Japan, and four studies employed it as a single agent in this disease. In summary, one may say that the oral fluoropyrimidines achieve marginal activity when employed as single agents. The Taxanes
In an MTT assay of 88 gastric cancer specimens, Maeda et al reported that docetaxel and paclitaxel showed a higher efficacy rate vs mitomycin, 5-FU, and cisplatin, with the patterns of antitumor activity of the taxanes independent from those of the conventional agents. Nine singleagent phase II studies have been reported with the taxanes: five employing docetaxel and four using paclitaxel. The response rates reported in these studies are very similar, ranging between 5% and 40%. The two taxanes are considered equivalent, and perhaps might be used in patients resistant to FUP. Camptothecins and Oxaliplatin
Few single phase II single-agent trials of irinotecan have been published, and investigators have reported response rates ranging between 0% and 30%.[19-21] For example, Kohne et al reported a response rate of 20%, with a median survival of 7.1 months in a study of 35 patients with ad advanced gastric cancer. A new camptothecin analog rubitecan has also been studied as a single agent, but no activity was reported. Thus, although this class of compound may be potentially useful as a combination partner, their use as single agents do not appear beneficial. There are no studies of single-agent oxaliplatin yet published in advanced gastric cancer. However, the ongoing REAL-2 phase II/III randomized, multicenter trial in the United Kingdom is investigating oxaliplatin in a 22 design by substituting either protracted venous infusion 5-FU with capecitabine or cisplatin with oxaliplatin.[ 22] Preliminary efficacy analyses indicated that the epirubicin/ oxaliplatin/capecitabine (EOX) regimen achieved an improved response rate of 52% vs epirubicin/cisplatin/ 5-FU (ECF, 31%), epirubicin/oxaliplatin/ 5-FU (EOF, 33%), or epirubicin/ cisplatin/capecitabine (ECX, 35%). The preliminary toxicity results on the first 204 randomized patients accrued suggested that oxaliplatin-containing combinations are associated with milder toxicity vs cisplatin-containing regimens. The dose-limiting toxicities associated with the fluoropyrimidines were stomatitis, palmar plantar erythema, and diarrhea, with 5.1% of capecitabine-treated patients reporting grade 3/4 toxicities. Moreover, nonhematologic grade 3/4 toxicity affected 10.7% of patients who received capecitabine at 1,250 mg/m2 (the second dose escalation), confirming this optimal dose-one that will continue up to the target accrual of 600 patients. The primary end point of this trial is survival, defined as time from randomization to death (from any cause). Antifolates and Pemetrexed
Methotrexate is an active compound against gastric cancer. It appears that its role as a component in the FAMTX combination serves not only to modulate 5-FU, but itself to act as a cytotoxic agent. Pemetrexed is a novel antifolate (ie, it inhibits at least three folatedependent enzymes) that is approved with cisplatin by the US Food and Drug Administration for the treatment of mesothelioma. It has also been widely investigated in clinical trials either as a single agent or in combination for treatment of non-small-cell lung (NSCLC), breast, pancreatic, colon, and gastric cancers. There is one recently published trial of pemetrexed in advanced gastric cancer. Bajetta et al accrued 38 previously untreated patients with stage IV disease (39% had three or more metastatic sites), and administered pemetrexed 500 mg/m2 as a 10- minute infusion every 21 days. While the original study design did not incorporate folate or vitamin B12 supplementation, toxicity was prominent in the first six patients. Subsequently, the trial was amended to include supplementation the week before treatment with pemetrexed (folic acid given at 5 mg/d on days -2 to +2 of every cycle). Folic acid and vitamin B12 supplementation are now included in clinical applications of pemetrexed, either in the clinical or trial setting. The efficacy and safety profiles for this trial are summarized in Tables 1 and 2. Toxicity was very mild in the cohort of patients receiving vitamin supplementation. In particular, the "subjective" adverse events (ie, mucositis, diarrhea, and vomiting) were mild. The intent-to-treat response rate was 21% in previously untreated patients (6 nonsupplemented patients and 30 supplemented), including two complete and six partial responses. (The analysis incorporated data from the earlier cohort who did not receive vitamin supplementation, and in whom investigators noted a lack of objective response.) The overall median survival was 7.8 months, and duration of response was 4.6 months. The authors noted that the promising activity of pemetrexed warranted combination studies. This reported level of activity with pemetrexed thus compares well with the activity of the other chemotherapeutic agents described in this article. Notably, this activity has been obtained with very mild toxicity (provided vitamin supplementation is given). Therefore, pemetrexed may be a good candidate for inclusion into combination chemotherapy regimens in gastric cancer. Moreover, the hypothesis that the multitargeted antifolates synergize in vitro with a host of active compounds in gastric cancer (ie, cisplatin, epirubicin, oxaliplatin) lend further support to a role for pemetrexed in treatment of gastric cancer. Conclusions The treatment of advanced gastric cancer remains largely unsatisfactory; despite the development of several active agents, median survival remains below 10 months at best. Incremental improvements may be obtained by the substitution of key drugs in standard combinations (FUP or ECF). The oral fluoropyrimidines (ie, UFT, capecitabine, S1) might substitute for 5-FU when issues of administration convenience are paramount; accordingly, pemetrexed might also be used when both enhanced efficacy and convenience are important. The results of the REAL-2 trial might validate the concept of oxaliplatin replacing cisplatin to reduce toxicity while maintaining efficacy. The added value of the taxanes also needs to be confirmed due to the added toxicity of the triple-agent TCF combination. Finally, these trials, in conjunction with ongoing research in the molecular pathogenesis of gastric cancer, may yet offer key hints for the development of targeted therapies that could prove effective in this disease.
2. Moertel CG, Childs DS, O’Fallon JR, et al: Combined 5-fluorouracil and radiation therapy as a surgical adjuvant for poor prognosis gastric carcinoma. J Clin Oncol 2(11):1249-1254, 1984.
3. Coombes RC, Schein PS, Chilvers CE, et al: A randomized trial comparing adjuvant fluorouracil, doxorubicin, and mitomycin with no treatment in operable gastric cancer. International Collaborative Cancer Group. J Clin Oncol 8:1362-1369, 1990.
4. Krook JE, O’Connell MJ, Wieand HS, et al: A prospective, randomized evaluation of intensive-course 5-fluorouracil plus doxorubicin as surgical adjuvant chemotherapy for resected gastric cancers. Cancer 67:2454-2458, 1991.
5. Klein HO: Long-term results with FAMTX (5-fluorouracil, adriamycin, methotrexate) in advanced gastric cancer. Anticancer Res 9:1025-1026, 1989.
6. Kim NK, Park YS, Heo DS, et al: A phase III randomized study of 5-fluorouracil and cisplatin versus 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouarcil alone in the treatment of advanced gastric cancer. Cancer 71:3813-3818, 1993.
7. Wilke H, Preusser P, Fink U, et al: High dose folinic acid/etoposide/5-fluorouracil in advanced gastric cancer—A phase II study in elderly patients or patients with cardiac risk. Invest New Drugs 8:65-70, 1990.
8. Taal BG, Teller FG, ten Bokkel Huinink WW, et al: Etoposide, leucovorin, 5-fluorouracil (ELF) combination chemotherapy for advanced gastric cancer: Experience with two treatment schedules incorporating intravenous and oral etoposide. Ann Oncol 5:90-92, 1994.
9. Waters JS, Norman A, Cunningham D, et al: Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: Results of a randomised trial. Br J Cancer 80:269-272, 1999.
10. Webb A, Cunningam D, Scarffe JH: Randomized trial comparing epirubicin, cisplatin and fluorouracil versus fluorouracil, doxorubicin and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15: 261- 267, 1997.
11. Ajani JA, Van Cutsem E, Moiseyenko S, et al: Docetaxel (D), cisplatin, 5-fluorouracil compare to cisplatin (C) and 5-fluorouracil (F) for chemotherapy-naïve patients with metastatic or locally recurrent, unresectable gastric carcinoma (MGC): Interim results of a randomized phase III trial (V325) (abstract 999). Proc Am Soc Clin Oncol 22:249, 2003.
12. Kang YK, Kim W, Chang HM, et al: Phase I-II study of docetaxel, capecitabine and cisplatin as first-line chemotherapy in advanced gastric cancer (abstract 1319). Proc Am Soc Clin Oncol 22:328, 2003.
13. Cocconi G, Carlini P, Gamboni A, et al: Cisplatin, epirubicin, leucovorin and 5-fluorouracil (PELF) is more active than 5-fluorouracil, doxorubicin and methotrexate (FAMTX) in advanced gastrica carcinoma. Ann Oncol 14:1258-1263, 2003.
14. Vanhoefer U, Rougier P, Wilke H, et al: Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 18:2648-2657, 2000.
15. Chollet P, Schoffski P, Weigang-Kohler K, et al: Phase II trial with S-1 in chemotherapy– naïve patients with gastric cancer. A trial performed by the EORTC Early Clinical Studies Group (ECSG). Eur J Cancer 39:1264- 1270, 2003.
16. Sasaki T: Current topics of S-1 at the 74th Japanese Gastica Cancer Congress. Gastric Cancer 6(suppl 1):9-12, 2003.
17. Koizumi W, Saigenji K, Ujiie S, et al: A pilot phase II study of capecitabine in advanced or recurrent gastric cancer. Oncology 64:232- 236, 2003.
18. Maeda S, Saikawa Y, Kubota T, et al: No cross-resistance of taxotere and taxol to conventional chemotherapeutic agents against gastric cancers as detected by MTT assay. Anticancer Res 23:3147-50, 2003.
19. Wilke HJ, Van Cutsem E: Current treatments and future perspectives in colorectal and gastric cancer. Ann Oncol 14(suppl 2):49-55, 2003.
20. Garcia-Carbonero R, Supko JG: Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins. Clin Cancer Res 8:641-61, 2002.
21. Kohne CH, Catane R, Klein B, et al: Irinotecan is active in chemonaive patients with metastatic gastric cancer: A phase II multicentric trial. Br J Cancer 89:997-1001, 2003.
22. Sumpter K, Harper-Wynne C, Cunningham D, et al: Randomized, multicenter phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced esophagogastric cancer: Confirmation of dose escalation (abstract 1031). Proc Am Soc Clin Oncol 22:257, 2003.
23. Bajetta E, Celio L, Buzzoni R, et al: Phase II study of pemetrexed disodium (Alimta) administered with oral folic in patients with advanced gastric cancer. Ann Oncol 14:1543-1548, 2003.
24. Leichman L, Pendyala L, Leichmman CG: Definitive and neoadjuvant therapies for esophageal and gastroiesophageal junction tumors: A look back and toward the future. Semin Oncol 30(4 suppl 11):11-18, 2003.