Original article
`
`Annals of Oncology 14:1543 1548, 2003
`
`DOI: 10.1093/ ...... /mdg406
`
`Phase II study of pemetrexed disodium (Alimta®) administered
`with oral folic acid in patients with advanced gastric cancer
`
`E. Bajetta1., L. Celio1, R. Buzzoni1, L. Ferrari1, A. Marchian61, A. Martinetti1, R. Longarini1,
`C. Becerra2, C. Ilardi3 & W. John4
`
`~Medical Oncology Unit B and Department of Radiology, lstituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; 2 UniversiO, qf Texas Southwestern
`
`Medical Center at Dallas, Dallas, TX; 3Eli Lilly Italia, Sesto Fiorentino, Italy; 4Eli Lilly & Co., Indianapolis, IN, USA
`
`Received 21 February 2003; revised 27May 2003; accepted 4 June 2003
`
`Background: The aim of this study was to assess the activity of pemetrexed in patients with advanced gastric
`cancer.
`
`Patients and methods: Thirty-eight eligible patients (median age 60 years) received pemetrexed 500 mg/m2
`every 3 weeks. Since toxicity was considerable in the first six patients, the protocol was amended to supplement
`
`subsequent patients with oral folic acid (5 mg/day on days -2 to +2 of every cycle).
`
`Results: Among 36 stage IV patients evaluable for efficacy (six non-supplemented\30 supplemented), there
`
`were two complete and six partial responses. The response rate was 21% (95% confidence interval 8% to 32%)
`
`according to intention-to-treat analysis. All responding patients were in the supplemented group. The median
`
`duration of response was 4.6 months and the median survival was 7.8 months. Five of six non-supplemented
`
`patients (83%) developed grade 3/4 neutropenia; two (33%) unsupplemented patients discontinued; two (33%)
`
`patients died due to toxicity. In the supplemented group, 12 of 32 patients (37%) had grade 3/4 neutropenia.
`
`None of the supplemented patients discontinued treatment due to hematological toxicity. Severe non-hemato-
`
`logical toxicities were infrequent.
`
`Conclusions: The activity of pemetrexed is promising in light of the tumor burden in these patients (all
`
`patients were stage IV and 39% had three or more organs involved). Toxicities were remarkably decreased with
`
`folic acid supplementation. Combination studies are warranted.
`
`Key words: folic acid, gastric cancer, pemetrexed, phase II trial
`
`Introduction
`
`Gastric cancer remains a significant problem for global health as it
`is the second most common cause of tumor-related death world-
`wide [1]. The antimetabolite 5-fluorouracil (5-FU) is the most
`widely used chemotherapeutic agent in advanced gastric cancer,
`with response rates of -20% [2]. A variety of chemotherapy regi-
`mens have been evaluated that result in higher response rates,
`although they show little improvement in median survival [3-5].
`Recently, results from a large randomized trial of epirubicin,
`cisplatin and protracted venous infusion 5-FU have shown an
`improvement in patient survival and response rate [3]. However,
`much potential for improvement in survival and in tolerability
`exists. Thus, a search for new drugs is needed in order to improve
`the therapeutic outcome of patients suffering from this aggressive
`malignancy.
`The investigational agent pemetrexed disodium (Alimta®; Eli
`Lilly & Co., Indianapolis, IN) is a novel antifolate analog which
`predominantly inhibits the thymidylate synthase (TS) enzyme, but
`
`*Correspondence to: Dr E. Bajetta, U.O. Oncologia Medica B, Istituto
`Nazionale per 1o Studio e la Cura dei Tumori, Via Venezian 1, 20133
`Milano, Italy. Tel: +39-02-23902500; Fax: +39-02-23902149;
`E-mail: emilio, baj etta @ istitutotumori.mi.it
`
`© 2003 European Society for Medical Oncology
`
`is also active against dihydrofolate reductase and glycinamide
`ribonucleotide formyltransferase--folate-dependent enzymes
`involved in de novo purine biosynthesis [6]. In the clinical setting,
`this agent administered at a dose of 500 or 600 mg/m2 once every
`21 days has shown promising activity against a variety of solid
`tumors [7].
`The broad range of antitumor activity of pemetrexed prompted
`the present study. However, toxicity at the starting dose of 500
`mg/m2 was considerable; in the first six patients enrolled, there
`was at least one episode of severe toxicity, two patients discontin-
`ued and two died, all due to toxicity related to the study drug. This
`unexpected high rate of toxicity, as well as treatment-associated
`fatalities, resulted in the accrual being halted prematurely.
`Experimentation in mice revealed that nutritional folic acid
`(FA) supplementation preserved the antitumor activity of peme-
`trexed while dramatically reducing toxicity [8]. In addition,
`preliminary results from an ongoing phase I trial combining
`pemetrexed and high-dose intermittent oral FA (5 mg/day on days
`-2 to +2 of every cycle) indicated that the addition of folate
`ameliorates toxicities, permitting dose escalation of the agent up
`to at least 925 mg/m2 in heavily pretreated patients [9]. Based on
`these findings, the study protocol was amended to supplement all
`patients treated with pemetrexed on this trial with oral FA to
`
`Sandoz Inc.
`Exhibit 1037-0001
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`JOINT 1037-0001
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`

`
`1544
`
`improve patient safety. We report on the results of this phase II
`study, which provided an opportunity, for the first time, to pro-
`spectively evaluate the effect of folate supplementation on the
`efficacy and safety profile of pemetrexed in a homogeneous
`subset of patients.
`
`begin the next cycle of treatment: neutrophils _>1.5 x 109/1; platelets _>100 x
`109/1; calculated creatinine clearance _>45 ml/min; resolution or improvement
`
`of clinically significant non-hematological adverse events to grade 1 or 0. If
`a patient could not be retreated within 42 days fi’om the last course of peme-
`trexed, they were excluded from further treatment.
`
`Patients and methods
`
`Patient selection
`
`For inclusion in the trial, patients had to be _>18 yem’s of age, have histo-
`logically proven adenocarcinoma of the stomach or gastro-esophageal junction
`with stage IIIB or IV disease, according to the American Joint Committee on
`Cancer Staging criteria [10], and at least one measurable disease site, and to
`have received no prior systemic chemotherapy or radiation therapy for gastric
`cancer. Lesions could not be amenable to curative surgery or radiotherapy. An
`Eastern Cooperative Oncology Group (ECOG) performance status <2 and a
`life expectancy of at least 12 weeks were required. Women of childbearing
`potential must have taken adequate precautions to prevent pregnancy. Patients
`were required to have adequate organ function as defined by the following:
`neutrophils, _>1.5 x 109/1; hemoglobin, _>9 g/dl; platelets, _>100 x 109/1;
`bifu’ubin, <l.5x the upper limit of normal (ULN); aspartate transaminase
`(AST) or alanine transaminase (ALT) <3.0x ULN (AST or ALT <5x ULN
`was acceptable if documented liver metastases were present); and calculated
`creatinine clearance, _>45 ml/min, using the modified Cockcroft and Gault
`calculated creatinine clearance formula. The study was conducted only after
`the appropriate approvals had been obtained from the human subjects research
`committees of the participating institutions. All patients signed a written
`informed consent document before em’ollment. Patients were excluded if they
`had a history of second primary malignancy. Patients with clinically significant
`effusions (pleural or peritoneal) or albumin <2.5 g/dl were ineligible. Pregnant
`women, patients with active infection or symptomatic brain metastasis were
`also excluded from the study. Patients who could not discontinue therapy with
`aspirin and other non-steroidal anti-inflammatory agents tbr 2 days before, the
`day of and 2 days after administration of pemetrexed were excluded fi’om the
`trial.
`Pre-treatment investigations, performed within 3 weeks of commencing
`treatment, included full history and examination, complete blood count, blood
`chemistries, tu’inalysis, electrocardiogram, calculated creatinine clearance and
`assessment of vital signs. Dtu’ing therapy, hematology was measured at the
`start of every cycle and on a weekly basis thereafter. Blood chemistries were
`performed before the start of treatment and 1 week after every cycle. Urinalysis,
`vital signs and calculated creatinine clearance were also assessed at the start of
`each cycle.
`
`Treatment
`
`Pemetrexed was administered at a dose of 500 mg/m~- as a 10-rain intravenous
`
`infusion, once every 21 days. Dexamethasone 4 mg, a prophylactic measure
`
`for skin rash, was given orally in the USA and intramuscularly in Italy twice a
`
`day, starting the day before and continuing until the day after study drug
`
`administration. Supplemental FA was given orally at a dose of 5 mg once a
`
`day, on days 2 to +2 for every cycle. Therapy was continued unless the patient
`
`met withdrawal criteria or had progressive disease. All adverse events were
`
`scored according to National Cancer Institute Common Toxicity Criteria.
`
`Grade 4 neutropenia lasting >5 days required a 15% dose reduction. Grade 3
`
`and grade 4 thrombocytopenia required 15% and 50% dose reductions,
`
`respectively. A 25% dose reduction was required in case of concomitant grade 4
`
`neutropenia and grade 3 thrombocytopenia. Grade 3 and 4 mucositis required
`
`a 25% and 50% dose reduction, respectively. Once a dose reduction had
`
`occurred, it was not permitted to re-escalate for subsequent courses. Patients
`
`who required more than two dose reductions for toxicity were removed from
`
`the study. Patients were requh’ed to meet all the tbllowing criteria in order to
`
`Efficacy assessment and statistical analysis
`
`The study plan was to enroll eligible patients from one American and five
`Italian centers. Participating Italian institutions were coordinated by means of
`the Italian Trials in Medical Oncology (ITMO) Group. The primary objective
`of the study was to evaluate the response rate; secondary objectives being the
`estimation of the toxicity profile and the time-to-event efficacy measures. A
`two-stage design was utilized to permit early study termination it" significant
`antitumor activity was not observed. Thirteen qualified patients had to be
`enrolled into the first stage and it" one or more patients responded to peme-
`trexed, 22 additional patients would be accrued. It" fewer than seven of 35
`patients responded, the study drug would be rejected as inactive in this indica-
`tion. This procedure tested the null hypothesis (H0) that the true response rate
`was <10% versus the alternative hypothesis (HA) that the U’ue response rate
`was at least 25%. The significance level (probability of rejecting the H0 when
`it is U’ue) was 0.06, and the power (probability of rejecting the H0 when the HA
`is U’ue) was 80%. The efficacy analysis was pertbrmed on data from all
`patients who qualified for the protocol and who received at least two doses of
`pemeU’exed. A patient who discontinued fi’om study due to unacceptable drug
`toxicity prior to receiving two doses was also included in the efficacy analysis.
`
`Tumor measurements were assessed by radiographic scan within 4 weeks
`prior to study entry and were restaged after every second cycle. Patients with
`tumor responses required a confirmatory disease assessment at least 4 weeks
`later. All responses were confirmed by independent radiology review and
`determined using standard Southwest Oncology Group criteria. Response
`duration was defined as the time fi’om U’eatment initiation to the appearance of
`objective evidence of disease progression. Overall survival was measured
`fi’om the date of study enrollment to the date of death and was estimated by the
`Kaplan Meier method. The safety analysis was performed on data from all 38
`
`patients who received at least one dose of pemeU’exed.
`
`Results
`
`From July 1997 to May 2001, 38 patients entered the study. Six
`were enrolled in the early group of unsupplemented patients, and
`32 were enrolled from February 1999 when the accrual started
`again, after the study protocol was amended to administer oral FA
`with pemetrexed. Thirty (79%) of a total of 38 patients were
`treated at the National Cancer Institute of Milan, with the remain-
`ing eight patients treated at one of the outside institutions. Thirty-
`six patients had adenocarcinoma of the stomach and two cases
`were diagnosed with adenocarcinoma of the gastro-esophageal
`junction. Table 1 lists the patient demographics.
`
`Efficacy
`
`Thirty-six patients (95%) qualified for efficacy analysis. Two
`patients in the supplemented group were not evaluable for
`response due to insufficient therapy, as per protocol. One patient
`with liver metastases and pulmonary lymphangitis had an early
`deterioration in their physical condition not considered to be
`related to study drug and died soon after administration of the first
`cycle. Another patient who complained of significant upper
`gastrointestinal bleeding after the first dose of pemetrexed had a
`
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`
`Table 1. Patient characteristics (n = 38)
`
`Toxicity
`
`1545
`
`Characteristic
`
`Age, years
`
`Median
`
`Range
`
`Sex
`
`Male
`
`Female
`
`ECOG pertbrmance status
`
`0
`
`1
`
`Disease stage~
`
`IV
`
`Sites of metastases
`
`Liver
`
`Lymph node
`
`Lung
`
`Other
`
`Number of disease sites
`
`1
`
`2
`
`>3
`
`Prior surgery
`
`None
`
`Curative
`
`Exploratory/palliative
`
`Patients, n (%)
`
`60
`
`43 76
`
`29 (76)
`
`9 (24)
`
`26 (68)
`
`12 (32)
`
`38 (100)
`
`24 (63)
`
`24 (63)
`
`7 (18)
`
`16 (42)
`
`12 (32)
`
`11 (29)
`
`15 (39)
`
`12 (32)
`
`14 (36)
`
`12 (32)
`
`~According to the American Joint Committee on Cancer
`
`Staging Criteria.
`
`ECOG, Eastern Cooperative Oncology Group.
`
`rapid progression of gastric primary tumor as documented by an
`abdominal computed tomography scan.
`Eight of 36 evaluable patients achieved confirmed objective
`regressions. Among the supplemented patients, a complete response
`
`was observed in two patients, while six patients achieved a partial
`response. The response rate was 21% (95% confidence interval
`8% to 32%) according to intention-to-treat analysis. A complete
`response occurred in patients who had tumor recurrence after cur-
`ative surgery, while no patient retaining the primary tumor experi-
`enced objective regression at this site. Six of eight responders
`were males. Sites of response included liver, lymph nodes, lung
`
`and peritoneum. Stabilization of disease was observed in 12
`patients (33%). The median duration of response was 4.6 months
`(range 3-10), the median time to disease progression 2.8 months
`and the median survival 7.8 months (range 0.7 to >24). The prob-
`ability of being alive at 1 year was 27%. Six of 17 patients who
`received second-line chemotherapy after progression on pemetrexed
`treatment experienced partial remission.
`
`All 38 patients who received at least one dose ofpemetrexed were
`evaluated for toxicity. A total of 144 cycles of pemetrexed were
`administered. The median number of cycles per patient was three
`(range 1-8). The mean delivered dose intensity was 158.8 rag/m2/
`week (planned 166.7 mg/m2/week), which corresponds to 95 % of
`the planned dose intensity. There were 35 dose delays (24% of
`doses administered). Common reasons for dose delays were
`scheduling conflicts (51%), decrease in creatinine clearance (20%)
`and increase in transaminases (9%). Five patients had one dose
`reduction for the following reasons: increased transaminases in
`two patients, and one patient each, leukopenia, thrombocytopenia
`and stomatitis.
`All six patients in the non-supplemented group had at least one
`episode of severe toxicity. Two of these patients discontinued
`treatment due to grade 4 leukopenia and grade 2 vomiting,
`respectively. In addition, two patients had a lethal toxicity. Acute
`myocardial infarction occurred soon after the first cycle of therapy
`in a 76-year-old patient with lymph node and liver metastases who
`was known to have a history of myocardial infarction. The patient
`was found to have grade 3 or 4 toxicities of anemia, neutropenia,
`stomatitis and diarrhea during his hospital stay. Despite thera-
`peutic measures, the patient died due to heart failure. Another
`patient, a 66-year-old man with liver metastases, developed grade 3
`stomatitis and vomiting, and grade 2 diarrhea after the second
`cycle of pemetrexed. The patient was hospitalized for severe
`dehydration and died due to acute renal failure.
`In the supplemented group, there was one death that occurred in
`a 62-year-old patient with liver metastases. After the first cycle of
`therapy, the patient experienced grade 3 stomatitis and grade 2
`skin rash that led to a dose reduction as per protocol. One week
`after the second course, the patient developed febrile neutropenia,
`grade 4 thrombocytopenia, watery diarrhea and grade 3 increased
`bilirubin. Despite aggressive measures, the patient died due to
`hepatic failure possibly related to study drug. In fact, it was
`unclear whether hepatic failure represented a toxic event or was
`also secondary to disease progression, as the baseline work-up
`revealed extensive metastatic disease in the liver along with
`normal bilirubin and transaminase levels. The exact cause of death
`remained unknown because the patient was unevaluable for
`response based on failure to obtain a second tumor assessment and
`post mortem examination.
`Hematological toxicities are summarized in Table 2. Percentages
`of severe hematological events were higher in the non-supple-
`mented group than in the supplemented group. Five of six non-
`supplemented patients (83%) developed grade 3/4 neutropenia;
`severe neutropenia occurred in 10 (67%) of 15 cycles completed.
`In the supplemented group, 12 of 32 patients (37%) experienced
`grade 3/4 neutropenia. There was no evidence of cumulative
`toxicity. No patient in the supplemented group discontinued treat-
`ment due to hematological toxicity.
`Severe non-hematological toxicities occurred infrequently, but
`were observed mainly in the non-supplemented group (Table 3).
`Patients not receiving supplemental FA experienced the following
`toxic effects: grade 3/4 mucositis (two patients), grade 4 diarrhea
`
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`
`1546
`
`Table 2. Hematological toxicity with or without folic acid supplementation
`(worst grade per patient)
`
`Event
`
`No. of
`patients
`(,~ = 38)
`
`Grade, n (%)~
`
`Non-supplemented group
`
`Neutropenia
`
`Leukopenia
`
`Thrombocytopenia
`
`Anemia
`
`Supplemented group
`
`Neutropenia
`
`Leukopenia
`
`Thrombocytopenia
`
`Anemia
`
`6
`
`6
`
`6
`
`6
`
`32
`
`32
`
`32
`
`32
`
`1 (16)
`
`3 (50)
`
`1 (16)
`
`1 (16)
`
`4 (67)
`
`2 (33)
`
`0 (0)
`
`0 (0)
`
`5 (15)
`
`7 (22)
`
`9 (28)
`
`1 (3)
`
`3 (9)
`
`1 (3)
`
`1 (3)
`
`0 (0)
`
`~Toxicity graded according to National Cancer Institute Common Toxicity
`Criteria.
`
`(two patients), grade 3 nausea (two patients), grade 3 vomiting
`(one patient), grade 4 infection (one patient) and grade 3 fatigue
`(one patient). Severe non-hematological events observed in the 32
`supplemented patients were grade 3 mucositis (one patient) and
`grade 3 fatigue (one patient). Transient deterioration in liver func-
`tion tests were observed in all patients, with grade 2-3 increases in
`serum levels of transaminases (24%) and alkaline phosphatase
`(5%). However, no clinical symptoms associated with these
`changes were noted.
`
`Discussion
`
`Results of this clinical trial represent the first published evidence
`of the activity of pemetrexed in gastric cancer. Furthermore, this is
`
`the first report on efficacy and safety of pemetrexed with FA
`supplementation in a clearly defined subset of patients. Responses
`were usually observed after two courses of pemetrexed and
`occurred in a variety of metastatic sites, including liver and retro-
`peritoneal lymph nodes, with a median survival of 7.8 months.
`The response rate achieved was comparable to single-agent activity
`observed with the most active conventional drugs, but also with
`newer agents, including taxanes and irinotecan [2].
`Some characteristics of the study population should be considered
`when analyzing the efficacy data. All patients enrolled presented
`with distant metastases, with 39% of cases showing involvement
`of at least three organs, a high-risk prognostic factor [11]. It is
`known that patients with metastatic gastric cancer may have
`poorer outcomes than those with locally advanced disease in
`terms of both response rate and short-term survival [3]. In the
`majority of patients (63%) in this study, the primary tumor had not
`been resected. Interestingly, in a European phase II trial of
`docetaxel in advanced untreated gastric cancer, responses
`occurred more frequently in patients who had primary tumor
`resection [ 12]. It is likely that patients whose gastric tumor was not
`removed have more advanced disease with a larger tumor burden.
`These data suggest that the 21% response rate achieved with
`pemetrexed monotherapy in this patient population is promising.
`In light of this, it is worth pointing out that no activity against this
`malignancy was observed in a phase II study of raltitrexed, a
`specific TS inhibitor [13]. A study in which -50% of patients had
`received previous 5-FU-based therapy, which might have contrib-
`uted to the lack of tumor responses due to the up-regulation of TS
`expression [14]. However, it is possible that the ability of peme-
`trexed to inhibit more than one folate-dependent enzyme may help
`to increase the spectrum of tumors potentially sensitive to the drug.
`Adverse events observed during this trial were predictable
`based upon the mechanism of action of pemetrexed. In the majority
`of clinical trials, the dose-limiting toxicity of pemetrexed was
`neutropenia; other non-dose-limiting toxicities included transient
`
`Table 3. Non-hematological toxicity (worst grade per patient) (n = 38)
`
`Toxicity
`
`Nausea
`
`Grade, n (%)~
`
`1
`
`2
`
`3
`
`2 (5)
`
`4
`
`0 (0)
`
`Vomiting
`
`Infection
`
`Diarrhea
`
`Skin rash
`
`Mucositis
`
`Fatigue
`
`Transaminases
`
`Alkaline phosphatase
`
`Bilirubin
`
`Creatinine
`
`10 (26)
`
`2 (5)
`
`2 (5)
`
`3 (8)
`
`10 (26)
`
`4 (10)
`
`7 (18)
`
`14 (37)
`
`15 (39)
`
`0 (0)
`
`1 (3)
`
`0 (0)
`
`1 (3)
`
`0 (0)
`
`4 (10)
`
`4 (10)
`
`1 (3)
`
`0 (0)
`
`6 (16)
`
`1 (3)
`
`2 (5)
`
`1" (3)
`
`1 (3)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`2 (5)
`
`2 (5)
`
`3 (8)
`
`1 (3)
`
`3b (8)
`
`0 (0)
`
`0 (0)
`
`1 (3)
`
`2 (5)
`
`0 (0)
`
`1 (3)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`0 (0)
`
`~Toxicity graded according to National Cancer Institute Common Toxicity Criteria.
`bOne non-supplemented and one supplemented patient died.
`"Non-supplemented patient died.
`
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`
`transaminase elevations, skin rash, mucosal toxicity, fatigue and
`diarrhea [7]. However, such toxicities were not a serious problem
`in those phase II trials in which patients had a generally good
`performance and nutritional status [7].
`No detailed information on patients’ nutritional status was
`available, but it is plausible that the unexpectedly high rate of
`hematological toxicity observed in the non-supplemented patients
`enrolled in this study reflects their generally poor functional folate
`status due to the gastric carcinoma. In support of this conclusion,
`the comparison of clinical data from patients receiving versus
`those not receiving FA supplementation suggests that, although
`the groups are small and non-randomized, the concomitant use of
`FA is able to markedly improve the safety profile of pemetrexed in
`this patient population.
`Since hematological toxicity of pemetrexed has been correlated
`with drug exposure, another possible explanation for the increase
`in hematological toxicity may be the occurrence of higher plasma
`concentrations of drug in non-supplemented patients. It is of interest
`that in a recently reported trial with pemetrexed 500 mg/m2,
`administered without supplemental FA in 35 patients with
`advanced head and neck cancer, hematological toxicity was also
`higher than that previously observed in other trials with this anti-
`folate [15]. When the pharmacokinetics of pemetrexed in head
`and neck cancer patients was compared with that in patients with
`other cancer types, a large degree of overlap between the two popu-
`lations without any significant difference was observed. Since
`head and neck cancer patients with advanced disease have generally
`poor nutritional status, it was suggested that this condition could
`have played a major role in the incidence and severity of toxicities.
`Also, studies with other antifolates have reported that poor nutri-
`tional status contributes to the likelihood that a patient will experi-
`ence severe toxicity when exposed to these drugs [16-18]. The
`importance of FA supplementation in reducing the toxic effects
`and increasing the therapeutic index of pemetrexed has been
`shown preclinically, and a multivariate analysis involving a large
`number of patients showed an association between high pretreat-
`ment levels of serum homocysteine, which reflects a low folate
`status of the patient, and more severe hematological or non-
`hematological toxicities [8, 19]. It is noteworthy that the main
`circulating folate, methyltetrahydrofolate, is a substrate for the
`enzyme methionine synthase, which converts homocysteine to
`methionine in a B12-dependent reaction, and deficiency in folate
`or vitamin B12 results in a rise in plasma homocysteine [20, 21].
`Accordingly, following a programmatic change to supplement
`patients with daily low-dose FA and vitamin B~, it has recently
`been reported that pemetrexed-induced toxic effects can be proac-
`tively managed [22].
`In summary, we conclude that high-dose intermittent oral FA
`allowed administration of pemetrexed at the dose and schedule
`explored with a highly satisfactory safety profile and with no com-
`promise in efficacy. Further investigations combining pemetrexed
`with other known active agents against gastric carcinoma are war-
`ranted to put the role of this agent in proper perspective [23].
`Accordingly, a phase II trial of pemetrexed in combination with
`the platinum analog oxaliplatin in locally advanced or metastatic
`disease has been planned.
`
`1547
`
`Acknowledgements
`
`We thank Barbara Formisano and Caterina Somenzi for their
`excellent secretarial assistance.
`
`References
`
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`global picture. Eur J Cancer 2001; 37: S~$66.
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`2. Kat-peh MS, Kelsen DP, Tepper JE. Cancer of the stomach. In DeVita VT
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`Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of
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