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Annals of Oncology Advance Access published February 13, 2009
Pemetrexed in combination with oxaliplatin asa first-line therapy for advanced gastric cancer:a multi-institutional phase II study L. Celio1, C. N. Sternberg2, R. Labianca3, I. La Torre4, V. Amoroso5, C. Barone6, G. Pinotti7,S. Cascinu8, F. Di Costanzo9, G. L. Cetto10 & E. Bajetta1*1Medical Oncology Unit 2, Foundation IRCCS National Tumour Institute, Milan; 2Department of Medical Oncology, San Camillo Forlanini Hospital, Rome; 3Department ofMedical Oncology, Reunited Hospitals, Bergamo; 4Medical Department, Eli Lilly Italy, Sesto Fiorentino; 5Department of Medical Oncology, Civil Hospitals, Brescia;6Department of Medical Oncology, Catholic University of the Sacred Heart; 7Department of Oncology, Circle’s Hospital, Varese; 8Department of Medical Oncology,University Hospital, Ancona; 9Department of Medical Oncology, Careggi Hospital, Florence; 10Department of Medical Oncology, Borgo Trento Hospital, Verona Received 4 November 2008; revised 14 November 2008; accepted 25 November 2008 Background: This clinical trial assessed the efficacy of pemetrexed combined with oxaliplatin (PEMOX) in patients with advanced gastric cancer (AGC).
Patients and methods: Forty-four patients with untreated AGC were enrolled to evaluate response rate (RR).
Patients received pemetrexed (500 mg/m2) with vitamin supplementation and oxaliplatin (120 mg/m2) every 21 days for six cycles or until disease progression occurred.
Results: Median age was 62 years (range 26–76). The majority of patients (93%) had metastatic disease. Sixteen of the 44 patients achieved confirmed response [RR 36%; 95% confidence interval (CI) 22% to 52%]; four complete responses and 12 partial responses (complete and partial responses according to the RECIST guidelines are the confirmed-responses observed in the study population). Median time to tumor progression (TTP) was 6.2 months (95% CI 4.3–7.5) and median survival was 10.8 months (95% CI 7.7–17.2). A total of 220 cycles were administered, with a median of six cycles. Most common grade 3/4 toxic effects were neutropenia in 41% of patients (19% of cycles) and thrombocytopenia in 11% of patients (4% of cycles). Treatment delays or dose reductions for toxicity occurred in 10% and 5% of cycles, respectively.
Conclusions: PEMOX is active and well tolerated in AGC. RR, TTP, and survival were comparable to those achieved in studies using different 5-fluorouracil (5-FU)–oxaliplatin combinations, without the inconvenience of prolonged 5-FU schedules.
Key words: advanced gastric cancer, chemotherapy, oxaliplatin, pemetrexed, phase II trial addition, cisplatin-based combinations are difficult toadminister in this often-debilitated population and have the Patients suffering from advanced gastric cancer (AGC) remain potential for severe toxicity. Therefore, effective treatment a therapeutic challenge for medical oncologists. Despite regimens with acceptable toxicity profiles are needed, with increasing evidence that the appropriate management of fit increasing attention toward patient convenience and quality patients should be with systemic chemotherapy, nocombination has yet emerged as the standard of care. To date, chemotherapy relies heavily upon 5-fluorouracil (5-FU) and/or Oxaliplatin is a third-generation platinum derivative with cisplatin, with 5-FU–cisplatin (CF) and epirubicin–cisplatin– a more favorable toxicity profile than cisplatin [4]. Oxaliplatin 5-FU (ECF) being currently regarded as reference regimens [1].
does not cause ototoxicity or nephrotoxicity and its A recent phase III study comparing docetaxel–cisplatin–5-FU administration does not require aggressive i.v. hydration.
(DCF) to the reference arm of CF showed that DCF improved Several phase II studies have demonstrated that oxaliplatin in survival significantly compared with that seen in the cohort combination with 5-FU may be an effective and well-tolerated treated with CF alone [2]. However, the DCF regimen induced treatment of patients with AGC [5–9]. However, major severe toxicity, thereby limiting its clinical application. In drawbacks of oxaliplatin-based doublets are the inconvenienceof the 5-FU dosing schedule and the requirement for centralvenous access catheter and infusion device.
*Correspondence to: Dr E. Bajetta, Medical Oncology Unit 2, Fondazione IRCCS Istituto The new multitargeted antifolate pemetrexed has an Nazionale dei Tumori, Via G. Venezian 1, 20133 Milan, Italy. Tel: +39-02-23902500;Fax: +39-02-23902149; E-mail: important advantage compared with prolonged 5-FU schedules ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: in that it can be administered via a single short injection [10].
twice daily beginning the day before and ending the day after each Pemetrexed has proved to be more active than 5-FU against pemetrexed dose. Antiemetic prophylaxis that included a 5-HT3 antagonist several human gastric cancer cell lines [11]. Myelosuppression was the predominant dose-limiting toxicity of this antifolate inthe clinical setting, but concomitant folic acid (FA) and vitamin Pretreatment investigations included a complete medical history and 12 supplementation was able to markedly reduce the toxicity profile [10]. Single-agent pemetrexed has demonstrated clinical physical examination, blood cell count, chemistry panel, urinalysis, and activity against several tumor types, including gastric cancer calculated CrCl. In addition, imaging studies were completed within4 weeks before enrollment. Response to treatment was assessed every two cycles of therapy. Objective responses were evaluated using RECIST Additive or synergistic cytotoxicity between pemetrexed and guidelines and were to be confirmed at least 4 weeks after the first oxaliplatin was reported in a preclinical study [13]. Therefore, documentation of response [15]. Blood cell counts were monitored every in an attempt to develop a new chemotherapeutic regimen, the week; blood chemistry and calculated CrCl were assessed before each cycle.
combination of pemetrexed with no vitamin supplementation Adverse events were assessed before each cycle using National Cancer and oxaliplatin (PEMOX) was investigated in a phase I study, Institute—Common Toxicity Criteria (version 2.0; 1999). Peripheral which demonstrated a safe toxicity profile of the regimen when neuropathy was graded according to the oxaliplatin-specific scale [16].
administered using full therapeutic doses of each agent every Drug doses were delayed and/or modified because of either absolute 3 weeks in patients with solid tumors [14]. With this neutrophil count of <0.5 · 109/l and a platelet count of ‡50 · 109/l (25% background, a multicenter phase II trial was conducted to dose reduction) or a platelet count of <50 · 109/l (50% reduction).
evaluate the efficacy and safety of the PEMOX regimen in Similarly, treatment was delayed because of grade 3 or 4 non-hematologic toxic effects (except for grade 3 transaminase elevation, nausea, andvomiting) or calculated CrCl <45 ml/min. When non-hematologic toxiceffects resolved, therapy with pemetrexed resumed at 50% of the previous level because of grade 3 or 4 mucositis and 75% of the previous levelbecause of grade 3 or 4 diarrhea (in the event of diarrhea, oxaliplatin dose was to be reduced to 100 mg/m2). Treatment resumed at 25% of the Patients with histologically confirmed inoperable or metastatic previous level because of any other grade 3 or 4 non-hematologic toxicity, adenocarcinoma of the stomach or gastroesophageal junction were eligible as appropriate. In cases of grade ‡2 neuropathy, oxaliplatin dosing was provided they were ‡18 years of age with an Eastern Cooperative Oncology delayed until recovery and then resumed at 25% of the previous level Group performance status of zero to two and had a life expectancy of at because of first-time and second-time events lasting >7 days or least 12 weeks. Other inclusion criteria were measurable disease according discontinued if grade 3 neuropathy became persistent. Dose re-escalation to RECIST and adequate organ function, as indicated by absolute was not allowed. Any patient requiring a third dose reduction or >42 days neutrophil count ‡1.5 · 109/l, a platelet count ‡100 · 109/l, hemoglobin between treatments discontinued the study.
‡10 g/dl, serum bilirubin £1.5· upper limit of normal (ULN), serumalkaline phosphatase and transaminases £3.0· ULN (£5.0 · ULN if liver metastases were present), and calculated creatinine clearance (CrCl) ‡45 The primary end point of this study was the overall response rate (ORR) to ml/min using the standard Cockcroft and Gault formula. No prior PEMOX regimen. A Simon’s optimal two-stage design was used to calculate chemotherapy was allowed, except adjuvant chemotherapy that had been sample size with p0 = 0.20 (null hypothesis) and p1 = 0.40 (alternative completed at least 12 months before enrollment. Exclusion criteria included hypothesis) with a significance level of 0.05 and a power of 80%. This brain metastases, other primary malignancy (except for in situ cervical resulted in a sample size of 13 patients for the first stage. If more than three cancer or adequately treated nonmelanoma skin cancer or other malignancy objective responses were observed, further 30 patients were to be recruited treated with no evidence of recurrence within 5 years before study entry), in the second stage. The regimen was considered active if a total of ‡13 uncontrolled clinically significant effusions (pleural or peritoneal), severe patients achieved a confirmed objective response. All patients who had comorbid conditions, and inability to interrupt nonsteroidal anti- received at least one cycle of protocol treatment were included in the inflammatory drugs for 2 days before and after pemetrexed administration.
response, safety, and survival analyses on an intention-to-treat basis. Time All patients signed written informed consent before enrollment and the to tumor progression (TTP) was measured from the date of study protocol was approved before commencement by the local Ethical Review enrollment to the first observation of progressive disease (PD), duration of Board of the participating institutions.
response from the first observation of response to the first observation ofPD, and overall survival (OS) from the date of study enrollment to the time of death from any cause. Time-related efficacy parameters for all patients This was a multicenter, nonrandomized, open-label, phase II study of were updated to 26 November 2007. TTP and OS were estimated using the PEMOX regimen. Pemetrexed 500 mg/m2 was given as a 10-min i.v.
Kaplan–Meier method. All estimates of treatment effects were conducted at infusion followed by oxaliplatin 120 mg/m2 as a 2-h infusion on day 1 of a two-sided a level of 0.05 and the 95% confidence intervals (CIs) were a 21-day cycle, as recommended by Misset et al. [14]. Treatment was administered for six cycles but a maximum of eight cycles were permitted atthe discretion of the treating physician. Reasons for early discontinuationincluded disease progression, unacceptable toxicity, or patient’s refusal.
Patients were instructed to take oral FA (350–600 lg) daily beginning 1–2 weeks before the first pemetrexed dose until 3 weeks after the final dose.
Vitamin B From May 2004 to October 2005, 44 patients were treated at 12 (1000 lg i.m. injection) was administered 1–2 weeks before the first pemetrexed dose and every 9 weeks thereafter until 3 weeks after the nine Italian oncology centers. Fourteen patients were enrolled final dose. Dexamethasone (4 mg or equivalent) was administered orally at the coordinating site of Milan and the remaining 30 patients were enrolled at the other sites. A median of four patients Table 1. Baseline patient characteristics (n = 44) (range 1–14) were enrolled per site. Five patients who receivedstudy treatment did not meet eligibility criteria because of increased serum total bilirubin or alkaline phosphatase (one patient each) and decreased hemoglobin level (three patients).
Baseline patient characteristics are summarized in Table 1. The median age was 62 years (range 26–76). No patients had primary tumor of gastroesophageal junction and the majority of them (29 of 44, 66%) retained the gastric lesion. The median number of organs that were involved was two (range 1–4), with 15 (34%) patients having involvement of at least three organs.
Eleven of the 25 (44%) patients who underwent prior surgery Discontinuation due to early disease progression occurred in one patient after the first cycle, and one further patient, who dropped out of study because of toxicity, was not assessable due to failure to obtain a follow-up tumor assessment. The details of treatment efficacy are shown in Table 2. Confirmed responses were observed in 16 out of 44 patients (ORR 36%; 95% CI 22% to 52%), with a complete response occurring in three patients with nodal metastases and one patient with liver involvement. Disease stabilization as best response was observed in 15 (34%) patients. Sites of response included liver, nodes, lung, pancreas, and ovary. Response rates (RRs) according to extension and main sites of disease are With a median follow-up of 9.4 months (range 1.8–29.1), the aBone (two patients), abdominal wall (one patient), adrenal gland (one median TTP was 6.2 months (95% CI 4.3–7.5). The median patient), esophagus (one patient), mesentery (one patient), ovary (one survival was 10.8 months (95% CI 7.7–17.2); 11 of the 44 patient), pancreas (one patient), perineum (one patient), pleura (one (25%) patients were still alive at the last follow-up. Estimated patient), and retroperitoneum (one patient).
ECOG, Eastern Cooperative Oncology Group.
After completion of the trial, 28 (64%) patients with disease progression received second-line chemotherapy that mostfrequently was as follows: a combination containing 5-FU plus having a dose reduction in a total of 10 cycles (5% of cycles).
irinotecan or cisplatin and docetaxel alone. One responsive Seven patients needed a dose reduction of both pemetrexed patient with locally advanced disease who underwent surgery and oxaliplatin because of severe thrombocytopenia (four and postoperative ECF-based chemotherapy was alive at 22 patients), vomiting (one patient), diarrhea (one patient), and months after starting protocol treatment. One further fatigue (one patient). Not only the pemetrexed but also the responsive patient underwent resection of a progressive ovary oxaliplatin dose was reduced in one patient who developed lesion before receiving second-line therapy.
deep vein thrombosis during the study. Pemetrexed dose wasreduced in one patient due to grade 3 alanine aminotransferase elevation, whereas oxaliplatin dose was A total of 220 treatment cycles were administered, with reduced in one patient due to grade 3 neurotoxicity following a median of six cycles per patient (range 1–8). Nineteen three cycles. The investigator decided to reduce the dose of (43%) patients received six cycles of treatment; six (14%) oxaliplatin to 85% of the full dose in another patient during patients received eight cycles. The median relative dose intensities were 94% for pemetrexed and 93% for oxaliplatin.
The median cumulative dose was 4400 and 1050 mg for pemetrexed and oxaliplatin, respectively. There were 64 cycle The majority of treatment-related adverse events were mild to delays (29% of cycles administered), but only 21 cycles were moderate in intensity (Table 4). Grade 3/4 neutropenia delayed due to hematologic or non-hematologic adverse occurred in 41% of patients and 19% of cycles, but no patients events (3% and 7% of cycles, respectively). Forty-three cycles developed febrile neutropenia. Two patients discontinued the (20% of cycles) were delayed due to reasons unrelated to study because of treatment-related adverse events, one because treatment, including scheduling conflict, patient’s request, or of mucositis with dehydration after two cycles and the other pending imaging studies for response evaluation. Forty-three because of hematologic toxicity after five cycles of therapy. A patients received more than one cycle, with 10 (23%) of them 70-year-old patient died during the study due to acute renal Table 2. Efficacy and survival in 44 patients (intention-to-treat analysis) studies, the majority of patients in the current study presentedwith a good performance status and metastatic disease; their median age (62 years) was in the same range as in thepreviously published trials. In accordance with two mentioned studies where the frequency of second-line chemotherapy was reported, the majority of our patients received second-line therapy that frequently included irinotecan or docetaxel [8, 9].
Evidence from phase II studies suggests that irinotecan-based regimens or docetaxel may have been effective in AGC patients progressing after first-line chemotherapy [17–19]. Therefore, the use of second-line therapy may have had a positive impact on survival in the study cohort. It also should be noted that response assessments were planned every two cycles of treatment, but 20% of cycles were delayed due to reasons unrelated to treatment. We cannot exclude that delayed assessments might have had an impact on the TTP in the More recently, the results of a randomized phase III trial comparing 5-FU, leucovorin plus either oxaliplatin (FLO) or cisplatin in patients with advanced disease were published [20]. Although there was only a trend toward improved progression-free survival (primary end point) with FLO, the efficacy results lend support to the view that oxaliplatin is at least as effective as cisplatin in AGC. While the usual limitations of cross-study comparisons should be taken into account, the ORR of 36% seen in the PEMOX study in CI, confidence interval; TTP, time to tumor progression.
a similar population of patients compares well with thatobserved in the FLO arm (ORR of 35%) of the German study.
The median survival in patients who underwent FLO was 10.7 Table 3. Response according to extension and site of disease months (95% CI 8.5–13.9), which is comparable to the10.8-month median survival observed in the current study The toxicity profile of PEMOX was extremely favorable and resulted in a low incidence (<10%) of severe non-hematologic adverse events. In the current study, in which oxaliplatin was administered at 120 mg/m2 every 3 weeks, grade 3 peripheral neuropathy was seen in only one patient. However, the cumulative dose of oxaliplatin delivered was low, with a median of six cycles per patient. Compliance with the treatment regimen was very good because relative dose intensity forpemetrexed and oxaliplatin was 94% and 93%, respectively. As CR, complete response; PR, partial response; SD, stable disease; PD, expected with pemetrexed-containing regimens, hematologic toxicity was more frequently noted. Grade 3/4 neutropeniaoccurred in 41% of patients but no patients experienced failure that was not considered by the investigator as related to neutropenic fever or infection. Grade 3/4 thrombocytopenia occurred in 11% of patients and grade 3 anemia occurred in11% of cases. These figures are consistent with the reported findings of a phase II trial assessing PEMOX in the first-linetherapy of colorectal cancer [21]. As in the previously published In a multicenter setting, we explored the efficacy and safety of study, the high toxicity observed in the current study may be the PEMOX regimen as a first-line therapy for AGC. Four related to the weekly examination of blood counts carried out complete responses and 12 partial responses occurred in 44 during the treatment period per protocol. Indeed, clinically assessable patients, with an ORR of 36%. The median TTP was significant hematologic toxic effects were infrequent and 6.2 months, and median survival was 10.8 months. These required dose reduction and treatment discontinuation in only results compare well with those from previously published 9% and 2% of the patients, respectively.
studies using different dose schedules of 5-FU/oxaliplatin, Since accrual of the current study, a meta-analysis has which reported RRs from 38% to 56%, and median TTP and indicated an advantage to three-drug regimens containing survival ranging from 5 to 7 months and 8 to 11 months, 5-FU, an anthracycline, and cisplatin in the management of respectively, in patients with untreated AGC [5–9]. As in these AGC [22]. Although the ECF regimen results to be better Table 4. Worst toxicity by patient and cycle aGraded according to National Cancer Institute—Common Toxicity Criteria, version 2.0.
tolerated among three-drug combinations, the addition of epirubicin to CF was never explored in a randomized trial.
In addition, intensive regimens may represent a meaningful This study was presented in part at the 31st European Society treatment option only for younger and fit patients [23].
for Medical Oncology Congress, Istanbul, Turkey, 29 A recent phase III study comparing DCF with CF demonstrated September to 3 October 2006. We would like to thank Dr a significant superiority of DCF in terms of ORR (37% Angela Denaro (Medical Oncology Unit 2, National Cancer versus 25%), TTP (5.6 versus 3.7 months), and survival (9.2 Institute, Milan) and Dr Stefania Mosconi (Department of versus 8.6 months) [2]. However, DCF was associated with Medical Oncology, Ospedali Riuniti, Bergamo) who a high incidence of severe toxicity, including neutropenia and participated in the study as investigators. We also thank Anne- diarrhea. More recently, in a Korean phase II study of Laure Michel (Statistical Department, Eli Lilly France) for a vitamin-supplemented combination of pemetrexed plus cisplatin, only modest activity (ORR of 26%) was seen in 50assessable patients with untreated AGC [24]. It is worth to note that the efficacy of pemetrexed–cisplatin doublet is 1. Van Cutsem E, Van de Velde C, Roth A et al. Expert opinion on management of consistent with that (ORR of 25%) seen for protracted infusion gastric and gastro-oesophageal junction adenocarcinoma on behalf of the of 5-FU plus cisplatin as reference treatment in three recently European Organisation for Research and treatment of Cancer reported phase III trials in gastric cancer [2, 20, 25].
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