Phase II Study on Pemetrexed-based Chemotherapy in Treating Patients with Metastatic Gastric Cancer not Responding to Prior Palliative Chemotherapy

PURPOSE
This study was to determine the efficacy and safety of pemetrexed based chemotherapy in treating patients with metastatic gastric cancer who failed to respond to first and (or) second line chemotherapy.


PATIENTS AND METHODS
Metastatic gastric cancer patients who failed first and (or) second line chemotherapy, were enrolled. All patients were recruited from Jiangsu Cancer Hospital and Research Institute, and were treated with pemetrexed 500 mg/m2 (intravenous; on day 1), and a platinum (or irinotecan) every 3 weeks until disease progression, or intolerable toxicity. Evaluation on efficacy was conducted after two cycles of chemotherapy using the Response Evaluation Criteria for Solid Tumors. Toxicity was recorded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.


RESULTS
From Jun 2011 to May 2013, 23 patients were enrolled. All eligible 23 patients completed at least 2 cycles of chemotherapy with pemetrexed based chemotherapy, and were evaluable. Their median age was 55 years (range 40 to 78 years). Seventeen patients were male and 6 female. Three patients (13%) achieved partial response, five patients (22%) stable, 15 patients (65%) with disease progression, and none with complete response. Grade 2 neutrophil suppression occurred in 4.3%, grade 3 in 13% of patients, and no grade 4 was reported. Thrombocytopenia was encountered as follows: 4.3% grade 2, 4.3% grade 3 and 4.3% grade 4. Incidence of anemia was 34.8% in grade 2, 8.7% grade 3 and 0% grade 4. Only 4.3% of patients required packed red blood cell infusion. Elevated transaminase were 4.3% in grade 2 and 0% in grade 3 or 4. Other toxicity included oral mucositis.


CONCLUSIONS
Pemetrexed based chemotherapy is mildly effective in treating patients with metastatic gastric cancer with tolerable toxicity.


Introduction
Gastric cancer remains one of the leading causes of cancer death worldwide (Parkin et al., 2002).Patients suffering from advanced gastric cancer (AGC) remain a therapeutic challenge for medical oncologists.Randomized trials proved that palliative chemotherapy brings survival benefits over best supportive care for metastatic gastric cancer (Wagner et al., 2010).Despite increasing evidence that appropriate management for fit patients is chemotherapy, no combination is considered as a standard of care.Active chemotherapeutic agents in first line chemotherapy for advanced gastric cancer include 5-fluorouracil, cisplatin, and anthracyclines (Ohtsu, 2008).New generation agents, including taxanes, ironotecan, oxaliplatin and pemetrexed are reported to be active in treating patients with gastric cancer (Pozzo et al., 2008).The response rate of above-mentioned single agent is around 10 to 25%, with significant toxicities.

Phase II Study on Pemetrexed-based Chemotherapy in Treating
Patients with Metastatic Gastric Cancer not Responding to Prior Palliative Chemotherapy Guo-Li Wei 1,2& , Xin-En Huang 1& *, Jie-Ge Huo 2 *, Xiao-Ning Wang 2 , Jin-Hai Tang 3 * Therefore, it is urgent to develop effective regimens with acceptable toxicity profiles, and patient convenience, as well as improving quality of life for these patients (Ajani, 2005).
New multitargeted antifolate pemetrexed is suggested to have an important advantage compared with prolonged 5-FU schedules in that it is administered via a single short injection (Celio et al., 2009).Pemetrexed demonstrated activity in a variety of tumor types based on previous reports, including non-small cell lung cancer, malignant pleural mesothelioma, pancreas, colorectal, gastric, bladder, breast, head and neck cancers (Martin, 2006;Bajetta et al., 2003).Pemetrexed is reported to be more active than 5-FU against several human gastric cancer cell lines (Kim et al., 2005).
Thus we conduct this phase II trail to study the clinical efficacy and tolerability of pemetrexed in treating patients with metastatic gastric cancer who failed to respond to first and (or) second line chemotherapy.

Patient eligibility
Eligible patients should be histologically confirmed adenocarcinoma of the stomach or gastro-esophageal junction with clinical evidence of metastatic disease, and have received prior systemic chemotherapy or radiation therapy for gastric cancer.Other eligible criteria include: age≥18 years; adequate bone marrow (platelets≥100×10 9 cells/l, absolute neutrophil count≥1.5×10 9 cells/l), hepatic (total bilirubin ≤ 2×the upper limit of normal;aspartate transaminase ≤ 3×the upper limit of normal or ≤ 5× the upper limit of normal if metastatic disease was present in the liver) and calculated creatinine clearance, ≥ 45 ml/ min, using the modified Cockcroft and Gault calculated creatinine clearance formula; a life expectancy of ≥ 3 months; sign an informed consent before chemotherapy.Complete patient histories, physical examinations, complete blood cell counts, chemistries (aspartate aminotransferase, total bilirubin, creatinine, albumin), calculated creatinine clearance were performed at baseline prior to each course of treatment.Complete blood cell count was repeated weekly.Radiological studies (roentgenograms,computed axial tomographic scans or magnetic resonance imaging) were performed at baseline and after every two cycles of therapy to assess tumor response.CR was defined as complete disappearance of all measurable disease.Partial response (PR) was defined as at least 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions.Progression was defined as 50% increase or an increase of 10 cm 2 (whichever is smaller) in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) or appearance of any new lesion, or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).Stable disease (SD) was documented when there was persistence of disease without meeting the criteria for progression, PR or CR.

Treatment
Pemetrexed 500 mg/m 2 was given intravenously on day 1, premedication was conducted, and repeated every 3 weeks: 400 μg of folic acid was given orally daily and 1000 μg of vitamin B12 was given intramuscularly every 9 weeks starting 7 days prior to the first dose and until 3 weeks after the last dose of pemetrexed; 4.5 mg of dexamethasone was given orally every 12 h on the day before, day of and the day after pemetrexed.Antiemetics were given with chemotherapy on days 1. Colony-stimulating factors were not used prophylactically to prevent granulocytopenia.Treatment continued until disease progression, unacceptable toxicities.All toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (version2.0)(National Cancer Institute, 1998).

Patients
A total of 23 patients were enrolled from Jun 2011 to May 2013.All patients received at least one systemic chemotherapy.Twenty-one patients had adenocarcinoma of the stomach and two cases were diagnosed with adenocarcinoma of the gastro-esophageal junction.Fourteen patients received pemetrexed based combination therapy as second line, 6 as third, and 3 as 4th line chemotherapy.General characteristics of patients were listed in Table 1.

Toxicity
Without prophylactic colony-stimulating factors support, 4.3% of patients had absolute neutrophil count nadir values constituting grade 2 toxicity, 13% had grade 3 toxicity, no one had grade 4 toxicity.Anemia occurred with incidences of 34% in grade2, 8.7% in grade 3 and 0% in grade 4.Only 4.3% of patients required packed red blood cell transfusion.Thrombocytopenia was 4.3% in grade 2, 0% in grade 3 and 4.3% in grade 4. One patient (4.3%) required packed platelet transfusion.Bilirubin abnormal incidence was 8.7% in grad 2, 0% in grad 3 and 4. No Creatinine changed abnormally.Other toxicities include elevated transaminase, oral mucositis and skin rash.No neurological , renal and ototoxic adverse reaction were recorded (Table 3).

Discussion
Gastric cancer is the second most common cause of tumor-related death worldwide (Parkin et al., 2001).Fluorouracil (5-FU) remains the most widely used chemotherapeutic agent for patients with advanced gastric cancer, with a response rate of 20% (Karpeh et al., 2001).However, patients with metastatic gastric cancer are associated with poorer prognosis compared with those with locally advanced disease (Ross et al , 2002).At present, no standard therapy is established when patients failed to response to fluorouracil based chemotherapy.Pemetrexed is a recently developed antifolate agent with a favorable toxicity profile, and could be well tolerated in patients who were treated with third-or further-line treatment (Pozzo et al., 2008).Although activity of pemetrexed against breast, gastric, pancreatic and colorectal adenocarcinoma cell lines was reported (Adjei, 2004), only several phase I or II studies containing pemetrexed were conducted for patients with gastric cancer, with a response rate ranging from 21% to 36% (Celio et al., 2002;Bajetta1 et al., 2003;Kim, 2008;Celio et al., 2009;Chen, 2010).In this study, all patients were staged IV and failed after treatment with fluorouracil based chemotherapy.There are 12 (61%) patients received pemetrexed based combination therapy as second line, 6 (26%) patients as third line , and 3 (13%) patients as 4 lines.Overall, Three patients (13% , two as second line and one as third line ) achieved PR, while five patients (22%) remained stable, progression of disease, with no completer emission, RR was 13%, DCR 35%.Toxicity of pemetrexed based combination therapy was mild and resulted in a low incidence of severe adverse events (< 5%).Main toxicity was myelosuppressionin in this trial.Three to 4 grade neutropenia, anemia and thrombocytopenia were 13%, 8.7% and 4.3% respectively.
Leukocyte and platelet returned to normal level after treatment with colony-stimulating factor, interleukin 11 and recombinant human thrombopoietin.
In conclusion, our study provides a treatment option for patients with metastatic gastric cancer who failed after at least one chemotherapy.Pemetrexed based chemotherapy is mildly effective in this setting, with tolerable toxicities.However, we should get more evidence to know which is the best combination with pemetrexed before further phase III studies.