Journal of Chemotherapy
Vol. 20 - n. 6 (744-748) - 2008
? E.S.I.F.T. srl - Firenze ISSN 1120-009X
INTRODUCTION
Gastric cancer is the second leading cause of can-cer death worldwide. It is expected that nearly 930,000 people per year will be diagnosed with gas-tric cancer, and that 700,000 will die from this disease 1
. In contrast to resectable cancer, where surgery is po-tentially curative, the majority of patients with gastric cancer have advanced disease at presentation. Ad-vanced gastric cancer patients have a poor prognosis with a median survival time, if untreated, of 90-150days. Systemic chemotherapy is widely accepted as palliative treatment, leading to improvement in the quality of life, and prolonged survival 2,3.
The biweekly 5-florouracil and leucovorin (LV5FU2) regimen associated with oxaliplatin (FOL-
FOX) is active in advanced gastric cancer patients with response rates of 38%–45%,a median overall survival of 215-340 days, and manageable toxic side-effects 4-6
. Paclitaxel monotherapy is also active in advanced gastric cancer patients with response rates of 11%–28% 7-9. Given these data, this phase II study was performed to evaluate the efficacy and toxicity of a reg-imen combining paclitaxel with FOLFOX chemother-apy, for unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma.
PATIENTS AND METHODS
Patient eligibility
Patients with advanced, unresectable, histologically confirmed adenocarcinoma of the gastric or gastroe-
A Phase II Study of 5-Fluorouracil/Leucovorin in Combination with Paclitaxel and Oxaliplatin as First-Line Treatment for Patients with Advanced Gastric Cancer
RONG-BO LIN - NAN-FENG FAN - ZENG-QING GUO - XIAO-JIE WANG - JIE LIU - LING CHEN
Department of Medical Oncology, Fujian Provincial Tumor Hospital, Fuzhou, 350014, P.R. China.
Correspondence: Dr. Nan-feng Fan, Department of Medical Oncology, Fujian Provincial Tumor Hospital, Fuzhou,
350014, P.R. China. Phone: +86137********. E-mail: fannanfeng8256@https://www.doczj.com/doc/596338046.html,
Summary
The objective of this study was to evaluate the efficacy and safety of the POF reg-imen (biweekly 5-florouracil/leucovorin combined with paclitaxel and oxaliplatin) as first-line treatment for advanced gastric cancer (AGC). Twenty-seven previously un-treated patients with advanced adenocarcinoma of the gastric or gastroesophageal junction were eligible for this study. The chemotherapy regimen consisted of a 3-hour infusion of paclitaxel (135 mg/m 2) followed by oxaliplatin (85 mg/m 2) and leucovorin (400 mg/m 2), administered simultaneously over a 2-hour infusion period, followed by an infusion of 5-florouracil (2400 mg/m 2) over a 46-hour period. Twenty-one patients had measurable lesions: four complete responses, eight partial responses and seven stable diseases. At a median follow-up of 610 days, median survival was 348 days. Fre-quent grade 3 to 4 toxicities were: neutropenia (29.6%), stomatitis (7.4%), nausea (7.4%), vomiting (7.4%), hepatic dysfunction (3.7%), and fatigue (18.5%). No treat-ment-related deaths occurred. The POF regimen appears to be efficacious and is well tolerated in patients with AGC.
Key words: Gastric cancer, paclitaxel, oxaliplatin, 5-fluorouracil, leucovorin,chemotherapy
REPRINT
A PHASE II STUDY OF 5-FLUOROURACIL/LEUCOVORIN IN COMBINATION WITH PACLITAXEL AND OXALIPLATIN AS A FIRST-LINE TREATMENT (745)
sophageal junction were assessed for eligibility. Eligi-bility criteria for inclusion in the study consisted of: 1) age ≥18 years; 2) Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2; 3) no pre-vious treatment with chemotherapy or radiation ther-apy,and 4) the following laboratory values - neutrophil count >1000/mm3,platelet count >750,000/mm3; serum creatinine ≤1.5 × upper limit of normal, alanine aminotransferase and aspartate aminotransferase ≤2.5× upper limit of normal (≤5 × upper limit of normal in the presence of liver metastases), and total bilirubin ≤1.5 × upper limit of normal. Patients who received adjuvant therapy were eligible provided >6 months had elapsed between the end of adjuvant therapy and reg-istration for the study. Patients with prior chemother-apy for advanced cancer were not included.Patients were also considered ineligible if they satisfied any of the following criteria: concurrent cancer; neuropathy; brain or leptomeningeal involvement. All patients pro-vided written informed consent for this study.
Treatment
The chemotherapy regimen consisted of a 3-hour infusion of paclitaxel (135 mg/m2)followed by oxali-platin (85 mg/m2)and leucovorin(400 mg/m2), ad-ministered simultaneously over a 2-hour infusion period.Subsequently,a 46-hour infusion of 5-flor-ouracil(2400mg/m2) was administered using an am-bulatory pump. Treatment continued until disease progression, unacceptable toxicity, or patient choice. All patients received a standard supportive regimen in-cluding oral corticosteroids, antihistamines and anti-emetics. No prophylactic administration of hematopoietic growth factors was allowed. With the eventual failure of this combination chemotherapy, a second-line chemotherapy was recommended to all pa-tients if their performance status was preserved.
Efficacy and toxicity assessment
Routine evaluation of patients was carried out on a weekly basis during therapy. These evaluations in-cluded a physical examination, vital signs, ECOG PS, laboratory hematological and serum chemistry, and the recording of adverse events. The response evaluation of the tumor to therapy was based on computed to-mography or magnetic resonance scan. Patients were assessed for response if they received at least two courses of therapy. Tumor response was evaluated ac-cording to the response evaluation criteria in solid tu-mors (RECIST). Time to progression was measured from the day of initial treatment to the first evidence of progression or death. Survival was defined from the date of initial treatment to death from any cause. Tox-icity was graded according to the National Cancer In-stitute Common Toxicity Criteria Version 3.0.
Statistics
The median probability of survival was estimated by the Kaplan–Meier method.Confidence intervals for response rates were calculated using methods for the exact binomial confidence interval (CI). Statistical analysis was performed using SPSS13.0 statistical soft-ware (SPSS Inc, Chicago, IL).
RESULTS
Patient population
A total of 27 patients with advanced, unresectable, gastric or gastroesophageal junction adenocarcinoma were enrolled in this study at our center between Sep-tember 19, 2005 and December 31, 2006. The pa-tient characteristics are listed in Table 1. All 27 enrolled patients were evaluated for safety and overall survival calculations and 21were assessable for re-sponse. Six patients with unmeasurable lesions were not assessable for response. Five patients (18.5%) had received prior adjuvant chemotherapy.
T ABLE1-Patient characteristics. Characteristic N. patients%
Sex
Male2177.8
Female622.2 Age years
Median57
Range26-77
ECOG PS
0933.3
11244.4
2622.2 Histology
Adenocarcinoma
G1/21 3.7
G3/42177.8
Unknown518.5 Primary tumor site
Gastric2074.1
Esophagogastric junction725.9
N. organs involved
11451.9
21140.7
>227.4 Organs involved
Lymph nodes1980.4
Peritoneum1037.0
Liver622.2
Lung311.1
Other*311.1
*Ovaries, bone, adrenal gland, skin
746RONG-BO LIN - NAN-FENG FAN - ZENG-QING GUO - XIAO-JIE WANG - JIE LIU - LING CHEN
Response
The data on treatment response are presented in Table 2.Of the 21 assessable patients, 4(19.0%) had complete responses and 8 (38.1%) had partial re-sponses, giving an overall best response rate of 57.1% (95% CI, 36.0% to 78.3%). Seven patients (33.3%) maintained a stable disease state and 2patients (9.5%) showed disease progression. The disease control (complete response plus partial response plus stable disease) was 90.5%. The objective responses were three complete responses, three partial responses, and two stable diseases in the 9 patients with one organ in-volved, while one complete response, five partial re-sponses, and five stable diseases in the 12 patients with two or more organs involved. The number of organs involved did not affect the treatment response.
T ABLE2-Overall response.
Parameter N. patients % Complete response419.0 Partial response838.1 Stable disease733.3 Progressive disease29.5 Overall response rate(95% CI)1257.1
(36.0% to 78.3%)
At a median follow-up of 610 days, the median survival was 348 days and curves, estimated by the Ka-plan–Meier method from the first day of treatment, are shown in Figure 1. Three patients (one complete re-sponse and two partial responses) with unresectable lo-cally advanced disease were submitted to surgical removal of residual disease. At the cutoff date of De-cember 31, 2007, their survivals were 197, 618 and 435+ days, respectively. One patient with liver metas-tases achieved a partial response after 4 cycles of chemotherapy and underwent radiotherapy for liver metastases. This patient’s time to progression was 273 days and survival was 329 days. Two patients obtained a complete response after 8 cycles of chemotherapy and transfusion of irradiated allogeneic blood mononu-clear cells. One patient remained alive without evi-dence of disease (survival was 744+ days). In another patient, time to progression was 340 days and survival was 536+ days.
Five (23.8%) patients received second-line treat-ment;one docetaxel plus epirubicin, and four 5-fluo-rouracil/leucovorin plus irinotecan.
Safety
Twenty-seven patients received a total of 172 treat-ment cycles. The median number of cycles adminis-tered was six (range, two to twelve cycles). Of these patients, 66.7% received at least six cycles and 29.6%received at least eight cycles. The median cumulative doses were 810 mg/m2(range, 270 to 1,620 mg/m2) for paclitaxel, 510 mg/m2(range, 170 to 1,020 mg/m2) for oxaliplatin, 14,400 mg/m2(range, 2,400 to 28,800 mg/m2) for 5-fluorouracil, and 2,400mg/m2(range 800 to 4,800mg/m2) for leucovorin. No reduction in treatment doses was al-lowed. There were no treatment-related deaths.
F IGURE1- Kaplan–Meier plot for overall survival
Toxicities observed during the treatment are listed in Table 3. The most common toxic effects were ane-mia, nausea, peripheral neurotoxicity, fatigue, hyper-transaminasemia, vomiting, stomatitis, neutropenia, diarrhea, and thrombocytopenia.No febrile neutrope-nia or neutropenic infection was reported. The most common grade 3-4 non-hematological toxic effects were fatigue(18.5%), peripheral neurotoxicity (14.8%), stomatitis (7.4%), nausea (7.4%), and vomit-ing (7.4%).
DISCUSSION
Docetaxel and cisplatin plus 5-florouracil(DCF)has been reported to be superior to cisplatin and 5-flor-ouracil(CF)for treatment of advanced gastric cancer 10. The benefit of DCF however is small and toxicity high. Therefore this regimen has not been generally ac-cepted as the standard treatment11-13
The POF regimen,consisting of a three-drug com-bination, is a modified DCF regimen. Both paclitaxel and docetaxel show efficacy against advanced gastric cancer. Park et al.14reported the results of a ran-domized phase II study comparing a combination of paclitaxel plus 5-fluorouracil (PF) with docetaxel plus 5-fluorouracil (DF) as first-line chemotherapy in ad-vanced gastric cancer patients. In that
study, PF and
A PHASE II STUDY OF 5-FLUOROURACIL/LEUCOVORIN IN COMBINATION WITH PACLITAXEL AND OXALIPLATIN AS A FIRST-LINE TREATMENT (747)
DF provided no significant differences in terms of re-sponse rate, failure-free and overall survival. Dose re-duction was required more frequently in the DF group, being 9 and 19%, respectively (P <0.01). In addition, PF was associated with, although statistically insignifi-cant, substantially less grade 3 or 4 toxicity than DF (68 versus 85%; P = 0.09). Therefore, in our study, paclitaxel was considered a treatment alternative for docetaxel.
In some recently reported clinical trials,the third generation platinum compound,oxaliplatin,proved to be equal, if not better, than cisplatin with regard to ef-ficacy. Moreover, oxalipatin was associated with slightly reduced toxicity and better tolerability com-pared to cisplatin15,16. Therefore, oxaliplatin was substituted for cisplatin in the POF regimen. In our study, we administered 5-fluorouracil with the bio-chemical modulation of leucovorin as a 46-h continu-ous infusion without any bolus, according to the simplified de Gramont schedule.Such a protocol enabled us to reduce the related toxic effects, thus fa-voring its combination with optimal doses of paclitaxel and oxaliplatin. According to Gompertzian kinetics, chemotherapy schedules as applied every2 weeks have been shown to improve efficacy as compared with every-3-week schedules. These theoretical models were confirmed as tested in different tumors17,18. Therefore, chemotherapy cycles were administered every 2 weeks with the POF regimen as opposed to the3-weekly schedule used with DCF. Furthermore, Gu et al. 19showed the enhanced antitumor effect of paclitaxel when used with oxaliplatin in MKN-28 and MKN-45 gastric cancer cell lines.
Our study showed a high response rate (57.1%) and an acceptable median overall survival of 348 days in advanced gastric cancer patients and POF may re-sult in fewer side effects than DCF.
Both paclitaxel and oxaliplatin cause cumulative peripheral neuropathy20-24. In this study, the toxicity profile was moderate with grade 1 and 2 peripheral neuropathy. Grade 3 neuropathy was observed in 4 patients (14.8%).In our study, the low median cumu-lative doses of oxaliplatin (510 mg/m2) are probably related to the low incidence of grade 3 neuropathy. The importance of oxaliplatin in treatment efficacy makes early discontinuation or dose reduction due to neurotoxicity undesirable because patients may continue to be actively responsive to POF. The stop-and-go concept has been utilized in colorectal can-cer and may deserve further investigation in gastric cancer23.
In conclusion, the POF regimen appears to be ef-fective and is well tolerated by advanced gastric cancer patients. Currently, this regimen is being tested in phase III trials in patients with advanced gastric can-cer.
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Leukopenia1244.4622.2 Neutropenia1037.0829.6 Anemia2281.5311.1 Thrombocytopenia622.21 3.7 Gastrointestinal toxicity
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748RONG-BO LIN - NAN-FENG FAN - ZENG-QING GUO - XIAO-JIE WANG - JIE LIU - LING CHEN
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