despite the declining incidence of gastric cancer in western countries , gastric cancer is the most frequently diagnosed cancer worldwide , and is one of the main causes of cancer deaths . in patients with advanced gastric cancer with distant metastasis or recurrence , systemic chemotherapy has been recommended as standard treatment , and the prolongation of survival or increase in the quality of life is well - established . however , patients with advanced gastric cancer with distant metastasis or recurrence remain incurable , and these patients have a median survival of only 7 - 13 months , despite receiving chemotherapy . also , first - line standard chemotherapy regimens have not been defined for patients with advanced gastric cancer . cisplatin - based regimens have demonstrated superior efficacy compared to platinum - free regiments , although cisplatin - based regimens have significant toxicity . oxaliplatin is a third generation platinum compound with a lack of cross - drug resistance with cisplatin , a synergistic effect with 5-fluorouracil ( 5-fu ) , and a satisfactory safety profile compared to cisplatin [ 6 - 9 ] . moreover , many adducts of oxaliplatin appear to be more effective in inhibiting dna synthesis than adducts of cisplatin [ 10 - 12 ] . two phase iii trials have directly compared oxaliplatin - based versus cisplatin - based regimens , both of which have concluded that oxaliplatin is at least as effective as cisplatin , and has a lower toxicity profile , except neurotoxicity , in combination regimens for patients with advanced gastric cancer . in several phase ii studies involving the treatment of advanced gastric cancer , various combinations of oxaliplatin , 5-fu , and folinic acid ( fa ) , as first- or second - line treatments , however , the optimal dose and schedule of combination oxaliplatin , 5-fu , and fa were not established . the aim of this retrospective study was to report the efficacy and toxicity of a biweekly protocol of oxaliplatin ( 100 mg / m ) combined with 5-fu ( 2,400 mg / m ; 46-hour continuous infusion ) , and fa ( 200 mg / m ) as first - line treatment on response , survival , and toxicity rates of metastatic and recurrent gastric cancer in korean patients . the eligibility criteria were as follows : 1 ) histologically - confirmed metastatic or recurrent adenocarcinoma of the stomach and 18 years of age ; 2 ) no previous chemotherapy , except post - operative adjuvant chemotherapy or chemoradiation that was received > 6 months previously ; 3 ) an eastern cooperative oncology group ( ecog ) performance status of 0 - 2 ; 4 ) no serious or uncontrolled concurrent medical illness ; 5 ) at least one measurable lesion ; and 6 ) adequate baseline hematologic function ( absolute neutrophil count [ anc]1.510/l , platelet count10010/l ) , adequate hepatic function ( serum bilirubin1.25upper normal limit [ unl ] , serum aspartate aminotransferase , alanine aminotransferase2.5unl , serum alkaline phosphatase5.0unl ) , and adequate renal function ( serum creatinine1.5 mg / dl ) . the exclusion criteria were as follows : 1 ) preexisting peripheral neuropathy ; 2 ) concurrent or prior malignancy , except curative resection of cervical carcinoma in situ or squamous cell carcinoma of the skin ; 3 ) active infection ; and 4 ) concurrent treatments that interfered with the evaluation of the study . oxaliplatin ( 100 mg / m ) and fa ( 200 mg / m ) were given as a 2-hour intravenous infusion followed by 5-fu ( 2,400 mg / m ) as a 46-hour continuous infusion every 2 weeks . treatment was continued until disease progression , unacceptable toxicity , patient refusal , or at the discretion of the physician . each cycle was started if the anc and platelet count on the day of treatment were > 1.510/l and > 10010/l , respectively . in the case of toxicity grade 3 , except alopecia , chemotherapy was delayed 1 week , then restarted after full recovery . a reduction of 25% in all drug doses was applied to grade 3/4 thrombocytopenia or febrile neutropenia , grade 4 neutropenia , and grade 3/4 non - hematologic toxicity in the previous cycle of chemotherapy . the response to treatment was assessed according to the response evaluation criteria in solid tumors ( recist ) criteria ( ver . computed tomography ( ct ) scans of the measurable lesions were performed within 2 weeks prior to treatment . after every 4th cycle of chemotherapy , ct scans were performed to determine the response of the disease , or sooner if there was evidence of any clinical deterioration . complete blood cell counts with differentials and serum biochemistries were repeated prior to the start of each chemotherapy cycle , and the toxicity was graded according to the national cancer institute common toxicity criteria ( nci - ctc , ver.3.0 ) . overall survival ( os ) was calculated from the first day of chemotherapy to the date of death . time - to - progression ( ttp ) was calculated from the first day of chemotherapy to the date of disease progression . the kaplan - meier method was used to analyze the ttp and os , and the 95% confidence interval ( ci ) for the median time - to - event was computed . the eligibility criteria were as follows : 1 ) histologically - confirmed metastatic or recurrent adenocarcinoma of the stomach and 18 years of age ; 2 ) no previous chemotherapy , except post - operative adjuvant chemotherapy or chemoradiation that was received > 6 months previously ; 3 ) an eastern cooperative oncology group ( ecog ) performance status of 0 - 2 ; 4 ) no serious or uncontrolled concurrent medical illness ; 5 ) at least one measurable lesion ; and 6 ) adequate baseline hematologic function ( absolute neutrophil count [ anc]1.510/l , platelet count10010/l ) , adequate hepatic function ( serum bilirubin1.25upper normal limit [ unl ] , serum aspartate aminotransferase , alanine aminotransferase2.5unl , serum alkaline phosphatase5.0unl ) , and adequate renal function ( serum creatinine1.5 mg / dl ) . the exclusion criteria were as follows : 1 ) preexisting peripheral neuropathy ; 2 ) concurrent or prior malignancy , except curative resection of cervical carcinoma in situ or squamous cell carcinoma of the skin ; 3 ) active infection ; and 4 ) concurrent treatments that interfered with the evaluation of the study . oxaliplatin ( 100 mg / m ) and fa ( 200 mg / m ) were given as a 2-hour intravenous infusion followed by 5-fu ( 2,400 mg / m ) as a 46-hour continuous infusion every 2 weeks . treatment was continued until disease progression , unacceptable toxicity , patient refusal , or at the discretion of the physician . each cycle was started if the anc and platelet count on the day of treatment were > 1.510/l and > 10010/l , respectively . in the case of toxicity grade 3 , except alopecia , chemotherapy was delayed 1 week , then restarted after full recovery . a reduction of 25% in all drug doses was applied to grade 3/4 thrombocytopenia or febrile neutropenia , grade 4 neutropenia , and grade 3/4 non - hematologic toxicity in the previous cycle of chemotherapy . oxaliplatin ( 100 mg / m ) and fa ( 200 mg / m ) were given as a 2-hour intravenous infusion followed by 5-fu ( 2,400 mg / m ) as a 46-hour continuous infusion every 2 weeks . treatment was continued until disease progression , unacceptable toxicity , patient refusal , or at the discretion of the physician . each cycle was started if the anc and platelet count on the day of treatment were > 1.510/l and > 10010/l , respectively . in the case of toxicity grade 3 , except alopecia , chemotherapy was delayed 1 week , then restarted after full recovery . a reduction of 25% in all drug doses was applied to grade 3/4 thrombocytopenia or febrile neutropenia , grade 4 neutropenia , and grade 3/4 non - hematologic toxicity in the previous cycle of chemotherapy . the response to treatment was assessed according to the response evaluation criteria in solid tumors ( recist ) criteria ( ver . computed tomography ( ct ) scans of the measurable lesions were performed within 2 weeks prior to treatment . after every 4th cycle of chemotherapy , ct scans were performed to determine the response of the disease , or sooner if there was evidence of any clinical deterioration . complete blood cell counts with differentials and serum biochemistries were repeated prior to the start of each chemotherapy cycle , and the toxicity was graded according to the national cancer institute common toxicity criteria ( nci - ctc , ver.3.0 ) . overall survival ( os ) was calculated from the first day of chemotherapy to the date of death . time - to - progression ( ttp ) was calculated from the first day of chemotherapy to the date of disease progression . the kaplan - meier method was used to analyze the ttp and os , and the 95% confidence interval ( ci ) for the median time - to - event was computed . between january 2006 and august 2009 , 39 patients with a median age of 62 years ( range , 38 to 78 years ) were retrospectively studied in seoul , bucheon , and cheonan soonchunhyang university hospitals . there were 22 men and 17 women , and 2 patients ( 5.1% ) had an ecog performance status of 2 . thirty - one patients ( 79.5% ) had primary metastatic disease and 8 patients ( 20.5% ) had recurrent disease . the metastasis involved two organs in 11 patients ( 28.2% ) and > 3 organs in 11 patients ( 28.2% ) . the majority of the patients ( 71.8% ) had 1 or 2 involved regions , and the common target lesion was a lymph node or the liver . thirty - two of the 39 patients were evaluable for response according to the recist criteria ( ver . the response was not assessable in 7 patients who were lost to follow - up ( n=3 ) , voluntary refusal for further treatment after 1 or 2 cycles ( n=2 ) , and death before the 4 cycles of chemotherapy ( n=2 ) . eleven patients ( 28.2% ) achieved a partial response , 14 patients ( 35.9% ) had stable disease , and 7 patients ( 17.9% ) had progressed during the course of treatment ( table 2 ) . treat analysis , the overall response rate ( orr ) and disease control rates were 28.2% ( 95% ci , 11.7 to 44.7% ) and 64.1% ( 95% ci , 49.9 to 78.3% ) , respectively . the median duration of follow - up was 20.1 months ( range , 2.1 to 63.0 months ) . the ttp and os were 4.3 months ( 95% ci , 2.0 to 6.5 months ) ( fig . 1 ) and 9.8 months ( 95% ci , 3.5 to 16.0 months ) ( fig . then , age ( 0 - 64 years vs.>65 years ) , gender , a history of surgery or chemotherapy , ecog performance status ( 0 - 1 vs. 2 ) , disease status before chemotherapy ( newly diagnosed vs. recurrent ) , and the number of metastases ( 0 - 2 vs.>3 ) were compared between the two groups . based on univariate analysis , the ecog performance status ( p=0.004 ) and the number of metastases ( p=0.033 ) only the ecog performance status was a significant factor affecting survival based on multivariate analysis ( hazard ratio , 0.134 ; p=0.043 ) . table 3 shows the summaries of the incidence of main toxicities . the major grade 3 or 4 hematologic toxicities per cycle were neutropenia ( 15.2% ) and thrombocytopenia ( 7.6% ) . the major non - hematologic toxicities per cycle were constipation ( 46.2% ) and nausea ( 41.9% ) . peripheral neuropathy per cycle occurred in 33.8% of the patients and all cases were grade 1 - 2 ; there were no treatment interruptions or discontinuations due to neuropathy . one patient ( 2.6% ) had acute renal failure after 1 treatment cycle , which required transient hemodialysis . the relative dose intensities of oxaliplatin and 5-fu were 87.4% and 86.2% of the planned doses , respectively . between january 2006 and august 2009 , 39 patients with a median age of 62 years ( range , 38 to 78 years ) were retrospectively studied in seoul , bucheon , and cheonan soonchunhyang university hospitals . there were 22 men and 17 women , and 2 patients ( 5.1% ) had an ecog performance status of 2 . thirty - one patients ( 79.5% ) had primary metastatic disease and 8 patients ( 20.5% ) had recurrent disease . the metastasis involved two organs in 11 patients ( 28.2% ) and > 3 organs in 11 patients ( 28.2% ) . the majority of the patients ( 71.8% ) had 1 or 2 involved regions , and the common target lesion was a lymph node or the liver . thirty - two of the 39 patients were evaluable for response according to the recist criteria ( ver . the response was not assessable in 7 patients who were lost to follow - up ( n=3 ) , voluntary refusal for further treatment after 1 or 2 cycles ( n=2 ) , and death before the 4 cycles of chemotherapy ( n=2 ) . eleven patients ( 28.2% ) achieved a partial response , 14 patients ( 35.9% ) had stable disease , and 7 patients ( 17.9% ) had progressed during the course of treatment ( table 2 ) . treat analysis , the overall response rate ( orr ) and disease control rates were 28.2% ( 95% ci , 11.7 to 44.7% ) and 64.1% ( 95% ci , 49.9 to 78.3% ) , respectively . the median duration of follow - up was 20.1 months ( range , 2.1 to 63.0 months ) . the ttp and os were 4.3 months ( 95% ci , 2.0 to 6.5 months ) ( fig . 1 ) and 9.8 months ( 95% ci , 3.5 to 16.0 months ) ( fig . then , age ( 0 - 64 years vs.>65 years ) , gender , a history of surgery or chemotherapy , ecog performance status ( 0 - 1 vs. 2 ) , disease status before chemotherapy ( newly diagnosed vs. recurrent ) , and the number of metastases ( 0 - 2 vs.>3 ) were compared between the two groups . based on univariate analysis , the ecog performance status ( p=0.004 ) and the number of metastases ( p=0.033 ) were significantly different between the two groups . only the ecog performance status was a significant factor affecting survival based on multivariate analysis ( hazard ratio , 0.134 ; p=0.043 ) . table 3 shows the summaries of the incidence of main toxicities . the major grade 3 or 4 hematologic toxicities per cycle were neutropenia ( 15.2% ) and thrombocytopenia ( 7.6% ) . the major non - hematologic toxicities per cycle were constipation ( 46.2% ) and nausea ( 41.9% ) . peripheral neuropathy per cycle occurred in 33.8% of the patients and all cases were grade 1 - 2 ; there were no treatment interruptions or discontinuations due to neuropathy . one patient ( 2.6% ) had acute renal failure after 1 treatment cycle , which required transient hemodialysis . the relative dose intensities of oxaliplatin and 5-fu were 87.4% and 86.2% of the planned doses , respectively . despite a large number of randomized trials , the best agent or optimal regimen for the first - line treatment of advanced gastric cancer has not been determined . a variety of different oxaliplatin combination regimens have been studied ( oxaliplatin plus 5-fu , epirubicin , or capecitabine ) in phase ii trials . also , several studies involving various combinations of oxaliplatin/5-fu / fa for treating advanced gastric cancer have been published ; these studies have shown consistent results regarding the activity of oxaliplatin combinations [ 15 - 19 ] . the range of ttp , median os , and orr of these trials were 4.3 - 6.2 and 7.3 - 9.6 months , and 26 - 45% , respectively . although data from randomized controlled phase iii trials have not been published , in practice various combinations of oxaliplatin/5-fu / fa are used for the treatment of advanced gastric cancer in korea . however , one prospective study involving oxaliplatin/5-fu / fa as first - line chemotherapy in korean patients with advanced gastric cancer has been conducted . in that study , all 37 patients were elderly ( > 65 years of age ) . the objective of our study was to assess the efficacy and toxicity of a biweekly combination of oxaliplatin ( 100 mg / m in a 2-hour infusion ) , fa ( 200 mg / m in a 2-hour infusion ) , and 5-fu ( 2,400 mg / m in a 46-hour continuous infusion ) as first - line treatment for treating younger patients with advanced gastric cancer in korea . although our study was retrospective , the results showed that the chemotherapy regimen was an effective and safe combination for advanced gastric cancer as first - line treatment in korea , as well as western countries . the os of 9.8 months was within the range of previous trials ( 7 - 12 months ) using platinum - containing and taxane- or irinotecan - based regimens . although survival is not a reliable point for evaluation of efficacy in a retrospective study , the median survival of 9.8 months in the current study compared favorably with previous studies . the treatment compliance for this regimen was good , with a dose adherence to both oxaliplatin and 5-fu of > 85% . owing to the patient selection bias , a comparison of the toxicity profiles in this study with other phase ii studies that used various oxaliplatin and 5-fu administration schedules is not relevant . compared with previous biweekly regimens [ 15 - 17 ] , the biweekly protocol in the current study used higher levels of oxaliplatin ( 100 mg / m vs. 85 - 100 mg / m ) , and lower levels of fa ( 200 mg / m vs. 400 - 500 mg / m ) and 5-fu ( 2.4 g / m vs. 2.4 - 3.0 g / m ) . in the current study , major grade 3/4 hematologic toxicity , including neutropenia ( 30.8% ) and thrombocytopenia ( 20.0% ) , was encountered . although we infused 5-fu continuously without bolus to reduce hematologic toxicity , the rates of grade 3/4 neutropenia and thrombocytopenia were relatively high compared with other studies . it is possible that the rate of hematologic toxicity reflected the relatively high dose of oxaliplatin ; however , to make such an assumption , more evidence should be provided , such as 85 mg / m vs. 100 mg / m of oxaliplatin in caucasian and asian populations . nevertheless , the toxicities were manageable . neurotoxicity is the most common side effect in an oxaliplatin - containing protocol , but there was no grade 3/4 neurotoxicity encountered during the current study , which may have been due to the relatively low cumulative dose of oxaliplatin ( median , 521 mg / m ) used in this setting ; indeed , neuropathy is particularly prevalent for cumulative doses > 540 mg / m . one female patient had acute renal failure after one treatment cycle requiring transient hemodialysis ; she had normal renal function before treatment and did not receive medications with renal toxicity . further , she declined continuation of treatment for voluntary withdrawal after one cycle . therefore , the investigator considered renal toxicity a possible untoward effect related to oxaliplatin . in the current study , diarrhea occurred in 6.7% of the cycles , but 46.2% of the cycles had associated constipation ( grade 1 or 2 ) . compared with the other oxaliplatin/5-fu / lv regimens studied in gastric cancer , the rate of constipation was high . it would be worthwhile to determine whether or not oxaliplatin would slow the intestinal transit time in asians . although our study was retrospective , biweekly combination chemotherapy with oxaliplatin , 5-fu , and fa was well - tolerated and active as first - line treatment in patients with metastatic or recurrent gastric cancer .