most patients with small cell lung cancer ( sclc ) relapse within a year of initial therapy , and many are candidates for second - line treatment .
although many patients are in excellent physical condition at the time of relapse , few drugs or drug combinations are capable of achieving tumor regression in this setting .
patients with sensitive relapse may respond to a number of agents including topotecan , irinotecan , vinorelbine , paclitaxel , and gemcitabine [ 1 - 4 ] .
topotecan is the best - documented second - line therapy for previouslytreated sclc , although treatment outcomes have been disappointing .
topotecan produces an 18% response in patients with sensitive relapse , and in refractory patients , the response is less than 10% .
a topotecan / cisplatin doublet showed a higher response rate in patients with sensitive relapse although median survival times were similar to those obtained with topotecan alone .
for some patients with sensitive relapse , re - induction with the same regimen or topotecan might be considered , but for patients with refractory relapse , no regimen is a standard option .
thus , patients with good performance status are candidates for clinical trials for further treatment . as a single agent
, paclitaxel produces a response rate of 27% in sclc patients with sensitive relapse and a response rate of 20% in those with refractory relapse .
gemcitabine has a response rate of 16% in sclc patients with sensitive relapse and a response rate of 6%-13% in those with resistant relapse . because of their single - agent activity , different mechanism of action , non - overlapping toxicities , in vitro synergy , and beneficial pharmacologic interaction , the use of a combination of paclitaxel and gemcitabine is an attractive option .
paclitaxel significantly decreases the systemic clearance and volume of distribution of gemcitabine , and significantly increased steady - state concentrations of gemcitabine .
interpatient and intrapatient variability in gemcitabine pharmacokinetics was not observed when gemcitabine was administered in combination with paclitaxel in non - small cell lung cancer ( nsclc ) patients .
some phase ii trials of first - line gemcitabine plus paclitaxel in nsclc patients showed encouraging response rates of 41%-53% [ 12 - 14 ] .
these combination chemotherapies , in which paclitaxel was administered every 3 weeks , were associated with substantial toxicity , and grade 3 - 4 neutropenia developed in 70%-80% of patients .
weekly paclitaxel treatment has an efficacy comparable to that of the every-3-weekly paclitaxel but with less myelosuppression and neurotoxicity . based on these studies , we selected a combination of weekly paclitaxel ( 80 mg / m ) and gemcitabine ( 1,000 mg / m ) and conducted a phase ii study to evaluate the efficacy and safety of this combination in patients with sclc who have relapsed or failed to respond to first - line platinum - based therapy .
eligibility in the study required histologically- or cytologically - confirmed sclc that progressed during or after first - line chemotherapy or chemoradiotherapy .
patients needed to have measurable disease according to the response evaluation criteria in solid tumors ( recist ) .
additional criteria were as follows : patients must ( 1 ) be at least 18 years old ; ( 2 ) have an eastern cooperative oncology group performance status ( ecog ps ) of 0 to 2 ; ( 3 ) have not had prior radiotherapy on measurable lesions ( but previous surgery and/or chest radiotherapy for the primary lesion was allowed ) ; ( 4 ) have had a minimum of 28 days since any prior chemotherapy or radiation before study entry ; and ( 5 ) have adequate bone marrow , hepatic , and renal functions , defined as a white blood cell count  3,500/mm , absolute neutrophil count ( anc )  1,500/mm , platelets  100,000/mm , alanine aminotransferase or aspartate aminotransferase  2.5 times the upper normal limit , serum bilirubin < 1.5 times the upper normal limit , and serum creatinine  1.5 mg / dl .
patients were excluded if there was severe comorbidity such as a myocardial infarction within the preceding six months , symptomatic heart disease ( including unstable angina , congestive heart failure , or uncontrolled arrhythmia ) , or serious concomitant infection , including post obstructive pneumonia .
the presence of central nervous system ( cns ) metastases , however , was not an exclusion criterion , provided that cns symptoms were absent or sufficiently minor to be well - controlled with corticosteroids . written informed consent approved by the institutional review board of the national cancer center was obtained from all patients prior to entering the study .
this study was registered with clinicaltrials.gov ( identifier : nct00453 167 ) . a complete history and physical examination , including documentation of concomitant medications and performance status , standard laboratory studies , and an electrocardiogram , was performed within 14 days prior to study entry .
chest x - ray , computed tomography scans of the chest including the upper abdomen , magnetic resonance imaging of the brain , and a radionuclide bone scan were performed within 4 weeks prior to study entry .
complete blood cell counts and chemistry were performed on days 1 and 8 of each cycle .
paclitaxel ( padexol , seoul , korea ) and gemcitabine ( geroam , seoul , korea ) were administered to patients .
treatment consisted of 80 mg / m paclitaxel and 1,000 mg / m gemcitabine by intravenous infusion on days 1 and 8 every 3 weeks until disease progression .
paclitaxel was given first as a 60-minute intravenous infusion , immediately followed by a 30-minute gemcitabine intravenously .
premedication consisted of dexamethasone ( 10 - 20 mg intravenously ) , pheniramine maleate ( 45.5 mg intravenously ) , and famotidine ( 20 mg intravenously ) before paclitaxel infusion .
during the course of chemotherapy , paclitaxel doses were decreased by 15 mg / m for grade 4 hematologic toxicities or grade 3 or 4 non - hematologic toxicities .
gemcitabine doses were decreased by 20% for grade 4 hematologic toxicities or grade 3 or 4 non - hematologic toxicities .
the primary objective of this study was to estimate the overall response rate of paclitaxel and gemcitabine as second - line chemotherapy in patients with metastatic or recurrent sclc .
the secondary objectives were to estimate the time to progression ( ttp ) and overall survival ( os ) .
with 80% power and a 5% one - sided type i error , 18 patients were needed in the first stage , and 33 patients were needed in total . at the first stage ,
if there were five or fewer responses out of the initial 18 patients , the study would conclude that the anticipated response rate is less than 20% and would terminate .
otherwise , accrual would continue to a full sample of 33 assessable patients . at the second stage ,
at least 11 objective responses among 33 patients were required for this regimen to be regarded as worthy of further investigation .
the response rate of the treatment was calculated as the ratio of the number of complete and partial responders to the total number of evaluable patients . a 95% confidence interval for the response rate
the toxicity profile was estimated as the ratio of the number of occurrence to the total number of evaluable patients .
the os was defined as the period of time from the first day of treatment to death from any cause .
patients still alive were censored at the last day on which they were known to be alive .
the ttp was defined from the first day of treatment to the date that disease progression was assessed .
the duration of response for all responders was defined as the period of time from the date of the first response , i.e. , either partial response or complete response ( whichever occurred first ) , to the date of disease progression .
eligibility in the study required histologically- or cytologically - confirmed sclc that progressed during or after first - line chemotherapy or chemoradiotherapy .
patients needed to have measurable disease according to the response evaluation criteria in solid tumors ( recist ) .
additional criteria were as follows : patients must ( 1 ) be at least 18 years old ; ( 2 ) have an eastern cooperative oncology group performance status ( ecog ps ) of 0 to 2 ; ( 3 ) have not had prior radiotherapy on measurable lesions ( but previous surgery and/or chest radiotherapy for the primary lesion was allowed ) ; ( 4 ) have had a minimum of 28 days since any prior chemotherapy or radiation before study entry ; and ( 5 ) have adequate bone marrow , hepatic , and renal functions , defined as a white blood cell count  3,500/mm , absolute neutrophil count ( anc )  1,500/mm , platelets  100,000/mm , alanine aminotransferase or aspartate aminotransferase  2.5 times the upper normal limit , serum bilirubin < 1.5 times the upper normal limit , and serum creatinine  1.5 mg / dl .
patients were excluded if there was severe comorbidity such as a myocardial infarction within the preceding six months , symptomatic heart disease ( including unstable angina , congestive heart failure , or uncontrolled arrhythmia ) , or serious concomitant infection , including post obstructive pneumonia .
the presence of central nervous system ( cns ) metastases , however , was not an exclusion criterion , provided that cns symptoms were absent or sufficiently minor to be well - controlled with corticosteroids . written informed consent approved by the institutional review board of the national cancer center was obtained from all patients prior to entering the study .
a complete history and physical examination , including documentation of concomitant medications and performance status , standard laboratory studies , and an electrocardiogram , was performed within 14 days prior to study entry .
chest x - ray , computed tomography scans of the chest including the upper abdomen , magnetic resonance imaging of the brain , and a radionuclide bone scan were performed within 4 weeks prior to study entry .
complete blood cell counts and chemistry were performed on days 1 and 8 of each cycle .
paclitaxel ( padexol , seoul , korea ) and gemcitabine ( geroam , seoul , korea ) were administered to patients .
treatment consisted of 80 mg / m paclitaxel and 1,000 mg / m gemcitabine by intravenous infusion on days 1 and 8 every 3 weeks until disease progression .
paclitaxel was given first as a 60-minute intravenous infusion , immediately followed by a 30-minute gemcitabine intravenously .
premedication consisted of dexamethasone ( 10 - 20 mg intravenously ) , pheniramine maleate ( 45.5 mg intravenously ) , and famotidine ( 20 mg intravenously ) before paclitaxel infusion .
granisetron ( 3 mg ) was given intravenously before paclitaxel infusion . during the course of chemotherapy ,
paclitaxel doses were decreased by 15 mg / m for grade 4 hematologic toxicities or grade 3 or 4 non - hematologic toxicities .
gemcitabine doses were decreased by 20% for grade 4 hematologic toxicities or grade 3 or 4 non - hematologic toxicities .
the primary objective of this study was to estimate the overall response rate of paclitaxel and gemcitabine as second - line chemotherapy in patients with metastatic or recurrent sclc .
the secondary objectives were to estimate the time to progression ( ttp ) and overall survival ( os ) .
with 80% power and a 5% one - sided type i error , 18 patients were needed in the first stage , and 33 patients were needed in total . at the first stage ,
if there were five or fewer responses out of the initial 18 patients , the study would conclude that the anticipated response rate is less than 20% and would terminate .
otherwise , accrual would continue to a full sample of 33 assessable patients . at the second stage ,
at least 11 objective responses among 33 patients were required for this regimen to be regarded as worthy of further investigation .
the response rate of the treatment was calculated as the ratio of the number of complete and partial responders to the total number of evaluable patients . a 95% confidence interval for the response rate
the toxicity profile was estimated as the ratio of the number of occurrence to the total number of evaluable patients .
the os was defined as the period of time from the first day of treatment to death from any cause .
patients still alive were censored at the last day on which they were known to be alive .
the ttp was defined from the first day of treatment to the date that disease progression was assessed .
the duration of response for all responders was defined as the period of time from the date of the first response , i.e. , either partial response or complete response ( whichever occurred first ) , to the date of disease progression .
thirty patients ( 91% ) were men , and 32 patients ( 97% ) had an ecog ps of 0 or 1 .
thirty patients ( 91% ) received irinotecan - platinum and three patients received etoposide - platinum .
as a prior therapy , 23 patients received chemotherapy alone , and 10 patients received chemoradiation . among the chemotherapy - only group ,
all 23 patients received irinotecan - platinum chemotherapy . among the 10 patients treated with chemoradiation , seven patients received irinotecan - platinum , and three patients received etoposide - platinum .
sensitive relapse was defined as a chemotherapy - free interval of 3 months or greater , and refractory relapse was defined as no response to initial therapy or progression within 3 months after initial therapy .
the median number of cycles administered was three ( range , 1 to 12 cycles ) , and 10 patients completed six cycles of chemotherapy . over 133 cycles , delayed chemotherapy administration occurred in 44 cycles ( 33% ) , and dose reduction occurred in 22 cycles ( 16% ) .
the most common cause for the delay in chemotherapy administration was either holiday ( 23 cycles ) or neutropenia ( 19 cycles ) .
twenty - two cycles required dose reduction , mainly because of neutropenia ( 18 cycles ) , thrombocytopenia ( 3 cycles ) , and pneumonia ( 1 cycle ) .
the overall response rate was 29.4% in sensitive relapse and 31.3% in refractory relapse ( table 2 ) .
the median ttp was 12.0 weeks ( 95% confidence interval [ ci ] , 7.57 to 16.44 ) , the median os was 31.0 weeks ( 95% ci , 23.44 to 38.56 ) , and the 1-year os rate was 30.3% ( 95% ci , 14.6 to 46.0 ) ( fig .
1 ) . no pretreatment characteristic , including sex ( male vs. female ) , ecog ps ( 0 vs. 1 - 2 ) , stage at diagnosis ( limited vs. extensive ) , smoking history ( never vs. ever ) , prior treatment ( chemotherapy only , concurrent chemoradiotherapy vs. chemotherapy followed by radiotherapy ) , best response of any prior treatment ( pr vs. non - pr ) , treatment - free interval ( < 3 months vs. 3 - 6 months vs.  6 months ) , was predictive of tumor response ( table 3 ) .
the salvage treatments included cyclophosphamideadriamycin - vincristine ( 6 patients ) , adriamycin - ifosfamide - vincristine ( 5 patients ) , etoposide - cisplatin ( 3 patients ) , irinotecan - cisplatin ( 2 patients ) , oral etoposide ( 2 patients ) , adriamycin - ifosfamide ( 1 patient ) , and pemetrexed ( 1 patient ) .
all patients ( n=33 ) who received at least one cycle of therapy were assessable for toxicity .
toxicity was reported as the maximum toxicity experienced during entire study treatment , rather than just during the first cycle .
hematologic and non - hematologic toxicities observed over the entire course of the study are summarized in table 4 .
g4 neutropenia was observed in 18.2% of patients and g3 thrombocytopenia was observed in 24.2% of patients .
another patient died of pneumonia during the third cycle , but g1 neutropenia was present ( anc , 1,219/l ) . g3
another patient developed g3 neuropathy after the first cycle , but recovered completely in 3 months .
thirty patients ( 91% ) were men , and 32 patients ( 97% ) had an ecog ps of 0 or 1 .
thirty patients ( 91% ) received irinotecan - platinum and three patients received etoposide - platinum .
as a prior therapy , 23 patients received chemotherapy alone , and 10 patients received chemoradiation . among the chemotherapy - only group ,
all 23 patients received irinotecan - platinum chemotherapy . among the 10 patients treated with chemoradiation , seven patients received irinotecan - platinum , and three patients received etoposide - platinum .
sensitive relapse was defined as a chemotherapy - free interval of 3 months or greater , and refractory relapse was defined as no response to initial therapy or progression within 3 months after initial therapy .
the median number of cycles administered was three ( range , 1 to 12 cycles ) , and 10 patients completed six cycles of chemotherapy . over 133 cycles , delayed chemotherapy administration occurred in 44 cycles ( 33% ) , and dose reduction occurred in 22 cycles ( 16% ) .
the most common cause for the delay in chemotherapy administration was either holiday ( 23 cycles ) or neutropenia ( 19 cycles ) .
twenty - two cycles required dose reduction , mainly because of neutropenia ( 18 cycles ) , thrombocytopenia ( 3 cycles ) , and pneumonia ( 1 cycle ) .
the overall response rate was 29.4% in sensitive relapse and 31.3% in refractory relapse ( table 2 ) .
the median ttp was 12.0 weeks ( 95% confidence interval [ ci ] , 7.57 to 16.44 ) , the median os was 31.0 weeks ( 95% ci , 23.44 to 38.56 ) , and the 1-year os rate was 30.3% ( 95% ci , 14.6 to 46.0 ) ( fig .
1 ) . no pretreatment characteristic , including sex ( male vs. female ) , ecog ps ( 0 vs. 1 - 2 ) , stage at diagnosis ( limited vs. extensive ) , smoking history ( never vs. ever ) , prior treatment ( chemotherapy only , concurrent chemoradiotherapy vs. chemotherapy followed by radiotherapy ) , best response of any prior treatment ( pr vs. non - pr ) , treatment - free interval ( < 3 months vs. 3 - 6 months vs.  6 months ) , was predictive of tumor response ( table 3 ) .
the salvage treatments included cyclophosphamideadriamycin - vincristine ( 6 patients ) , adriamycin - ifosfamide - vincristine ( 5 patients ) , etoposide - cisplatin ( 3 patients ) , irinotecan - cisplatin ( 2 patients ) , oral etoposide ( 2 patients ) , adriamycin - ifosfamide ( 1 patient ) , and pemetrexed ( 1 patient ) .
all patients ( n=33 ) who received at least one cycle of therapy were assessable for toxicity .
toxicity was reported as the maximum toxicity experienced during entire study treatment , rather than just during the first cycle .
hematologic and non - hematologic toxicities observed over the entire course of the study are summarized in table 4 .
g4 neutropenia was observed in 18.2% of patients and g3 thrombocytopenia was observed in 24.2% of patients
another patient died of pneumonia during the third cycle , but g1 neutropenia was present ( anc , 1,219/l ) . g3
another patient developed g3 neuropathy after the first cycle , but recovered completely in 3 months .
this study was a single - arm phase ii study to evaluate the efficacy of paclitaxel plus gemcitabine in patients with sclc that progressed or failed to respond to platinum - based chemotherapy . historically , the median os is only 14 weeks if no active therapy is given other than best supportive care ( bsc ) after first - line chemotherapy .
second - line chemotherapy increased os and resulted in better symptom control compared with bsc .
the strongest predictor of outcome for patients with relapsed sclc is the duration of remission .
patients with sensitive disease respond to the same initial therapy in approximately 50% of cases .
the median os from the start of a second - line therapy is approximately 6 months . in patients with refractory disease , response rates to second - line therapy are less than 10% , and the median os from the start of a second - line therapy is 4 months .
response rates to combination chemotherapy are higher than those to a single agent ; however , the reported response rates are variable , reflecting the population heterogeneity .
our study began in 2005 , and a similar study 's report was published in 2006 .
they showed that weekly paclitaxel and gemcitabine treatment were moderately active in sclc patients pretreated with platinum and etoposide .
paclitaxel ( 80 mg / m ) was given on days 1 , 8 , and 15 , and gemcitabine ( 1,000 mg / m ) was given on days 1 and 8 every 3 weeks .
of these patients , 32% had refractory disease , and the objective response rate was 26% , including 20% in patients with refractory sclc and 28.6% in patients with sensitive sclc .
the response rate was only slightly higher in patients with sensitive relapse than in those with refractory relapse , indicating that the regimen may be more useful in the former group .
predictive of response to second - line chemotherapy were the interval between the completion of induction and relapse , the extent of tumor regression achieved with the induction regimen , and the composition of the induction program .
platinum plus irinotecan has been the standard first - line chemotherapy for sclc at the national cancer center in korea since 2002 , when the japanese cooperative oncology group showed that irinotecan plus cisplatin was superior to etoposide plus cisplatin in terms of response rate , progression - free survival ( pfs ) , and os . in this study , 30 patients ( 91% ) received irinotecan plus platinum and three patients received etoposide plus platinum . sixteen patients ( 49% ) had refractory relapse . given the refractory nature of the disease , the overall response rate of 30.3% in the current study is remarkable , although we set our initial target response rate to be 40% .
our study design required at least 11 objective responses among 33 patients for this regimen to be regarded as worthy of further investigation ; 10 patients achieved pr .
we observed similar response rates in both groups ( 29.4% in sensitive relapse and 31.3% in refractory relapse ) .
also , high activity in patients with refractory disease may reflect a lack of adverse effects of prior treatment with irinotecan / platinum on the antitumor activity of paclitaxel / gemcitabine , which suggests a lack of cross - resistance between paclitaxel / gemcitabine and irinotecan / platinum . a recent randomized phase 3 trial of amrubicin versus topotecan as second - line treatment   reported a median os of 7.5 months with amrubicin versus 7.8 months with topotecan ; in refractory patients , median os was 6.2 and 5.7 months , respectively .
in this study , although amrubicin did not improve survival when compared with topotecan in the second - line treatment of patients with sclc , os did not differ significantly between treatment groups and improvement in os was noted in patients with refractory disease treated with amrubicin .
although direct comparison of phase 2 data with phase 3 data is not reasonable , the weekly paclitaxel / gemcitabine regimen in the current study showed efficacy comparable to amrubicin and topotecan .
because second - line chemotherapy in sclc patients is only palliative , we have to consider quality of life , toxicity , and cost .
in the second - line setting , all patients had already received platinum doublets , and thus , we had to consider cumulative toxic effects . a randomized phase iii trial comparing oral topotecan ( 2.3 mg / m / day for 5 days every 21 days ) to intravenous topotecan ( 1.5 mg / m / day for 5 days every 21 days ) , found reasonable response rates ( 18.3% vs. 21.9% )
however , g4 neutropenia was common ( 47% vs. 64.2% ) , and diarrhea of all grades was observed ( 35.9% vs. 19.9% ) .
a study of second - line weekly paclitaxel and gemcitabine showed g3 - 4 asthenia in 13% of patients .
the average relative dose intensity was 72% for paclitaxel and 83% for gemcitabine . in the current study ,
the dose intensity was 86.4% for paclitaxel and 85.4% for gemcitabine , and treatment - related toxicity was observed considerably less often ( 18.2% g4 neutropenia and 24.2% g3 thrombocytopenia ) . aside from myelosuppression ,
g3 non - hematologic toxicities were rare , and most of them were manageable with good compliance .
in conclusion , second - line paclitaxel and gemcitabine were well - tolerated with a 30.3% response rate in sclc patients previously treated with platinum - based chemotherapy .
our study suggests that paclitaxel and gemcitabine can be good options for second - line therapy in platinum - resistant sclc patients .
 purposepaclitaxel ( p ) and gemcitabine ( g ) are clinically synergistic in small cell lung cancer ( sclc ) . 
 we evaluated the efficacy of pg as a salvage treatment for sclc patients whose disease progressed after a platinum - containing regimen.materials and methodseligibility included histologically confirmed sclc , one dimensionally measurable disease , eastern cooperative oncology group performance status 0 - 2 , and progressive disease after platinum - based chemotherapy . 
 treatment consisted of p ( 80 mg / m2 ) and g ( 1,000 mg / m2 ) on days 1 and 8 of each cycle of 21 days until disease progression.resultsthirty-three patients seen between december 2005 and february 2009 were selected into this study . 
 thirty patients ( 91% ) had received irinotecan - platinum , and three had received etoposide - platinum . 
 sixteen patients ( 49% ) had a treatment - free interval of less than 3 months . 
 the overall response rate was 30.3% ( 29.4% in sensitive relapse and 31.3% in refractory relapse ) . 
 the median time to progression was 12.0 weeks and median overall survival ( os ) 31.0 weeks , with a 1-year os rate of 30.3% . 
 toxicities were moderate and manageable with 18.2% grade ( g ) 4 neutropenia , 24.2% g3 thrombocytopenia , 6.1% g3 sensory neuropathy , and 3% g3 asthenia . 
 one patient developed febrile neutropenia.conclusionsecond-line paclitaxel and gemcitabine were well - tolerated and moderately active in sclc patients previously treated with platinum - based chemotherapy . 