sarcoma is a heterogeneous group of cancers of the soft tissue and bone , and some are extremely rare . the rarity and diverse characteristics of sarcomas has impeded the development of new treatments .
doxorubicin and ifosfamide , either alone or in combination , have been the backbone of metastatic soft tissue sarcomas ( sts ) therapy for over 15 years .
few effective chemotherapeutic options for the treatment of metastatic sts beyond 1st line treatment with doxorubicin- and ifosfamide - based regimens exist . because alternative regimens for the effective treatment of metastatic sarcoma are unavailable
, varying combinations , including doxorubicin and/or ifosfamide , are sometimes used to treat patients who either not candidates for use or are resistant to treatment with doxorubicin and/or ifosfamide .
thus , a number of clinical trials have been conducted to explore alternative chemotherapeutic options .
the reported response rate ( rr ) from five phase ii trials of single - agent gemcitabine treatment in patients with soft tissue and bone sarcoma was 3 - 18% ( median rr , 5.5% ) .
docetaxel as a single agent ( 100 mg / m , iv every 3 weeks ) was examined as a second line therapy in a phase ii study conducted by the european organization for research and treatment of cancer ( eortc ) .
however , based on the results of several phase ii trials , the efficacy of single - agent docetaxel treatment in treating sts appears to be quite limited with a reported rr of 0 - 18% ( median rr , 15% ) [ 3 - 6 ] .
although use of gemcitabine or docetaxel as a single agent has limited efficacy , their use in combination has been shown to be effective in patients with sts . a clinical study by hensley et al
.   reported an impressive rr of 53% in patients with predominantly uterine leiomyosarcoma using a study regimen consisting of gemcitabine at a dose of 900 mg / m given over a 90-minute iv infusion on days 1 and 8 , and docetaxel at a dose of 100 mg / m given over a 60-minute iv infusion on day 8 , followed by granulocyte - colony stimulation factor ( g - csf ) , during a 21 day period .
in a subsequent retrospective study of 35 patients with a variety of histologic subtypes of adult sarcoma , the patients received a similar regimen but with lower dosages of gemcitabine ( 675 mg / m ) .
these patients had previously received doxorubicin and/or ifosfamide , or were patients for whom use of gemcitabine and docetaxel ( gd ) was preferable for other medical reasons .
the results of the trial demonstrated an overall rr of 43% and the responses included patients with osteosarcoma and ewing 's sarcoma .
the combination of gd also has been evaluated for use in treatment of a variety of malignancies , with activity demonstrated in non - small cell lung cancer ( nsclc ) , breast cancer , esophageal cancer and others .
recently , a multi - institutional , randomized phase ii study in adult metastatic sts patients demonstrated superior progression - free survival ( pfs ) and overall survival ( os ) for use of the combination regimen when compared with use of gemcitabine alone .
however , more than 40% of patients receiving a combination of gd needed to discontinue the treatment within 6 months of therapy due to a variety of toxicities , despite adhering to recommended dose reductions . therefore , to identify the optimum dose and schedule that has both an antitumor effect and acceptable toxicity , we administered weekly gemcitabine - docetaxel treatments to patients with metastatic or recurrent sts who had failed to improve using doxorubicin and ifosfamide combination chemotherapy . here , we report the results of our retrospective analysis of 22 patients with advanced and refractory sts .
from september 2008 to march 2011 , a total of 22 patients with a variety of sts were treated at yonsei cancer center ( table 1 ) , and the medical records of these patients were retrospectively reviewed .
all patients had metastatic or recurrent cancer and had previously received doxorubicin and ifosfamide combination chemotherapy . following a 21 day cycle ,
on days 1 and 8 , patients received 1,000 mg / m gemcitabine intravenously over a 100 minutes duration , followed immediately by 35 mg / m intravenous docetaxel over 60 minutes .
standard prophylactic premedications were provided on day 1 and day 8 of diphenhydramine and ondansetron or its equivalent .
in addition , patients received 8 - 15 mg intravenous dexamethasone , 30 minutes before docetaxel was administered . in almost all patients , radiological evaluation consisted of a computed tomography scan and bone scintigraphy , as indicated .
response was assessed every two to three cycles . when measurements were available , radiographic studies and/or reports were reassessed and responses were classified according to the response evaluation criteria in solid tumors ( recist ) .
toxicities were evaluated using the national cancer institute common terminology criteria for adverse events ( nci ctcae ) version 3.0 .
best overall response was defined as the best response designation recorded from the start of treatment until disease progression .
pfs was defined as the time from first treatment until clinical or radiographic progression , or death .
patients in the study included 12 females and 10 males with a median age of 41.5 years ( range , 22 to 67 years ) .
of the 22 patients , 20 were considered to be resistant to both drugs and 2 were unable to tolerate these drugs due to hematologic toxicity .
weekly gemcitabine - docetaxel was delivered as a second line chemotherapy to 14 patients ( 63.6% ) and as a third line or more for 8 patients ( 36.4% ) .
a median of 3 weekly gemcitabine - docetaxel chemotherapy courses were delivered ( range , 1 to 39 cycles ) with a total of 116 courses .
no major side effects or severe complications that could be attributed to treatment were reported . according to the medical records , only 4 patients ( 18.2% ) needed a dose reduction due to hematological toxicity .
the primary justification for therapy discontinuation was progressive disease ( pd ) in 20 patients .
of the other 2 patients , one withdrew due to grade 2 gastroparesis and one suffered acute renal failure due to tumor - associated obstructive uropathy .
prophylactic g - csf was not used for any patients , while therapeutic g - csf was used for patients with febrile or grade 4 neutropenia .
grade 3 - 4 neutropenia occurred in 18.2% of cases and grade 3 - 4 thrombocytopenia occurred in 13.6% of cases .
only 4 patients ( 18.2% ) required dose reduction , primarily due to myelosuppression ( table 2 ) .
an allergic reaction occurred with 6 patients when docetaxel was administered , and in these cases , the infusion of docetaxel was discontinued until the symptoms improved and then infusion was slowly restarted .
of the 22 patients reviewed , 2 were not evaluated due to untimely death and one patient was transferred to another hospital prior to evaluation . among the 22 treated patients , one patient ( 4.5% ) with uterine leiomyosarcoma had a partial response ( pr ) , 8 patients ( 36.4% ) had the best response of stable disease ( sd ) , and 11 ( 50% ) had pd .
thus , an overall rr of 4.5% was observed while the disease control rate ( dcr ) was 40.9% with a median follow - up of 6.1 months ( dcr : leiomyosarcoma , 66.7% ; non - leiomyosarcoma , 31.3% ) .
the median pfs was 2.7 months ( 95% confidence interval [ ci ] , 2.0 to 3.4 months ) and the 12-week pfs rate was 41.9% ( fig .
we performed univariate analyses and did not observe any statistical association between pfs and clinical parameters including age , sex , initial localization , prior treatment at baseline , eastern cooperative oncology group performance status ( ecog ps ) , histology , or previous lines of chemotherapy before the gd combination ( second line vs. third line or more ) ( fig .
however , pfs was correlated with the justification for the prior chemotherapy regimen change ( toxicities vs. pd ; p=0.027 ) ( fig .
3a ) and the treatment response to weekly gd treatment ( pr and sd vs. pd ; p<0.0001 ) ( fig .
median pfs was 4.0 months ( range , 2.5 to 28.2 months ) in patients achieving disease control ( pr and sd ) , compared with 1.4 months ( range , 1.2 to 2.7 months ) in those not achieving disease control .
the median survival duration was estimated to be 7.8 months ( 95% ci , 0.0 to 20.6 months ) .
the six - month survival rate was 58.7% and the one - year survival rate was estimated to be 45.7% ( fig .
no statistical association was observed between os and clinical parameters including age , sex , initial localization , prior treatment at baseline , ecog ps and justification for the prior chemotherapy regimen change ( fig .
interestingly , there was no significant difference in os between patients receiving weekly gd as a second line of treatment and those who received a third line or more of chemotherapy ( fig .
however , os did correlate with histology , suggesting patients with leiomyosarcoma have a higher survival rate than other histological subtypes ( p=0.026 ) ( fig .
median os was 24.7 months ( range , 6.4 to 28.2 months ) in patients with leiomyosarcoma , compared with 4.9 months ( range , 1.1 to 24.4 months ) in those with other histology subtypes .
treatment response to weekly gd treatment ( pr and sd vs. pd ) ( p=0.009 ) also correlated with os ( fig .
4b ) , and disease control ( pr and sd ) may be predictive of survival .
patients in the study included 12 females and 10 males with a median age of 41.5 years ( range , 22 to 67 years ) .
of the 22 patients , 20 were considered to be resistant to both drugs and 2 were unable to tolerate these drugs due to hematologic toxicity .
weekly gemcitabine - docetaxel was delivered as a second line chemotherapy to 14 patients ( 63.6% ) and as a third line or more for 8 patients ( 36.4% ) .
a median of 3 weekly gemcitabine - docetaxel chemotherapy courses were delivered ( range , 1 to 39 cycles ) with a total of 116 courses .
no major side effects or severe complications that could be attributed to treatment were reported . according to the medical records , only 4 patients ( 18.2% ) needed a dose reduction due to hematological toxicity .
the primary justification for therapy discontinuation was progressive disease ( pd ) in 20 patients .
of the other 2 patients , one withdrew due to grade 2 gastroparesis and one suffered acute renal failure due to tumor - associated obstructive uropathy .
prophylactic g - csf was not used for any patients , while therapeutic g - csf was used for patients with febrile or grade 4 neutropenia .
grade 3 - 4 neutropenia occurred in 18.2% of cases and grade 3 - 4 thrombocytopenia occurred in 13.6% of cases .
only 4 patients ( 18.2% ) required dose reduction , primarily due to myelosuppression ( table 2 ) .
an allergic reaction occurred with 6 patients when docetaxel was administered , and in these cases , the infusion of docetaxel was discontinued until the symptoms improved and then infusion was slowly restarted .
of the 22 patients reviewed , 2 were not evaluated due to untimely death and one patient was transferred to another hospital prior to evaluation . among the 22 treated patients , one patient ( 4.5% ) with uterine leiomyosarcoma had a partial response ( pr ) , 8 patients ( 36.4% ) had the best response of stable disease ( sd ) , and 11 ( 50% ) had pd .
thus , an overall rr of 4.5% was observed while the disease control rate ( dcr ) was 40.9% with a median follow - up of 6.1 months ( dcr : leiomyosarcoma , 66.7% ; non - leiomyosarcoma , 31.3% ) .
the median pfs was 2.7 months ( 95% confidence interval [ ci ] , 2.0 to 3.4 months ) and the 12-week pfs rate was 41.9% ( fig .
we performed univariate analyses and did not observe any statistical association between pfs and clinical parameters including age , sex , initial localization , prior treatment at baseline , eastern cooperative oncology group performance status ( ecog ps ) , histology , or previous lines of chemotherapy before the gd combination ( second line vs. third line or more ) ( fig .
however , pfs was correlated with the justification for the prior chemotherapy regimen change ( toxicities vs. pd ; p=0.027 ) ( fig .
3a ) and the treatment response to weekly gd treatment ( pr and sd vs. pd ; p<0.0001 ) ( fig .
median pfs was 4.0 months ( range , 2.5 to 28.2 months ) in patients achieving disease control ( pr and sd ) , compared with 1.4 months ( range , 1.2 to 2.7 months ) in those not achieving disease control .
the median survival duration was estimated to be 7.8 months ( 95% ci , 0.0 to 20.6 months ) .
the six - month survival rate was 58.7% and the one - year survival rate was estimated to be 45.7% ( fig .
no statistical association was observed between os and clinical parameters including age , sex , initial localization , prior treatment at baseline , ecog ps and justification for the prior chemotherapy regimen change ( fig .
interestingly , there was no significant difference in os between patients receiving weekly gd as a second line of treatment and those who received a third line or more of chemotherapy ( fig .
however , os did correlate with histology , suggesting patients with leiomyosarcoma have a higher survival rate than other histological subtypes ( p=0.026 ) ( fig .
median os was 24.7 months ( range , 6.4 to 28.2 months ) in patients with leiomyosarcoma , compared with 4.9 months ( range , 1.1 to 24.4 months ) in those with other histology subtypes .
treatment response to weekly gd treatment ( pr and sd vs. pd ) ( p=0.009 ) also correlated with os ( fig .
4b ) , and disease control ( pr and sd ) may be predictive of survival .
currently , the combination of doxorubicin and ifosfamide is a standard chemotherapeutic regimen for soft tissue sarcoma patients with a good performance status .
however , some patients are not candidates for this therapy for reasons such as underlying cardiac dysfunction , renal insufficiency or poor performance status .
furthermore , effective chemotherapeutic options for the treatment of metastatic sarcoma , beyond 1st line treatment with doxorubicin- and ifosfamide - based regimens , remain limited .
the active form , obtained by phosphorylation , inhibits ribonucleotide reductase as a diphosphate , while the triphosphate is incorporated into dna and blocks dna synthesis [ 13 - 16 ] .
therefore , combination of gd may provide synergistic effects due to their complementary mechanisms of action whereby gemcitabine induces cell cycle arrest and docetaxel promotes cell death .
the combination of gd has been shown in recent studies to be effective in patients with sts . in these studies , iv infusion of docetaxel at a dose of 100 mg
generally , the docetaxel dose was used to treat patients with nsclc , breast cancer and others as a one hour iv infusion administered once every 3 weeks ( 3-weekly ) at a dose ranging from 60 - 100 mg / m . in asia , conventional 3-weekly doses of 60 - 75 mg / m have typically been administered due to decreased tolerability compared to non - asian patients . however , in the 3-weekly docetaxel schedule , neutropenia occurs in virtually all patients , and grade 3/4 neutropenia occurs in 65 - 75% of patients given 60 - 75 mg / m .
hence , several clinical trials have examined docetaxel administered as weekly doses of 35 - 40 mg / m , which demonstrated significantly lower toxicity profiles , especially for hematologic toxicity , as well as efficacy similar to the 3-weekly schedule [ 22 - 25 ] .
our patients were heavily treated , and we administered docetaxel at a weekly dose of 35 mg / m . in a phase ii trial including 29 patients with unresectable uterine leiomyosarcoma and 5 patients with sts of other primary sites , an overall rr of 53% ( 95% ci , 35 to 70% ) with acceptable toxicity results was very encouraging .
this study was impressive in its demonstration of leiomyosarcoma as a subtype that is relatively sensitive to this chemotherapy combination .
several subsequent studies have observed antitumor activity using combinations of gd in patients with leiomyosarcoma .
therefore , the efficacy of gd depends on histology . while the os was superior in patients with leiomyosarcoma compared to those with other histological subtypes in our study ( p=0.026 ) ( fig .
4b ) , it is not known why leiomyosarcoma and malignant fibrous histiocytoma / high - grade undifferentiated pleomorphic sarcoma respond better to this combination .
we anticipated the response or survival of patients who received weekly gd as a second line to be superior than those who received it as third line or more .
interestingly , there was no significant difference in the os between the two groups ( fig .
we suspect many patients who received gd as a third line or more had leiomyosarcoma .
but , almost all patient who received it as a third line or more had non - leiomyosarcoma ( 87.5% ) , and only one patient had leiomyoma ( 12.5% ) .
in other studies , the overall rr or os was similar both for patients who had received prior treatments and for those who were treated with gd as a first line therapy .
the reason of this point is not clear , but we suppose it 's because the combination of gd have antitumor effect in a different way than other chemotherapeutic agents ( doxorubicin and ifosfamide ) , and the patents with relatively good performance received third line treatment .
our weekly gd treatment was well tolerated , and grade 3 - 4 neutropenia and thrombocytopenia occurred in only 18.2% and 13.6% of cases . in previous trials ,
the rate of grade 3 - 4 neutropenia and thrombocytopenia were 20 - 40% , though those who were treated with gd as a 1st line therapy were included . in comparison
also , no major side effects or severe complications that could be attributed to weekly gd administration were reported .
in addition , there may be a possibility of increasing dose intensity with proper g - csf support .
weekly infusions of gd were very well tolerated and showed moderate efficacy as second and third line treatments , indicating that this could be a reasonable salvage treatment option for metastatic sts , refractory to doxorubicin and ifosfamide .
the fact that the weekly gd treatment in this study resulted in better survival for patients with leiomyosarcoma highlights the importance of selecting histology subtype - specific treatment .
the fact that there was no significant difference in os between the patients receiving second or third line treatment or more , illustrated the possibility for use of weekly gd as an effective salvage treatment for heavily treated metastatic sts patients .
however , fewer patents were enrolled in this study than in the other studies , and our patients were selected based on good performance and organ function for this salvage treatment , criteria which could become the basis for a prospective validation study . with the result of our study in mind , future salvage treatment studies should be conducted for third line or greater patients , including a higher prophylactic g - csf treatment dose in patients with proper host status .
 purposethe combination of gemcitabine and docetaxel ( gd ) is used to effectively treat patients with soft tissue sarcoma ( sts ) . 
 it is widely considered that the conventional doses used are too high for long term use and many patients must discontinue gd treatment due to its toxicity . 
 therefore , to determine the appropriate dose meeting acceptable efficacy results , while minimizing toxic side effects , we treated patients with a weekly infusion of gd ( weekly gd).materials and methodsa total of 22 patients presenting a variety of stss were treated at yonsei cancer center . 
 all patients had metastatic or recurrent cancer and had previously received doxorubicin and ifosfamide combination chemotherapy . in all cases , gemcitabine ( 1,000 mg / m2 ) and docetaxel ( 35 mg / m2 ) were administered intravenously on days 1 and 8 of a 21-day cycle . 
 we retrospectively reviewed the medical records of these patients.resultsthe response rate was 4.5% , with one patient diagnosed with leiomyosarcoma having a partial response , and the disease control rate was 40.9% . 
 the median progression - free survival ( pfs ) duration was 2.7 months and the pfs was correlated with the treatment response to a weekly gd . 
 the median overall survival ( os ) duration was 7.8 months and the os was correlated with histology . 
 there was no significant difference in os between patients who received weekly gd as a 2nd line chemotherapy and those who received 3rd line or more . 
 treatment was generally well tolerated.conclusionweekly gd was well tolerated and showed moderate efficacy , indicating that this could be a reasonable option as a salvage treatment for metastatic sts . 
Introduction
Materials and Methods
Results
1. Patient characteristics
2. Treatment delivery
3. Toxicity
4. Efficacy
Discussion
Conclusion