***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: The purpose of this study was to evaluate tumour response and toxicity to ifosfamide and continuous infusion etoposide in metastatic or locally advanced soft tissue sarcoma , with dose escalations under G-CSF ( granulocyte colony-stimulating factor ) support . Of 92 eligible patients ( median age 51 years ) , 85 % had tumours of high- grade malignancy and 82 % had metastatic disease .  Chemotherapy , the baseline dose , consisted of etoposide 600 mg/m2 as a 72 h infusion and ifosfamide 1500 mg/ m2/day for 3 days , followed by G-CSF support ( VIG regimen ) . Stepwise 10 % dose escalations were performed depending on haematological toxicity . For patients considered operable after induction chemotherapy , surgical resection of all identifiable residual tumour was attempted . Complete and partial response rates were 11 % and 31 % , for an overall response rate of 42 % ( 95 % CI 31 - 52 % ) . Forty-eight per cent of courses were dose escalated by a median of 20 % . Complete responders had significantly higher , and patients with progressive disease had significantly lower , dose levels than other patients . None of 20 patients with liver metastases responded despite high dose levels . Compared to a preceding pilot study , the addition of G-CSF led to significantly higher dose levels , improved schedule adherence and less haematological toxicity , but no apparent increase in response rate . In view of the modest dose of ifosfamide applied in this study , it is possible that the prolonged infusion of etoposide made a significant contribution to the regimen 's antitumour activity , although this can only be determined definitively in a r and omised study This Phase I/II study investigates increasingly high doses of ifosfamide combined with full dose doxorubicin chemotherapy supported with peripheral blood stem cells ( PBSC ) and granulocyte‐colony stimulating factor ( G‐CSF ) in patients with metastatic soft tissue sarcoma ( STS ) PURPOSE To determine whether a prolonged 12-day continuous infusion allows the administration of high-dose ifosfamide ( IFO ) with an acceptable toxicity profile when combined with full-dose doxorubicin ( Adriamycin ; ADM ) as first-line chemotherapy in patients with advanced soft tissue sarcomas . PATIENTS AND METHODS Escalating doses of continuous infusion IFO ( 8 - 15 g/m2 ) given on days 1 to 12 in combination with ADM 75 mg/m2 given on day 8 and prophylactic granulocyte colony-stimulating factor support were administered every 4 weeks to 35 chemonaïve patients with advanced soft tissue sarcomas . RESULTS The maximum tolerated dose was IFO 15 g/m2 . Hematological toxicity was the main dose-limiting toxicity and was dose dependent . Furthermore , thrombocytopenia was cumulative . Grade 4 ( WHO ) neutropenia and thrombocytopenia were recorded in 48 % and 14 % of courses , respectively . Eight patients experienced febrile neutropenia . A partial response was observed in 16 out of 30 assessable patients [ 53 % , 95 % confidence interval ( CI ) 25 - 63 ] ; median time to progression was 25 weeks ( range 4 - 91 ) . CONCLUSIONS This study proved that a prolonged 12-day continuous infusion allows an increase in the total IFO dose that can be safely combined with ADM . A multicentric phase II study by the Italian Sarcoma Group to assess its antitumor activity is currently ongoing in patients with advanced soft tissue sarcomas Ifosfamide ( 5 g/m2 ) was compared with its parent analogue cyclophosphamide ( 1.5 g/m2 ) in a r and omized phase II study . Both drugs were given by 24-h intravenous ( i.v . ) infusion every 3 weeks along with i.v . bolus infusions of mesna ( 400 mg/m2 ) , which was given every 4 h for nine administrations . Eligibility criteria included an age of 15 - 75 years , biopsy-proven advanced metastatic soft-tissue sarcoma , and a World Health Organization performance status of 0 - 2 . Exclusion criteria were prior treatment with classic alkylating agents , a creatinine level of > 150 mumol/l , a bilirubin level of > 20 mumol/l , a leukocyte cell count of < 3.5 x 10(9)/l , and a platelet count of < 100 x 10(9)/l . A total of 171 patients were entered , 24 of whom were ineligible and 12 , inevaluable , leaving 135 patients evaluable . In all , 67 patients were treated with cyclophosphamide , and the overall response rate was 7.5 % . All responders to cyclophosphamide were patients who had not received prior chemotherapy ( 13 % of 38 patients ) . Another 68 patients were given ifosfamide , 18 % of whom responded to treatment . Of the 28 ifosfamide-treated patients who had received prior chemotherapy , 7 % were responders . The response rate for the remaining 40 patients was 25 % . The higher overall response rate ( P = 0.13 ) obtained with less myelosuppression in ifosfamide-treated patients suggests that this agent may have advantages over cyclophosphamide in combination therapy BACKGROUND Neutropenia and infections are the dose-limiting toxicities of the EID regimen and can cause dose reduction and /or delay in chemotherapy administration . The purpose of this study was to verify if EID + G-CSF is feasible with an acceptable toxicity in a day hospital setting and if G-CSF could allow an increase in the dose intensity of the EID regimen by shortening the intervals between the courses . PATIENTS AND METHODS 20 patients with inoperable primary , metastatic or residual disease after surgery or at high risk of recurrence after complete resection , histologically confirmed adult soft tissue sarcoma , entered the study . The dose and schedule of the chemotherapy agents were epidoxorubicin 30 mg/m2 days 1 , 2 , 3 , dacarbazine 300 mg/m2 days 1 , 2 , 3 , and ifosfamide 2500 mg/m2 with mesna uroprotection days 1 , 2 , 3 . G-CSF , 300 micrograms/day subcutaneously , was administered from day 7 for a maximum of 14 days and discontinued when WBC was greater than 10 x 10(9)/L. Courses were repeated " as soon as possible , " but never earlier than 10 days from the previous course and at least 48 hours after the last G-CSF injection . RESULTS A total of 66 EID + G-CSF courses were administered . A G3 and G4 ( WHO ) neutropenia occurred in 66 % of evaluables courses . Nonhematological toxicity was mild . The median number of G-CSF injections required during any interval between courses was 9 ( range : 4 - 14 injections ) and the median interval between courses was 21 days ( range : 13 - 36 days ) . The median dose intensity at the third course of chemotherapy was 1.15 ( range : 0.71 - 1.62 ) . CONCLUSION This study shows that G-CSF allows a moderate increase in the delivered dose intensity of chemotherapy with an acceptable toxicity . Further studies are needed to investigate if this increase in DI may translate into an improved response rate Purpose To evaluate the maximum tolerated doses ( MTD ) of ifosfamide when given as a continuous infusion and in combination with fixed doses of bolus 4′-epidoxorubicin in advanced previously untreated adult soft tissue sarcoma patients . Methods Treatment consisted of epidoxorubicin , 60 mg/m2 days one and two , and ifosfamide , 1.5 g/m2 every 12 hrs as a 72-hr infusion , at the first level . Further levels of ifosfamide were defined as increments of 12 hrs of the same infusion program . G-CSF 300 μg/die was administered from days + 7 to + 14 . Dose-limiting toxicity ( DLT ) was defined as : G4 leukopenia or thrombocytopenia of ≥5 days ; any G3 neuro or nephrotoxicity ; G4 toxicity of any kind . Patients had to complete at least 2 consecutive cycles , and MTD was defined as the level in which 20 % of patients developed a DLT ; 10 - 15 patients were entered in each level . Results First level : overall , 13 patients entered , 3 were not assessable for MTD , and only one developed a DLT . Second level : 18 patients entered , 3 were not assessable for MTD . Hematologic DLT was observed in 3/15 assessable patients . Therefore , the MTD was found at the ifosfamide level of 10.5 g/m2 given in 84 hrs . Eight patients of 29 assessable for response achieved an objective response : 1 complete and 7 partial . The overall response rate was 28 % ( 95 % CI : 13 - 47 % ) . Conclusions If we accept 4-day G4 leukopenia as a reliable cutoff for safety , ifosfamide intensification can not be substantially exploited over already available schedules with the combination of ifosfamide and anthracyclines PURPOSE This two-arm , double-blind , r and omized trial was conducted to determine the effects of lenograstim , a glycosylated recombinant human granulocyte colony-stimulating factor ( rHu-G-CSF ) , on the hematologic tolerance  of patients with sarcoma treated with mesna , doxorubicin , ifosfamide , and doxorubicin ( MAID ) chemotherapy .  PATIENTS AND METHODS Forty-eight patients with metastatic or locally advanced soft tissue sarcoma were , following the first cycle of a combination with doxorubicin 60 mg/m2 , ifosfamide 7.5 g/m2 , and dacarbazine 900 mg/m2 , ifosfamide 7.5 g/m2 , and dacarbazine 900 mg/m2 given on days 1 to 3 , r and omized to receive either lenograstim 5 micrograms/kg/d by once-daily injection from day 4 to day 13 , or its vehicle . For subsequent cycles , 28 patients continued on the same chemotherapy and lenograstim was systematic ally given as prophylactic treatment in an open manner . RESULTS Following the first cycle of MAID , the duration of neutropenia was reduced in patients who received lenograstim as compared with those who received placebo , with a median duration of neutropenia ( < 0.5 x 10(9)/L neutrophils ) of 0 days ( range , 0 to 3 ) and 5 days ( range , 0 to 10 ) , respectively ( P < .001 ) . All patients who received lenograstim had recovered at least 1 x 10(9)/L neutrophils ( polymorphonuclear lymphocytes [ PMN ] ) on day 14 , compared with only one of 26 in the placebo group ( P < .001 ) . The median time to recover this neutrophil level was 12 days ( range , 10 to 13 ) and 17 days ( range , 14 to 21 ) , respectively ( P < .001 ) . Neutropenic fever occurred in five ( 23 % ) and 15 ( 58 % ) patients respectively ( P = .02 ) . Twenty-eight patients received at least two cycles ( median , four ) of MAID at the same dose . Toxicity remained constant across all treatment cycles . A progressive increase in thrombocytopenia was noted , with median platelet nadirs of 102 x 10(9)/L at cycle 2 and 19.5 x 10(9)/L at cycle 6 , but did not result in significant treatment modifications . Consequently , median relative dose-intensities remained greater than 0.95 for up to six consecutive MAID cycles . CONCLUSION Lenograstim significantly improved hematologic tolerance in patients treated with the MAID chemotherapy regimen and , therefore , allowed optimal adhesion to the theoretic doses planned for up to six cycles . Whether such an optimization in relative dose-intensity will result in an improvement of treatment efficacy remains to be determined This study was conducted to determine the maximum tolerated dose of an intensified MAID ( mesna , adriamycin , ifosfamide , dacarbazine ) regimen with the support of lenograstim in patients with advanced soft tissue sarcomas . Following 1 cycle of MAID at the st and ard dose , four patients were to be treated at each of five dosage levels : + 25 % , + 45 % , + 65 % , + 85 % , + 100 % . Sixteen patients were treated . Because there were no significant differences in hematologic toxicity between patients receiving lenograstim 5 or 10 microg/kg/day ( levels 1 - 5 and 1 - 10 ) , the data were pooled for comparison with level 2 . The median duration of absolute neutrophil count < 0.5 x 10(9)/l was 3 days at level 1 and 7 days at level 2 ( p < 0.01 ) . The median platelet nadir was 2 
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PRACTICE GUIDELINE Based on the systematic review , consensus , and external review , the Sarcoma dsg makes these recommendations : Dose-intensive chemotherapy with growth factor support is not recommended in the first-line treatment of patients with inoperable locally advanced or metastatic soft tissue sarcoma .
The data are insufficient to support the use of high-dose chemotherapy with autologous bone marrow or stem-cell transplantation as first-line treatment in this group of patients .
QUALIFYING STATEMENTS High-dose chemotherapy with growth factor or autologous bone marrow or stem-cell transplantation has adverse effects similar to those seen with st and ard-dose chemotherapy .
With high-dose regimens , the incidence of grade s 3 and 4 thrombocytopenia is significantly higher , and neutropenic fever and febrile neutropenia occur more frequently .
Compared with st and ard treatment , the rate of treatment-related death is also higher with high-dose regimens