***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: Purpose : More than half of pediatric rhabdomyosarcoma cases have intermediate-risk features and suboptimal outcome ( 3-year failure-free survival estimates , 55 to 76 % ) . Dose intensification of known active agents may improve outcome . Experimental Design : This pilot study evaluated the feasibility of dose intensification of cyclophosphamide in previously untreated patients ages < 21 years with intermediate-risk rhabdomyosarcoma . Induction therapy comprised four 3-week cycles of VAC : vincristine ( V ) 1.5 mg/m2 on days 0 , 7 , and 14 ; actinomycin D ( A ) 1.35 mg/m2 on day 0 ; and dose-intensified cyclophosphamide ( C ) on days 0 , 1 , and 2 . The three cyclophosphamide dose levels tested were as follows : ( a ) 1.2 g/m2/dose ; ( b ) 1.5 g/m2/dose ; and ( c ) 1.8 g/m2/dose . Continuation therapy comprised nine additional cycles of VAC with 2.2 g/m2/cycle of C. Radiotherapy was administered at week 0 ( parameningeal tumors with intracranial extension ) or week 12 or 15 ( all others ) . Results : Between October 1996 and August 1999 , 115 eligible patients were enrolled . Three of 15 patients treated at dose level 2 experienced life-threatening dose-limiting toxicity ( typhlitis ± other severe toxicity ) . Dose level 1 was the maximum-tolerated dose , and 91 evaluable patients were treated at this level . The 3-year failure-free and overall survival estimates for patients treated at the maximum-tolerated dose were 52 % ( 95 % confidence interval , 41–64 % ) and 67 % ( 95 % confidence interval , 56–77 % ) , respectively , at a median follow-up of 3 years . Conclusions : A 64 % increase in the st and ard  cyclophosphamide  dosage during induction ( to 3.6 g/m2/cycle ) was tolerated . However , outcomes were similar to those observed at lower dosages , suggesting that alkylator dose intensification does not benefit patients with intermediate-risk rhabdomyosarcoma Summary One hundred and seventy-one patients with advanced soft tissue sarcoma entered a r and omized crossover phase II study comparing cyclophosphamide ( CYCLO ) with a new analogue , ifosfamide ( IFOS ) , both administered as 24 h i.v . infusions every 3 weeks . The doses used were CYCLO 1.5 g/m2 and IFOS 5 g/m2 , with provision for dose escalation . All patients received mesna 400 mg/m2 as an i.v . bolus 4 hourly x 9 doses , commencing at the start of the oxazophosphorine infusion . Patients who had received previous chemotherapy were eligible provided this did not include a classical alkylating agent . There were 22 patients who were ineligible , and response could not be evaluated in 12 additional patients .  IFOS produced two complete and ten partial remissions , for an overall response rate of 18 % . CYCLO was significantly ( P=0.04 ) less active , producing one complete and five partial remissions , an overall response rate of 9 % . Stabilization of disease was similar in both arms ( 27 % and 24 % respectively ) , but fewer patients showed progression on IFOS . The response rate was higher ( 20 % vs 5 % ) for patients who had not received previous chemotherapy , and also for female compared with male patients ( 21 % vs 5 % ) . When only patients who had not received previous chemotherapy were considered , the respective response rates for IFOS and CYCLO were 24 % and 15 % . There were no responses in previously treated patients receiving CYCLO . There were four partial responses in 33 patients crossing from CYCLO to IFOS , but no responses in 18 patients receiving CYCLO after IFOS .  Leucopenia was significantly more pronounced ( P=0.0004 ) with CYCLO , both after the first course and throughout treatment , although the incidence of severe infections , 6 % , was the same in both arms . Nausea and vomiting were more severe with IFOS ( P=0.022 ) , but other toxicities were mild . Grade 1 or 2 bladder ( haematuria ) or renal ( rise in serum creatinine ) toxicity was slightly more frequent with IFOS ( 7 vs 3 patients ) and was a reason for stopping treatment for one patient in each arm . Three episodes of mild to moderate drowsiness after IFOS were reported , but no severe encephalopathy . A higher response rate with less myelosuppression suggests that IFOS may have advantages over CYCLO in combination with such active agents as adriamycin Following observation of the predictive value of the histologic extent of tumor cell destruction after preoperative chemotherapy for metastasis-free survival ( MFS ) in osteosarcoma , a r and omized study was undertaken with the aim of ( 1 ) sparing some patients the unpleasant side effects of highly toxic drugs like doxorubicin ( DOX ) and cisplatin ( CPDD ) by administering these drugs postoperatively only after poor response with a milder preoperative regimen , and ( 2 ) improving the prognosis of patients responding poorly to the initial treatment by use of a  salvage chemotherapy  postoperatively . The available patients were divided into two groups . Those in the study arm received a preoperative chemotherapy consisting of high-dose methotrexate ( HDMTX ) and the triple drug combination of bleomycin , cyclophosphamide , and dactinomycin ( BCD ) and were switched to DOX/CPDD postoperatively in case of poor response . DOX/CPDD was used besides HDMTX for initial treatment in the control arm , and BCD alternatively with CPDD/ifosfamide ( IFO ) for postoperative salvage treatment . The response rate of the study arm was significantly inferior to the control arm ( 26 % v 60 % ; P less than .001 ) . The actuarial 4-year MFS rate of poor responders after salvage chemotherapy also was poorest in the study arm ( 41 % ) ; it was unchanged in the control arm ( 53 % ) as compared with that of poor responders from the COSS-80 study without salvage chemotherapy ( 52 % ) . The actuarial 4-year MFS rate of good responders was 73 % in the study arm , 79 % in the control arm , and not significantly different from that of the COSS-80 study ( 84 % ) , although postoperative chemotherapy of good responders had been markedly shortened as compared with the COSS-80 study . The actuarial 4-year MFS rate of the study arm as a whole was inferior to that of the control arm ( 49 % v 68 % ; P less than .1 ) and also inferior to the COSS-80 study ( 68 % ; P less than .01 ) , indicating a failure of the employed salvage strategy in general and especially of the effort to restrict the use of the very effective but highly toxic drugs DOX and CPDD to patients resistant to a less toxic initial treatment 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 Ifosfamide ( IFOS ) 5 g/m2 and its parent analog Cyclophosphamide ( CYCLO ) 1.5 g/m2 were studied in a r and omized phase II study , accruing 171 patients with advanced soft tissue sarcoma . Both drugs were administered as 24 hr infusions , every 3 weeks , with comcomitant Mesna 400 mg/m2 i.v . bolus 4 hourly X 9 doses . Twenty-four patients were ineligible and 12 were not evaluable . The groups were well matched for age , previous chemotherapy ( 42 % of the total ) or radiotherapy , the presence of distant metastases and performance status , but there were more females ( 59 % vs. 45 % ) in the IFOS arm . Among the 68 evaluable patients receiving IFOS , there were 2 CR , 10 PR ( overall response 18 % ) , 27 SD and 29 PD . For CYCLO , the corresponding results in 67 patients were 1 CR , 4 PR ( overall response 8 % ) , 23 SD and 39 PD . Using the chi-square test the P values for response rate and linear trend were 0.13 and 0.04 respectively . Response rates were higher for females ( 20 % vs. 5 % , P = 0.01 ) and patients who had not received previous chemotherapy ( 19 % vs. 4 % , P = 0.01 ) . Fourteen of the 17 responses came from a group of 43 females , who had not received previous chemotherapy , for whom the overall response rate was 37.5 % . Remissions were noted in only 4 histological subtypes ( central ly review ed material ) , i.e. , 5 of 17 synovial sarcomas , 7 of 13 mixed mesodermal sarcomas and 2 of 7 fibrosarcomas . One of the 31 leiomyosarcomas responded to Cyclophosphamide .  Duration s of response did not differ significantly between the 2 arms -- median 26 , range 10 - 81 + weeks . Leucopenia was significantly more severe on CYCLO , particularly in patients who had received previous chemotherapy ( P = 0.007 ) . Serious infections occurred in approx . 7 % of patients with no difference between the two drugs , although there was one toxic death on CYCLO .  Nausea and vomiting were significantly worse on  IFOS  and alopecia , related in extent to dose , was seen in both arms . Other side-effects , such as hematuria or rises in serum creatinine and encephalopathy , were infrequent and mild . A higher response rate with less myelosuppression suggests that IFOS may have advantages over CYCLO in combination therapy PURPOSE The purpose of this review is to characterize the nephrotoxicity noted in newly diagnosed patients under 21 years of age after treatment with ifosfamide-containing chemotherapy regimens and local irradiation for localized gross residual rhabdomyosarcoma or undifferentiated sarcoma . PATIENTS AND METHODS From 1987 to 1991 , 194 previously untreated patients received vincristine and ifosfamide plus dactinomycin or etoposide for 1 - 2 years . Ifosfamide was given at 1.8 g/m2/day for 5 days with sodium mercaptoethane sulfonate , or 9 g/m2 of ifosfamide per course . The three-drug regimen was repeated every 3 - 4 weeks . RESULTS Twenty-eight patients ( 14 % ) developed renal toxicity : 19 had renal tubular dysfunction ( RTD ) characterized by low serum phosphate ( < or = 3 mg/dl ) or bicarbonate ( < 20 or = mEq/L ) levels , five had decreased glomerular function ( DGF ) , and four had both RTD and DGF . When nine or more courses of ifosfamide ( > 72 g/m2 ) were given , children < 3 years of age had a higher incidence of RTD than did children > or = 3 years of age ( 34 % versus 6 % ; p < 0.001 ) . A similar age difference was observed even when eight or fewer courses ( < or = 72 g/m2 ) were given ( p = 0.03 ) . A matched case-control comparison showed that renal abnormalities at diagnosis , chiefly hydronephrosis , also increased the risk of renal tubular injury by ifosfamide by a factor of 13 ( p < 0.001 ) . Patients with DGF t 
    Output:
    
Therefore no definitive conclusions can be made about the effects of cyclophosphamide and ifosfamide in these patients .