High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue sarcomas. A study of the EORTC soft tissue and bone sarcoma group. Carminomycin vs adriamycin in advanced soft tissue sarcomas: an EORTC randomised phase II study. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Cyclophosphamide versus ifosfamide: final report of a randomized phase II trial in adult soft tissue sarcomas. Treatment of recurrent or advanced uterine sarcoma. A randomized trial of doxorubicin Versus doxorubicin and cyclophosphamide (a phase III trial of the gynecologic oncology group) High-dose DTIC in advanced soft-tissue sarcomas in the adult. A phase II study of the E.O.R.T.C. Soft Tissue and Bone Sarcoma Group. Combination chemotherapy with adriamycin and streptozotocin; I. Clinical results in patients with advanced sarcoma A randomized study of adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcomas Randomised study of high-dose epirubicin versus high-dose epirubicin-cisplatin chemotherapy for advanced soft tissue sarcoma. A comparison of adriamycin versus vincristine and adriamycin, and cyclophosphamide versus vincristine, actinomycin‐D, and cyclophosphamide for advanced sarcoma An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. Adriamycin versus epirubicin in advanced soft tissue sarcomas. A randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas.
The activity and toxicity of single-agent st and ard-dose doxorubicin were compared with that of two schedules of high-dose epirubicin . A total of 334 chemonaive patients with histologically confirmed advanced soft-tissue sarcomas received ( A ) doxorubicin 75 mg m(-2 ) on day 1 ( 112 patients ) , ( B ) epirubicin 150 mg m(-2 ) on day 1 ( 111 patients ) or ( C ) epirubicin 50 mg m(-2 ) day(-1 ) on days 1 , 2 and 3 ( 111 patients ) ; all given as bolus injection at 3-week intervals . A median of four treatment cycles was given . Median age was 52 years ( 19 - 70 years ) and performance score 1 ( 0 - 2 ) . Of 314 evaluable patients , 45 ( 14 % ) had an objective tumour response  ( eight complete response , 35 partial response ) . There were no differences among the three groups . Median time to progression for groups A , B and C was 16 , 14 and 12 weeks , and median survival 45 , 47 and 45 weeks respectively . Neither progression-free ( P = 0.93 ) nor overall survival ( P = 0.89 ) differed among the three groups . After the first cycle of therapy , two patients died of infection and one owing to cardiovascular disease , all on epirubicin . Both dose schedules of epirubicin were more myelotoxic than doxorubicin .  Cardiotoxicity ( > or = grade 3 ) occurred in 1 % , 0 % and 2 % respectively . Regardless of the schedule , high-dose epirubicin is not a preferred alternative to st and ard-dose doxorubicin in the treatment of patients with advanced soft-tissue sarcomas Eighty-three patients with advanced soft tissue sarcoma who had received no prior chemotherapy entered a r and omised phase II study comparing carminomycin ( CMM ) 20 mg/m2 with adriamycin ( ADM ) 75 mg/m2 , both administered i.v . bolus every 3 weeks . Six patients were ineligible and response could not be evaluated in 6 additional patients . Thirty-eight evaluable patients received ADM and 33 received CMM . There was one complete response to ADM and 10 partial responses , an overall response rate of 29 % . CMM showed significantly ( P = 0.01 ) lower antitumour activity -- one partial response ( 3 % ) . Stabilisation of disease was similar in both arms ( 47 and 45 % ) , but fewer patients progressed on ADM ( 24 compared to 52 % ) . Duration s of response dating from the start of chemotherapy were 5 months for complete remission on ADM , a median of 7 months ( range 4 - 17 ) for partial response on ADM and 14 months for the one partial remission on CMM . Although the median time to progression for all patients receiving CMM ( 2 months ) was significantly ( P = 0.001 ) shorter than for those receiving ADM ( 5 months ) , patients on ADM had only a marginally significant longer duration of survival ( P = 0.06 ) than the patients receiving CMM . A leucocyte nadir less than 2.0 X 10(9)/l occurred in 38 % of patients receiving ADM and 43 % receiving CMM .  Anaemia and thrombocytopoenia were uncommon . Other toxicities such as nausea , vomiting , anorexia and alopecia were more severe in the ADM group . There was one infective death secondary to leucopoenia in the ADM arm , and one patient who had received 109 mg/m2 CMM + 255 mg/m2 ADM developed progressively fatal cardiomyopathy PURPOSE The aim of this trial was to compare the activity and toxicity of single-agent doxorubicin with that of two multidrug regimens in the treatment of patients with adult advanced soft tissue sarcomas . PATIENTS AND METHODS This was a prospect i ve r and omized phase III trial performed by 35 cancer centers within the Soft Tissue and Bone Sarcoma Group of the European Organization for Research and Treatment of Cancer ( EORTC ) . Six hundred sixty-three eligible patients were r and omly allocated to receive either doxorubicin 75 mg/m2 ( arm A ) , cyclophosphamide , vincristine , doxorubicin , and dacarbazine ( CYVADIC ) ( arm B ) , or ifosfamide 5 g/m2 plus doxorubicin 50 mg/m2 ( arm C ) . RESULTS The overall response rate was 24 % ( 95 % confidence interval , 20.7 % to 27.3 % ) among eligible patients and 26 % among assessable patients . No statistically significant difference was detected among the three study arms in terms of response rate ( arm A , 23.3 % ; arm B , 28.4 % ; and arm C , 28.1 % ) , remission duration ( median , 46 weeks on arm A , 48 weeks on arm B , and 44 weeks on arm C ) , or overall survival ( median , 52 weeks on arm A , 51 weeks on arm B , and 55 weeks on arm C ) . The degree of myelosuppression was significantly greater for the combination of ifosfamide and doxorubicin than for the other two regimens . Cardiotoxicity was also more frequent in this arm , but other toxicities were similar . CONCLUSION In advanced soft tissue sarcomas of adults , single-agent doxorubicin is still the st and ard chemotherapy against which more intensive or new drug treatments should be compared . Combination chemotherapy can not be recommended outside a controlled clinical trial with the exclusion of some subsets of sarcoma patients for whom significant tumor volume reduction may be an important end point of a chemotherapy regimen 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 Recurrent or metastatic uterine sarcoma represents an ominous and aggressive form of malignant disease . In an attempt to define a beneficial treatment program , we compared treatment with doxorubicin ( A ) 60 mg/m2 versus a combination of doxorubicin 60 mg/m2 and cyclophosphamide 500 mg/m ( CA ) , each regimen given every 3 weeks . Of 132 patients entered on study , 104 were eligible ; 50 received A and 54 CA . Pretreatment characteristics were similar , and no patient had received prior chemotherapy . The proportion of complete responses ( CR ) + partial responses ( PR ) for measurable disease patients was 5 of 26 ( 19 % ) for both A and CA . Multivariate analysis done on progression‐free interval ( PFI ) and survival ( S ) showed CA to be of no benefit over A ( PFI , P = 0.22 ; S , P = 0.55 ) . For both A and CA patients , measurable disease ( PFI , P = 0.002 ; S , P = 0.02 , respectively ) , performance status ( PFI , P = 0.004 ; S , P = 0.0002 ; respectively ) , and sites of residual disease ( PFI , P = 0.008 ; S , P = 0.003 , respectively ) were detected as prognostic variables . Conversely , histologic type , age , and recurrence status ( primary versus recurrent at entry ) were not prognostic indicators . These data indicate no significant benefit of CA versus A alone in patients with uterine sarcoma Forty-four of 50 adult patients with advanced soft-tissue sarcoma who had received previous chemotherapy  were evaluable for response after treatment with DTIC . The therapeutic schedule consisted of DTIC 1.2 g/m2 infused over 20 minutes , and repeated every 3 weeks . There were 1 complete and 7 partial remissions ( objective activity 18 % , 95 % C.I. 7%-29 % ) , with a median duration of 8 weeks ( range 5 - 19 ) , with the complete remission lasting 1 yr . Hematologic toxicity was dose-limiting ; W.H.O. greater than or equal to 3 values were observed for WBC in 36 % , and for platelets in 26 % of patients . The non-hematologic toxicity included nausea and vomiting ( 90 % ) , a flu-like syndrome ( 49 % ) , diarrhea ( 35 % ) , pain in the infused vein ( 28 % ) and hypotensive episodes ( 4 % ) . Intermittent high-dose DTIC is active in advanced soft-tissue sarcoma and should be considered for inclusion in combination regimens In a prospect ively r and omized study , 17 evaluable patients treated with adriamycin alone , 60 mg/m2 intravenously every 3 wk , were compared with 14 patients treated with adriamycin in the same dose and schedule plus streptozotocin , 500 mg/m2/day intravenously for 5 days every 3 wk . All patients had advanced sarcomas , but none had previously received either adriamycin or streptozotocin .  Objective responses were seen in 9 patients on the single drug arm ( 4 with more than 50 % tumor shrinkage and 5 with stabilization of disease ) , and in 8 patients given the combination drug arm ( 2 with more than 50 % tumor shrinkage and 6 with stabilization oldisease ) . Duration of response and survivalfrom treatmentfor both treatment groups were similar . Transient hepatic dysfunction , renal function abnormalities , and nausea with vomiting were additive in the combination drug arm , the last two limiting therapy most . Leukopenia , thrombocytopenia , and mucositis appeared to be synergistically increased in patients receiving both adriamycin and streptozotocin . Patients with abnormal pretreatment renalfunction were able to tolerate the combination therapy without undue incidence or severity of renal toxicity . Patients who developed transient streptozotocin‐related renal dysfunction were able to toleratefurther doses of streptozotocin alter their renal parameters normalized . Adriamycin in combination with streptozotocin did not offer any therapeutic advantage over adriamycin alone Various drug combinations including Adriamycin have been tested in soft tissue sarcomas , but optimal treatment remains unclear . We have evaluated Adriamycin with and without dimethyl‐triazeno‐imid‐azole‐carboxamide ( DTIC ) in the treatment of Stage III or IV and recurrent sarcomas of the uterus . Two hundred and forty cases of these rare tumors were evaluable . Of 146 evaluable patients with measurable disease , 13/80 ( 16.3 % ) of  Adriamycin‐treated patients and 16/66 ( 24.2 % ) of patients receiving the combination showed an objective response ( P > 0.05 ) . Lung metastases responded more frequently ( P = 0.04 ) to combination therapy , but there was no survival advantage . For patients with nonmeasurable disease the progression‐free interval was similar ( 10.0 months for Adriamycin and 8.0 months for the combination ) . Leiomyosarcomas had a significantly longer survival than other cell types ( 12.1 versus 6.0 months , P < 0.001 ) but there was no advantage for either regimen . There was a suggestion that heterologous mixed mesodermal sarcomas were more responsive to the combination ( 27.3 versus 8.7 % ) . The addition of DTIC produced significantly more hematologic and gastrointestinal toxicity . Other Adriamycin combinations should be evaluated in uterine sarcomas A r and omised study was started in chemotherapy-naive patients with advanced soft tissue sarcomas who received either epirubicin 60 mg/m2/24 h ( total dose for cycle 180 mg/m2 ) days 1 , 2 and 3 , ( group A ) or epirubicin  60 mg/m2/24 h  days 1 , 2 and 3 and cisplatin  30 mg/m2/24 h days 2 , 3 , 4 and 5 ( group B ) . The maximal number of cycles foreseen in both groups was eight . Cardiotoxicity of the regimens was monitored by serial LVEF determinations . 106 patients entered this study , 50 ( 45 evaluable for activity ) r and omised to group A , and 56 ( 54 evaluable for activity ) to group B. The groups were well balanced for age , sex , performance status and histological type . In group A , there was 1 complete response ( CR ) and 12 partial responses ( PR ) , the overall response being 13/45 ( 29 % ) ; in group B , there were 7 CRs and 22 PRs , the overall response being 29/54 ( 54 % ) . The difference between the overall response was statistically significant ( chi 2 = 6.19 , P < 0.025 ) . The epirubicin-cisplatin regimen was found to be more toxic for platelets and more emetogenic , but cardiotoxicity , either acute or cumulative , was not found to be a major problem in both groups . However , a complete responder receiving a cumulative epirubicin dose of 1440 mg/m2 died from congestive heart failure after a disease-free interval of 27 months . The high response in group B could be the result of the synergism between high-dose epirubicin and cisplatin in patients with advanced soft tissue sarcomas This r and omized study , conducted by the Eastern Cooperative Oncology Group , compared Adriamycin ( doxorubicin ) ( 70 mg/m2 ) versus vincristine ( 1.4 mg/m2 ) and Adriamycin ( 50 mg/m2 ) ; and cyclophosphamide ( 750 mg/m2 ) versus vincristine ( 1.4 mg/m2 ) , actinomycin‐D , ( 0.4 mg/m2 ) , and cyclophosphamide ( 750 mg/m2 ) for treatment of metastatic mesenchymal malignancies . The respective response rate  seen in 200 evaluable patients to the treatments were , 27 , 19 , and 11 % . The response rate to Adriamycin was significantly better than the response to vincristine , actinomycin‐D , and cyclophosphamide ( P = 0.03 , two‐sided ) . The respective median survivals on the three treatments were 37 , 34 , and 41 weeks and were not significantly different . Moderate or severe vomiting occurred in 60 % of patients receiving vincristine — cyclophosphamide — adriamycin , a greater frequency than in Adriamycin alone ( P = .09 two‐sided ) . Severe or life‐threatening hematologic toxicity ( leukocytes < 2000 , platelets < 50,000 ) occurred in 30 % of patients receiving the Adriamycin combination , a markedly increased frequency when compared to the other two regimens ( P = 0.07 , P = 0.02 , two‐sided ) . This trial establishes that Adriamycin has a better response rate than the combination of vincristine — actinomycin‐D — cyclophosphamide in advanced sarcomas . The combination of vincristine , Adriamycin , and cyclophosphamide  increased toxicity and did not add to the therapeutic effect achieved with Adriamycin alone PURPOSE AND METHODS Doxorubicin alone or with dacarbazine ( DTIC ; AD ) is considered the best available therapy for metastatic adult sarcomas .  Ifosfamide is active in sarcomas that have failed to respond to a doxorubicin-based regimen . This study was design ed to determine if ifosfamide added to doxorubicin and DTIC ( ADI ) significantly effects toxicity , response rate , and survival .  Patients with measurable metastatic or unresectable sarcoma were r and omized to receive AD or ADI .  Patients with chondrosarcomas , fibrosarcomas , and other sarcomas of bone were eligible , although those with osteosarcoma , rhabdomyosarcoma , Ewing 's sarcoma , Kaposi 's sarcoma , and mesothelioma were excluded , as were patients with prior chemotherapy for sarcoma or prior doxorubicin .  RESULTS Between 1987 and 1989 , 340 eligible patients were r and omized . Significantly more myelosuppression , a higher response rate ( 17 % v 32 % ; P < .002 ) and longer time to progression ( 4 v 6 months ; P < .02 ) were observed for patients who received ifosfamide . An overall survival advantage for the two-drug regimen ( 12 v 13 months ; P = .04 ) was not significant by multivariate analysis . CONCLUSION In all three r and omized trials of doxorubicin with and without ifosfamide ( Eastern Cooperative Oncology Group [ ECOG ] , European Organization for Research and Treatment of Cancer [ EORTC ] , and this study ) , the response rate was higher for the ifosfamide-containing arm , significantly so in this and the ECOG studies . An improved response rate may be particularly important for the preoperative management of high- grade , borderline resectable lesions or pulmonary metastases , particularly in younger patients . In older patients , or for low-to intermediate- grade lesions , doxorubicin and DTIC followed by ifosfamide on progression is preferred The objective of this r and omized phase II/phase III study was to investigate the efficacy and toxicity of equimolar doses of adriamycin ( ADM ) and 4-epiadriamycin ( EPI ) in patients with locally advanced and /or metastatic soft tissue sarcoma . Doses of ADM and EPI were 75 mg/m2 given as an i.v . bolus injection every 3 weeks . Two hundred and ten patients were entered into the study by 18 institutions . Twenty-eight patients were ineligible and 15 were non-evaluable , leaving 167 evaluable patients . The two treatment groups were well balanced for sex , performance status , age , prior radiotherapy , extent and site of disease . Rates of response were similar , 25 % in the ADM group compared to 18 % in the EPI group ( P = 0.33 ) , and there were no significant differences between the ADM and EPI groups with respect to median duration of response ( 45 weeks vs. 77 weeks , P = 0.08 ) , time to progression ( 15 weeks vs. 12 weeks , P = 0.945 ) , and median survival ( 41 weeks vs. 48 weeks , P = 0.363 ) . Myelotoxicity as shown by leucopenia was significantly more pronounced in the ADM treated patients ( P = 0.002 ) . Other toxicities such as alopecia and nausea/vomiting were also more severe in the ADM group ( P = 0.02 and 0.06 , respectively ) . In conclusion , the use of equimolar doses of ADM and EPI in advanced soft tissue sarcoma produced response rates which did not differ significantly and were only slightly in favour of ADM . However , this was achieved at the expense of higher toxicity PURPOSE This three-armed phase III study in adults with advanced soft tissue sarcomas was planned as a comparison of objective regression rates , toxicity , and survival of patients receiving doxorubicin alone , ifosfamide plus doxorubicin , and mitomycin plus doxorubicin plus cisplatin .  PATIENTS AND METHODS Between December 1987 and July 1990 , 279 patients with histologically confirmed sarcomas were enrolled to receive treatment A ( doxorubicin 80 mg/m2 ) , treatment B ( ifosfamide 7.5 g/m2 plus doxorubicin 60 mg/m2 ) , or treatment C ( mitomycin 8 mg/m2 plus doxorubicin 40 mg/m2 plus cisplatin 60 mg/m2 ) . RESULTS Of 262 assessable patients , 74 ( 29 % ) achieved objective tumor regression . Objective regression occurred in 20 % of the 90 patients who received doxorubicin alone ( complete remission [ CR ] rate , 2 % ) , in 34 % of the 88 who received ifosfamide plus doxorubicin ( CR rate , 3 % ) , and in 32 % of the 84 who received mitomycin plus doxorubicin plus cisplatin ( CR rate , 7 % ) . With grade 3 or greater myelosuppression in 53 % of group A , 80 % of group B , and 55 % of group C , regimen B was significantly more myelosuppressive than either regimen A or C ( P = .01 ) with two , three , and one treatment-related deaths , respectively . Synovial sarcomas were responsive to ifosfamide plus doxorubicin , especially among patients younger than 40 years of age . CONCLUSION Ifosfamide plus doxorubicin produced a significantly higher regression rate ( P = .03 ) than did doxorubicin alone ; however , this was achieved at a level of myelosuppression significantly more intense than that produced by the single agent or by the three-drug combination . Mitomycin , doxorubicin , and cisplatin also appeared to be more active than the single agent ; however , at a myelosuppression level similar to that of doxorubicin alone , this trend ( P = .07 ) did not attain the usual level for significance . No significant survival differences were observed
To make recommendations for the use of doxorubicin-based chemotherapy in patients with soft-tissue sarcoma .
Patients .
The recommendations apply to patients with symptomatic unresectable locally advanced or metastatic soft-tissue sarcoma who are c and i date s for palliative chemotherapy .