Prospective treatment of advanced or recurrent endometrial carcinoma with cisplatin, doxorubicin, and cyclophosphamide. Randomized phase III trial of standard timed doxorubicin plus cisplatin versus circadian timed doxorubicin plus cisplatin in stage III and IV or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study. Phase II trial of methotrexate, vinblastine, doxorubicin, and cisplatin in advanced/recurrent endometrial carcinoma. Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group. Treatment of advanced or recurrent endometrial carcinoma with combination of etoposide, cisplatin, and 5-fluorouracil: a phase II study. Cisplatin-, epirubicin- and paclitaxel-containing chemotherapy in uterine adenocarcinoma. Treatment of uterine papillary serous carcinoma with paclitaxel. Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a phase II study. Phase II trial of adriamycin in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Multidrug Treatment of Advanced and Recurrent Endometrial Carcinoma: A Gynecologic Oncology Group Study Cisplatin Chemotherapy for Disseminated Endometrial Cancer Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a gynecologic oncology group study. A phase II trial of paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometrium: a Gynecologic Oncology Group study. Treatment of advanced or recurrent endometrial carcinoma with single-agent carboplatin. A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma: A Gynecologic Oncology Group study. Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: a Gynecologic Oncology Group study. Paclitaxel and cisplatin in advanced or recurrent carcinoma of the endometrium: long-term results of a phase II multicenter study. Cyclophosphamide or ifosfamide in patients with advanced and/or recurrent endometrial carcinoma: a randomized phase II study of the EORTC Gynecological Cancer Cooperative Group. Pegylated liposomal doxorubicin and carboplatin in advanced gynecologic tumors: a prospective phase I/II study of the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR). Treatment of Advanced or Recurrent Endometrial Adenocarcinoma With Cyclophosphamide, Doxorubicin, Cis-Platinum, and Megestrol Acetate Phase II trial of doxorubicin, 5-fluorouracil, etoposide, and cisplatin in advanced or recurrent endometrial carcinoma. Doxorubicin-cisplatin-vinblastine combination chemotherapy of advanced endometrial carcinoma: a Southwest Oncology Group Study. Cisplatin, adriamycin, etoposide, megestrol acetate versus melphalan, 5-fluorouracil, medroxyprogesterone acetate in the treatment of endometrial carcinoma. Phase II study of paclitaxel as salvage treatment in advanced endometrial cancer. Carboplatin, Methotrexate and 5-Fluorouracil in Combination with Medroxyprogesterone Acetate (JMF-M) in the Treatment of Advanced or Recurrent Endometrial Carcinoma: A Hellenic Cooperative Oncology Group Study
Both single-agent cisplatin and the combination of doxorubicin and cyclophosphamide demonstrated moderate activity against endometrial carcinoma in earlier salvage trials . Since January 1979 , 102 patients with advanced primary ( n = 42 ) or recurrent ( n = 60 ) endometrial carcinoma were prospect ively treated with cisplatin ( 50 mg/m2 ) , doxorubicin ( 50 mg/m2 ) , and cyclophosphamide ( 500 mg/m2 ) ( PAC ) . PAC was administered monthly until disease progression or toxicity precluded additional therapy . Patients received a median of five treatment cycles ( range 1 - 13 ) . Of the 87 patients with measurable disease , 12 had a complete clinical response , while 27 had a partial clinical response , for an overall objective response rate of 45 % . No differences in response rates between primary and recurrent disease patients were noted . Median time to response was 2.5 months with a median response duration of 4.8 months . Nonresponders included 33 patients with stable disease and 15 with progression . Median progression-free survival for all patients was 6 months . Dose escalation was possible in 25 % of patients ; however , 52 % of patients required dose reductions during treatment . Clinical ly significant toxicities included neutropenia ( 65 % ) , anemia ( 47 % ) , emesis ( 21 % ) , nephrotoxicity ( 17 % ) , and neurotoxicity ( 4 % ) . Our study indicates that endometrial cancer is significantly responsive to PAC . Enthusiasm for this regimen should be tempered by the limited duration of response and substantial treatment toxicity PURPOSE To determine if circadian timed ( CT ) chemotherapy results in improved response , progression-free survival ( PFS ) , overall survival ( OS ) , and lower toxicity , when compared with st and ard timed ( ST ) chemotherapy . MATERIAL S AND METHODS Eligibility criteria were stage III , IV , or recurrent endometrial cancer with poor potential for cure by radiation therapy or surgery ; measurable disease ; and no prior chemotherapy . Therapy was r and omized to schedules of ST doxorubicin 60 mg/m2 plus cisplatin 60 mg/m2 , or CT doxorubicin 60 mg/m2 at 6:00 am plus cisplatin 60 mg/m2 at 6:00 pm . Cycles were repeated every 3 weeks to a maximum of eight cycles . RESULTS The ST arm included 169 patients , and the CT arm included 173 patients . The objective response rate ( complete responses plus partial responses ) was 46 % in the ST group compared with 49 % in the CT group ( P = .26 , one tail ) . Median PFS and OS were 6.5 and 11.2 months , respectively , in the ST group ; and 5.9 and 13.2 months , respectively , in the CT group ( PFS : P = .31 ; OS : P = .21 , one tail ) . Median total doses were 209 mg/m2 doxorubicin and 349 mg/m2 cisplatin in the ST group , versus 246 mg/m2 doxorubicin and 354 mg/m2 cisplatin in the CT group . Grade 3 or 4 leukopenia occurred in 73 % of patients in the ST arm and in 63 % of patients in the CT arm . There were eight treatment-related deaths . CONCLUSION In this trial , no significant benefit in terms of response rate , PFS or OS , or toxicity profile was observed with CT doxorubicin plus cisplatin in patients with advanced or recurrent endometrial carcinoma A phase II combination chemotherapy protocol combining methotrexate , vinblastine , doxorubicin , and cisplatin was design ed to evaluate tumor response and survival in patients with advanced/recurrent endometrial carcinoma . Thirty patients with advanced/recurrent endometrial carcinoma were assigned to chemotherapy treatment at 4-week intervals with methotrexate 30 mg/m2 i.v . Days 1 , 15 , and 22 ; vinblastine 3 mg/m2 i.v . Days 2 , 15 , and 22 ; doxorubicin 30 mg/m2 i.v . Day 2 ; and cisplatin 70 mg/m2 i.v . Day 2 . After a median of four cycles ( maximum number two cycles beyond complete regression ; minimum six cycles for stable partial regression ) , we observed objective regression in 20 patients ( 67 % ) ( 95 % CI , 50 , 84 ) with complete regression in 8 patients ( 27 % ) and partial regression in 12 patients ( 40 % ) . Median overall survival was 9.9 months ( range , 0.3 - 34.2 ) , and median survival of responders was 11.0 months ( range , 2.6 - 34.2 ) from initial date of response . Toxicity was substantial with two treatment-related deaths and consisted predominantly of neutropenia ( grade 3 or greater in 93 % of the patients ) , alopecia , nausea , emesis , stomatitis , and azotemia . In conclusion , MVAC is a highly active outpatient chemotherapy regimen in patients with advanced/recurrent endometrial carcinoma , achieving a high complete and partial response rate . Toxicity is substantial in this elderly patient population BACKGROUND Combination chemotherapy yields better response rates which do not always lead to a survival advantage . The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin ( DOX ) versus combination therapy with cisplatin ( CDDP ) in endometrial adenocarcinoma lead to significant advantage in favour of the combination . PATIENTS AND METHODS Eligible patients had histologically-proven advanced and /or recurrent endometrial adenocarcinoma and were chemo-naïve . Treatment consisted of either DOX 60 mg/m(2 ) alone or CDDP 50 mg/m2 added to DOX 60 mg/m2 , every 4 weeks . RESULTS A total of 177 patients were entered and median follow-up is 7.1 years . The combination DOX-CDDP was more toxic than DOX alone . Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 ( 55 % versus 30 % ) . Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia ( 72 % versus 65 % ) and nausea/vomiting ( 36 % versus 12 % ) . The combination DOX-CDDP provided a significantly higher response rate than single agent DOX ( P < 0.001 ) . Thirty-nine patients ( 43 % ) responded on DOX-CDDP [ 13 complete responses ( CRs ) and 26 partial responses ( PRs ) ] , versus 15 patients ( 17 % ) on DOX alone ( 8 CR and 7 PR ) . The median overall survival ( OS ) was 9 months in the DOX-CDDP arm versus 7 months in the DOX alone arm ( Wilcoxon P = 0.0654 ) . Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival , and stratifying for this factor , treatment effect reaches significance ( hazard ratio = 1.46 , 95 % confidence interval 1.05 - 2.03 , P = 0.024 ) . CONCLUSIONS In comparison to single agent DOX , the combination of DOX-CDDP results in higher but acceptable toxicity . The response rate produced is significantly higher , and a modest survival benefit is achieved with this combination regimen , especially in patients with a good performance status Forty-nine consecutive patients with metastatic or recurrent endometrial carcinoma were treated with a monthly combination chemotherapy consisting of VP 16 - 213 80 mg/m2 i.v . Days 1 - 3 , 5-fluorouracil ( 5-FU ) 600 mg/m2 i.v . Days 1 - 3 , and cisplatin 35 mg/m2 i.v . Days 1 - 3 . The objective response rate was 41 % ( 95 % CI , 27 - 54 % ) with 14.3 % complete responses . The median survival duration was 14 months . The median response duration was 12 months . The estimated median survival for responders was 20 months . Three patients are still free of disease 5 years after treatment . The major toxic effects were myelosuppression ( less than 25 % of grade III and IV leucopenia , and 14 % grade III and IV thrombocytopenia ) . Grade III peripheral neuropathy was observed in five patients . Cisplatin administration had to be stopped due to renal toxicity in six patients . No treatment-related deaths occurred . The combination of etoposide , 5 fluorouracil , and cisplatin is an effective regimen with an acceptable toxicity in patients with recurrent or metastatic endometrial carcinoma PURPOSE To evaluate the toxic effects and antitumour activity of a multidrug regimen with cisplatin , epirubicin and paclitaxel ( CEP ) as initial therapy in patients with uterine adenocarcinoma . PATIENTS AND METHODS Forty-nine patients with histologically-confirmed diagnoses of locally advanced , recurrent or metastatic cervical or endometrial adenocarcinoma entered the study . Treatment consisted of epirubicin ( E ) given at 70 mg/m2 followed by paclitaxel ( P ) ( 175 mg/m2 over three hours ) and cisplatin ( C ) ( 50 mg/m2 ) , repeated every three weeks . Eligibility criteria also included age < or = 75 years , no previous chemotherapy , no previous radiotherapy to the tumour parameters , bidimensionally-measurable lesions , no previous or ongoing cardiac disease , and renal and liver function within normal limits .  Complete blood cell counts were repeated weekly , and tumor response was assessed every three cycles . A maximum of eight courses was administered in responding patients . RESULTS From January 1996 to January 1997 , 30 patients with endometrial adenocarcinoma and 19 with cervical adenocarcinoma entered the study , for a total of 213 cycles of treatment . In patients with endometrial carcinoma the overall clinical and pathological response rates were 73 % ( 95 % CI , range 54%-88 % ) and 35 % ( 95 % CI , range 16%-57 % ) respectively ; in patients with locally advanced cervical carcinoma the overall clinical and pathological response rates were 64 % and 62 % . WHO grade 3 - 4 neutropenia occurred in 61 % of the patients , with one possible toxic death . Retreatment had to be delayed for at least one week because of persisting neutropenia in 34 % of the patients . Mild peripheral neuropathy and stomatitis were observed in 46 % and 23 % of the patients . One patient presented acute congestive heart failure after the third cycle of treatment . CONCLUSION The high antitumour activity and the good tolerability of CEP  suggest that this regimen should be prospect ively compared to st and ard combinations as initial treatment of advanced endometrial carcinoma OBJECTIVE The aim of this study was to determine the effectiveness and toxicity of monthly treatment with intravenous paclitaxel for women with advanced or recurrent uterine papillary serous carcinoma ( UPSC ) . METHODS Consenting women with histologically confirmed advanced ( FIGO stage III or IV ) or recurrent UPSC were treated on an Institutional Review Board approved protocol of a 24-h intravenous infusion of 200 mg/m(2 ) of paclitaxel every 3 weeks . Both measurable and nonmeasurable disease cases were enrolled . Treatment was continued until disease progression , patient intolerance , or ( in women with nonmeasurable disease ) completion of six courses . RESULTS Twenty patients received from 1 to 11 cycles of therapy . Two women died of disease after 1 cycle of therapy and were not evaluable for response . Among 13 women with measurable tumor receiving 2 or more cycles of therapy , 4 had a complete clinical response and 6 had a partial response ( objective response rate , 77 % ) . The median time to progression was 7.3 months ( range , 2 - 21 months ) . All 3 remaining patients with measurable disease had stable disease for a median of 6 months . The 5 patients without evaluable disease received 5 to 6 cycles of adjuvant paclitaxel . Three developed recurrence ( range , 4 - 10 months ; median , 7.2 months ) . Neutropenia was the major toxicity . Eleven of the 20 patients required G-CSF support , and 9 were hospitalized for neutropenic fever . One woman had reversible cardiac symptoms , which might have been related to paclitaxel treatment . At the time of analysis ( mean follow-up , 23 months ; range , 4.3 - 59.9 months ) , 13 women had died of disease , 4 were alive with disease , and 2 were disease free . All 3 disease-free patients had been treated for nonmeasurable advanced stage disease . CONCLUSION Paclitaxel appears to have excellent activity in the treatment of advanced or recurrent UPSC , an uncommon but aggressive malignancy . Longer survival appears to be more common among women with small-volume disease PURPOSE To evaluate the efficacy of carboplatin plus paclitaxel in primarily advanced or recurrent endometrial cancers . PATIENTS AND METHODS Four distinct patient groups received carboplatin ( area under the curve , 5 to 7 ) plus paclitaxel 175 mg/m(2 ) for 3 hours at 4-week intervals : group 1 ( n = 21 ) , patients with primarily advanced , nonpapillary serous cancers ; group 2 ( n = 20 ) , the same as group 1 but with papillary serous cancers ; group 3 ( n = 18 ) , recurrent , nonpapillary serous cancers ; and group 4 ( n = 4 ) , recurrent , papillary serous cancers .  Involved-field irradiation was used in groups 1 and 2 for those with radioencompassable disease . RESULTS Sixty-three patients were treated .  Response rates to chemotherapy in the assessable patients in the four groups were 78 % ( 95 % confidence interval [ CI ] , 51 % to 100 % ) ; 60 % ( 95 % CI , 35 % to 85 % ) , 56 % ( 95 % CI , 34 % to 78 % ) , and 50 % , respectively . Nineteen patients ( 90 % ) in group 1 also were irradiated , and the median failure-free survival time for all 21 patients was 23 months , with a 62 % 3-year overall survival rate . Eleven patients ( 55 % ) in group 2 were irradiated , and the median failure-free survival time for all 18 patients was 18 months , with a 39 % 3-year overall survival rate . The median failure-free interval in the patients in group 3 was 6 months , with a 15-month median overall survival time . Toxicity was manageable , reversible , and predominantly hematologic . Two patients developed neutropenic fever , and three patients , including these two , were hospitalized for complications . CONCLUSION Carboplatin-paclitaxel is an efficacious , low-toxicity regimen for managing primarily advanced or recurrent endometrial cancers Forty-three patients with advanced or recurrent endometrial carcinoma no longer amenable to management with surgery or radiotherapy were treated with adriamycin .  Sixteen of the 43 patients demonstrated objective response to drug therapy with a greater than or equal to 50 % reduction in the size of measurable disease . There were 11 complete responses among these 16 responders . Responders had a significantly better survival than nonresponders ( P less than 0.05 ) . Initial performance status was the only factor of demonstrable prognostic significance . Toxicity was similar to that observed in other phase II trials of adriamycin . Adriamycin , based on these data , is an active agent in the treatment of advanced or recurrent endometrial carcinoma Patients ( 358 ) with advanced ( FIGO stages III and IV ) or recurrent endometrial cancer were treated with one of two regimens : 1 ) melphalan and 5-fluorouracil daily for four days , repeated every four weeks with megace daily for eight weeks and 2 ) adriamycin , 5-fluorouracil , and cyclophosphamide , intravenous bolus every 21 days with megace daily for eight weeks . All patients were r and omized except for 63 with known cardiac disease who were assigned to regimen 1 ( to avoid adriamycin ) and studied separately . Stratification was effected for performance status , history of previous progestational therapy , presence or absence of measurable disease , and stage of disease . The objective response rate in those with measurable disease was 36.8 % in both groups ; 36.8 % of each group had stable disease , and only 26.4 % progressed on treatment . Response was unaffected by site of recurrence , time to first recurrence , presence or absence of previous treatment by progestational or radiation therapy , or age . Grade of tumor and performance status did affect response , although 44 of 57 objective responders had undifferentiated tumors . The two combinations achieved response rapidly , required careful supervision , and were especially useful in treating patients with usually poor prognostic features Twenty-six women with advanced or recurrent endometrial cancer were treated with cisplatin at a dose of 50 , 70 , or 100 mg/m2 every 4 weeks . An objective response was obtained in 11 of 26 patients ( 42 % ) , with 10 partial responses and 1 complete response . The median duration of remission was 5 months , with a range of 2 to 11 months . The complete response lasted 8 months . Five patients had stable disease lasting an average of 5 months . One of 6 patients ( 16.6 % ) responded to cisplatin at a dose of 50 mg/m2 , 4 of 7 ( 57 % ) responded to the dose of 70 mg/m2 , and 6 of 13 ( 46 % ) responded to the dose of 100 mg/m2 , but the differences were not statistically significant ( P=.2 ) . In 8 of 26 cases ( 31 % ) cisplatin was discontinued because of toxicity . Three patients developed a peripheral neuropathy , 1 patient refused further therapy because of vomiting , 2 patients had nephrotoxicity , and 2 others had both nephrotoxicity and neurotoxicity . The average total cumulative dose of cisplatin administered when renal deterioration and neuropathy occurred was approximately 500 mg/m2 . Cisplatin is definitely active against endometrial cancer , but toxicity precludes its prolonged administration in high doses on an outpatient basis . By maintaining a forced diuresis , toxicity can probably be decreased , thereby permitting continued administration of cisplatin . The drug may also be more useful when used at a lower dose in combination with other active agents against endometrial cancer PURPOSE Doxorubicin and cisplatin have activity in endometrial carcinoma and at initiation of this study ranked as the most active agents . This trial of stage III , IV , or recurrent disease evaluated whether combining these agents increases response rate ( RR ) and prolongs progression-free survival ( PFS ) and overall survival ( OS ) over doxorubicin alone . PATIENTS AND METHODS Of 299 patients registered , 281 ( 94 % ) were eligible . Regimens were doxorubicin 60 mg/m(2 ) intravenously or doxorubicin 60 mg/m(2 ) plus cisplatin 50 mg/m(2 ) every 3 weeks until disease progression , unacceptable toxicity , or a total of 500 mg/m(2 ) doxorubicin . RESULTS There were 12 ( 8 % ) complete ( CR ) and 26 ( 17 % ) partial responses ( PR ) among 150 patients receiving doxorubicin versus 25 ( 19 % ) CRs and 30 ( 23 % ) PRs among patients receiving the combination . The overall response rate was higher among patients receiving the combination ( 42 % ) compared with patients receiving doxorubicin ( 25 % ; P = .004 ) . Median PFS was 5.7 and 3.8 months , respectively , for the combination and single agent . The PFS hazard ratio was 0.736 ( 95 % CI , 0.577 to 0.939 ; P = .014 ) . Median OS was 9.0 and 9.2 months , respectively , for the combination and single agent . Overall death rates were similar in the two groups ( hazard ratio , 0.928 ; 95 % CI , 0.727 to 1.185 ) . Nausea , vomiting , and hematologic toxicities were common . The combination produced more grade 3 to 4 leukopenia ( 62 % v 40 % ) , thrombocytopenia ( 14 % v 2 % ) , anemia ( 22 % v 4 % ) , and nausea/vomiting ( 13 % v 3 % ) . CONCLUSION Adding cisplatin to doxorubicin in advanced endometrial carcinoma improves RR and PFS with a negligible impact on OS and produces increased toxicity . These results have served as a building block for subsequent phase III trials in patients with disseminated and high-risk limited endometrial carcinoma OBJECTIVE To determine the efficacy and toxicity of paclitaxel in advanced or recurrent adenocarcinoma of the endometrium . METHODS Thirty patients with advanced or recurrent endometrial cancer with measurable disease not previously treated with chemotherapy were treated with paclitaxel , 250 mg/m2 , over 24 hr with G-CSF , 5 mcg/kg/day , from Days 2 to 12 . The cycle was repeated every 21 days . Patients who had received previous pelvic radiation were treated at an initial paclitaxel dose of 200 mg/m2 . Twenty-eight patients were evaluable for response , and 29 patients for toxicity .  All patients were Gynecologic Oncology Group performance status 0,1 , or 2 . RESULTS Complete responses were observed in 4 ( 14.3 % ) and partial responses in 6 patients ( 21.4 % ) for a response rate of 35.7 % . Severe ( grade 3 or 4 ) leukopenia or thrombocytopenia was seen in 18 and 2 patients , respectively . Grade 3 or 4 gastrointestinal toxicity was seen in 5 , neurotoxicity in 3 , anemia in 2 , and cardiac toxicity in 1 patients . Alopecia was reported in 16 patients . CONCLUSIONS This dose and schedule of paclitaxel are active in patients with advanced or recurrent adenocarcinoma of the endometrium and should be considered for inclusion in phase III trials Cisplatin and the combination of cisplatin , doxorubicin , and cyclophosphamide have documented activity in women with advanced or recurrent endometrial adenocarcinoma . However , response duration has been short and toxicity is substantial . To determine if similar activity could be obtained with less morbidity , we prospect ively treated 33 patients with 360 mg/m2 carboplatin  given intravenously every 28 days . Mean patient age was 69 years ( range 40 - 86 ) ; all had a Zubrod functional status of 2 or less . Seventeen patients had advanced primary tumors , and 16 had recurrent disease . Prior treatment included surgical resection in 29 cases , hormonal agents in 7 , and radiotherapy in 22 . No patient had received prior chemotherapy . Mean treatment was 5.7 cycles . Nine of 27 patients ( 33 % ) with measurable disease had objective responses , including three complete and six partial responses . Nonresponders included 10 patients with stable disease and 8 whose disease progressed while on treatment . Median time to response was 3 months . Median progression-free survival for responders and nonresponders was 5 and 4 months , respectively . At analysis , 20 patients had died of disease , 7 were alive with disease , and 6 were clinical ly free of disease . Disease-free patients include 1 with a complete response and 5 who began treatment without measurable disease . Median follow-up for surviving patients was 18 months ( range 4 - 32 ) . Treatment toxic effects were minimal and largely limited to myelosuppression ; 3 patients had grade 3 thrombocytopenia , 1 had grade 3 neutropenia , and 5 had grade 3 anemia .  Carboplatin has define activity in endometrial carcinoma and offers a well-tolerated palliative therapeutic alternative PURPOSE From 1979 to 1984 , 356 eligible patients with advanced or recurrent endometrial carcinoma no longer amenable to therapy with surgery , radiotherapy , or progestins were treated with doxorubicin alone or doxorubicin in combination with cyclophosphamide . PATIENTS AND METHODS Patients were r and omized to receive doxorubicin 60 mg/m2 intravenously ( i.v . ) with or without cyclophosphamide 500 mg/m2 i.v . every 3 weeks for eight drug courses . All patients had received prior therapy with progestins with subsequent progression of disease . No patients had received prior therapy with cytotoxic drugs . Of 356 patients , 300 had measurable disease . RESULTS Among 132 patients treated with doxorubicin alone , there were seven complete responses ( 5 % ) , 22 partial responses ( 17 % ) , 73 with stable disease ( 55 % ) , and 30 with increasing disease within 2 months of study entry ( 23 % ) . For the 144 patients who received the combination  , there were 18 complete responses ( 13 % ) , 25 partial responses ( 17 % ) , 75 with stable disease ( 52 % ) , and 26 with increasing disease ( 18 % ) . The median progression-free interval for those patients who received doxorubicin alone was 3.2 months , while it was 3.9 months for those who received the combination . The median survival duration for doxorubicin patients was 6.7 months , while it was 7.3 months for the combination patients . None of the unadjusted estimates of treatment differences are statistically significant . Prognostic features that had an impact on outcome included one factor associated with an increased likelihood of response ( presence of measurable lung metastases ) and four features associated with a poorer survival ( poor performance status [ PS ] of 2 or 3 , high pathologic grade , and presence of liver metastases or other intraabdominal disease ) . If these features are taken into account in multivariate analyses , there is no statistically significant evidence for differences in response rates ( relative odds of response , 1.58 ; P = .06 , one-tailed test ) , and survival duration is slightly longer in the combination regimen ( 17 % reduction in death rate ; P = .048 ) . CONCLUSION The combination of doxorubicin plus cyclophosphamide thus appears to offer a small advantage over doxorubicin alone in the management of endometrial carcinoma at the expense of more frequent and severe myelosuppression and gastrointestinal toxicity BACKGROUND This study was performed to determine whether 24-h paclitaxel plus doxorubicin and filgrastim was superior to cisplatin plus doxorubicin in patients with endometrial cancer with respect to response , progression-free survival ( PFS ) and overall survival ( OS ) . PATIENTS AND METHODS Eligible chemotherapy-naïve patients were r and omly assigned to doxorubicin 60 mg/m2 intravenously ( i.v . ) followed by cisplatin 50 mg/m2 i.v . ( arm 1 , n=157 ) or doxorubicin 50 mg/m2 i.v . followed 4 h later by paclitaxel 150 mg/m2 i.v . over 24 h plus filgrastim 5 microg/kg on days 3 - 12 ( arm 2 , n=160 ) . Starting doses were reduced for prior pelvic radiotherapy and age > 65 years . Both regimens were to be repeated every 3 weeks for a maximum of seven cycles . RESULTS There was no significant difference in response rate ( 40 % versus 43 % ) , PFS ( median 7.2 versus 6 months ) or OS ( median 12.6 versus 13.6 months ) for arm 1 and arm 2 , respectively . Toxicities were primarily hematological , with 54 % ( arm 1 ) and 50 % ( arm 2 ) of patients experiencing grade 4 granulocytopenia . Gastrointestinal toxicities were similar in both arms . CONCLUSIONS Doxorubicin and 24-h paclitaxel plus filgrastim was not superior to doxorubicin and cisplatin in terms of response , PFS or survival in advanced endometrial cancer OBJECTIVES Both paclitaxel and cisplatin have moderate activity in patients with metastatic or recurrent carcinoma of the endometrium , and the combination of these two agents has shown activity in a variety of solid tumors . We administered this combination to patients with metastatic or recurrent carcinoma of the endometrium to evaluate its activity and to define its toxicity . METHODS Twenty-four consecutive patients were treated on an outpatient basis with paclitaxel 175 mg/m(2 ) administered intravenously over a 3-h period followed by cisplatin 75 mg/m(2 ) administered intravenously with granulocyte colony-stimulating factor ( G-CSF ) support . The chemotherapy was repeated every 3 weeks for a maximum of six courses . RESULTS Sixteen patients ( 67 % ; 95 % confidence interval , 45 - 84 % ) achieved an objective response , including seven complete responses and nine partial responses . The median duration of response was 7 months , and the median times to progression and survival for all patients were 8.4 and 17.6 months , respectively . Some degree of neurotoxicity occurred in 44 % of patients . Grade 3 or 4 toxicity included granulocytopenia in 22 % of patients and peripheral neuropathy in 9 % . CONCLUSION The combination of paclitaxel with cisplatin with G-CSF support appears active in patients with metastatic or recurrent carcinoma of the endometrium . The significant incidence of neurotoxicity is of concern and alternative methods of administration of the two agents could be evaluated UNLABELLED Currently , available chemotherapy regimens for patients with advanced or recurrent endometrial cancer are generally not curative . Thus , there is a need to identify more active single agents in this disease . In this study patients pre-treated and not pre-treated with first line combination chemotherapy  were entered into a r and omized phase II study of either cyclophosphamide ( CYCLO ) or Ifosfamide ( IFOS ) . PATIENTS AND METHOD Sixty one eligible patients with recurrent or metastatic histologically proven , adenocarcinoma of the uterine corpus entered the study . The median age at entry was 62 ( range 40 - 74 ) years . Twenty patients ( 33 % ) had prior hormonal treatment and 31 ( 51 % ) prior chemotherapy .  CYCLO was given at a dose of 1200 mg/m2 and IFOS at a dose of 5 g/m2 . Both drugs were administered i.v . over 24 hours on day one every three weeks . Adequate pre- and post hydration as well as use of Mesna in the Ifosfamide arm were m and atory . RESULTS A median of two treatment cycles ( range 1 - 12 ) per patient were given . In the chemotherapy-naive patients , in the CYCLO arm two PRs ( RR 14 % , C.I. 2 - 43 % ) were seen and in the IFOS arm two CRs , two PRs , ( RR 25 % , C.I. 7 - 52 % ) were observed . No responses were seen in pre-treated patients . The duration of responses were : 15 + , 7 + months for the CRs , 15 + and 5 months for PRs in IFOS arm and 67 + , 4 months in CYCLO arm . The hematological toxicity was dose-limiting and similar in both treatment arms . No serious non hematological toxicities were reported , but a transient increase of the creatinine blood level was seen in two IFOS patients ( 6 % ) . CONCLUSION Ifosfamide is an active drug in the treatment of chemotherapy-naive patients with advanced endometrial cancer and its application in currently used ( combination ) regimens should be considered BACKGROUND Single-agent platinum and single-agent pegylated liposomal doxorubicin ( PLD ) are both effective in the treatment of gynecologic malignancies . Based on evidence that combination platinum-containing regimens offer superior efficacy versus single-agent regimens , we conducted this study to determine the maximum tolerated dose ( MTD ) of PLD in combination with carboplatin . PATIENTS AND METHODS In this phase I/II dose-finding study , six courses of PLD ( 20 , 30 , 40 or 50 mg/m2 ) and carboplatin ( AUC 6 ) were administered every 28 days to women with advanced gynecologic malignancies . Three to six patients were treated at each dose level ; an additional 12 patients were treated at the MTD . RESULTS PLD 40 mg/m2 was identified as the MTD when administered with carboplatin . Five of 18 patients experienced a dose-limiting toxicity at the MTD ; two patients had grade 3/4 neutropenia , and one each had grade 3 emesis and grade 3 thrombocytopenia and thrombosis . No patient developed cardiotoxicity . In 11 patients evaluable for response , there were two complete responses , two partial responses and four patients with stable disease . CONCLUSIONS The MTD for PLD when administered in combination with carboplatin is 40 mg/m2 . This regimen is well tolerated and offers promising activity in women with advanced gynecologic malignancies A prospect i ve clinical trial using combination chemotherapy consisting of cyclophosphamide , doxorubicin , cis-Platinum and megestrol acetate ( CAP-M ) was initiated to study its effect on advanced or recurrent endometrial adenocarcinoma . Fifteen patients were clinical ly evaluable . Nine patients ( 60 % ) demonstrated an overall objective clinical response result ing in either complete regression of disease ( 33 % ) or a reduction in tumor size . For all responders the mean progression free interval was eight months , with a range of five to 11 months . Similarly , a mean survival time of 12 months with a range of five to 21 months was observed . An additional four patients showed no progressive disease for a mean of seven months duration . Reversible cis-Platinum-induced nephrotoxicity occurred in two patients . This is the first reported series of endometrial cancer patients using nonhormonal cytotoxic agents , including cis-Platinum , in conjunction with a progestin . This preliminary experience is encouraging and appears worthy of further clinical evaluation We have previously reported an overall response rate of 41 % and a median survival duration of 14 months in a series of 49 patients with metastatic or recurrent endometrial carcinoma treated by a combination of etoposide , 5-fluorouracil , and cisplatin .  In order to increase response rate and survival duration , doxorubicin was added to this combination . From August 1992 to January 1996 , 20 consecutive patients were treated with a monthly combination chemotherapy consisting of doxorubicin 30 mg/m2 i.v . Day 1 , 5-fluorouracil 600 mg/m2 i.v . Days 1 to 3 , etoposide 80 mg/m2 i.v . Days 1 to 3 , and cisplatin 35 mg/m2 i.v . Days 1 to 3 ( AFEP ) . All patients were evaluable for response and toxicity .  Median age was 62 years ( range 45 - 72 ) . Two to eight cycles were delivered ( median 5 ) . Two of 20 patients had complete response and 7 of 20 had partial response . The objective response rate was 45 % ( CI 95 % : 23 - 68 % ) . The median survival duration was 17 months . The median progression-free survival was 8 months . Major toxic effect was myelosuppression : 75 % of grade 3 and 4 leukopenia and 20 % of grade 3 and 4 thrombocytopenia . Seven patients ( 35 % ) developed infection and 4 ( 20 % ) were hospitalized once or more for toxicity . These results indicate that AFEP is an effective combination therapy in metastatic endometrial carcinoma but its toxicity is unacceptable A combination of doxorubicin ( 30 mg/m2 iv ) , cisplatin ( 50 mg/m2 iv ) , and vinblastine ( 5 mg/m2 iv ) repeated every 3 - 4 weeks was used to treat 55 patients with advanced stage III or IV or recurrent disease . Of the 42 fully evaluable patients , there were 3 complete responders ( 7 % ) and 10 partial responders ( 24 % ) . Responses were of short duration ( median of 8 months , range 3 - 15 months ) and the median survival of all evaluable patients was only 10 months from the start of therapy . Leukopenia was the major toxicity and was at least moderate in two-thirds of patients . We conclude that the addition of cisplatin and vinblastine to doxorubicin does not improve the clinical utility of doxorubicin in patients with advanced endometrial cancer Fifty consecutive patients with documented advanced or recurrent endometrial carcinoma from 1978 through 1985 were prospect ively treated with melphalan , 5-fluorouracil , medroxyprogesterone acetate ( MFP ) as first-line chemotherapy .  From 1987 through 1993 , 50 consecutive patients with documented advanced or recurrent endometrial carcinoma were prospect ively treated with cisplatin , Adriamycin , etoposide , megestrol acetate ( PAV-M ) as first-line chemotherapy .  Response rates for MFP versus PAV-M  , 2- and 5-year survival , median survival , 2- and 5-year progression-free survival , and median progression-free survival were not statistically different . However , there was a significant improvement favoring PAV-M in 2-year ( 45 versus 14 % ) , 5-year ( 30 versus 5 % ) , and median survival ( 22.3 versus 8.7 months ) ( P = 0.008 ) compared to MFP in patients with primary advanced endometrial adenocarcinoma . Moreover , there was a significant improvement in 2- and 5-year and median survival ( 55 and 15 % and 26.7 months ) for PAV-M compared to MFP ( 7 and 0 % and 7.3 months ) ( P = 0.002 ) for the more aggressive other adenocarcinomas ( adenosquamous , clear cell , papillary serous , undifferentiated ) compared to the more common endometrioid adenocarcinoma . The current data suggest that cisplatin- and adriamycin-based chemotherapy results in some long-term survival benefit for patients with primary advanced endometrial adenocarcinoma and the more aggressive nonendometrioid adenocarcinoma histologies OBJECTIVE To evaluate the antitumour activity of paclitaxel in patients with endometrial cancer pretreated with cisplatin , doxorubicin and cyclophosphamide ( PAC ) .  MATERIAL S AND METHODS Eligible patients had complete initial surgery , expected survival > or = 3 months , performance status < or = 1 , measurable or evaluable disease .  Paclitaxel was given over three hours at the dose of 175 mg/m2 , repeated every 3 weeks . Tumour response was first evaluated after 3 cycles . A maximum of 10 cycles was given in responders . RESULTS 19 patients entered the study and a total of 105 cycles were administered . Complete and partial responses were achieved in 2 and 5 patients , respectively , for an overall response rate of 37 % ( 95 % CI : 16%-62 % ) . The response rate in patients refractory to platinum was 22 % . One patient is alive without evidence of disease 16 months after the start of treatment . The most common side effects were mild to moderate myalgia and peripheral neuropathy , which occurred in 31 % and 47 % of patients , respectively . In only 1 patient treatment had to be discontinued because of severe myalgia . CONCLUSION Paclitaxel is active in patients with endometrial cancer pretreated with PAC .  Further studies with paclitaxel incorporated in the initial treatment for advanced disease are warranted Twenty-three patients with advanced or recurrent endometrial carcinoma entered a prospect i ve study of chemotherapy which consisted of carboplatin ( 300 mg/m2 ) , methotrexate ( 30 mg/m2 ) , and 5-fluoruracil ( 500 mg/m2 ) given on day 1 , in a 3-weekly schedule , in combination with medroxyprogesterone acetate ( MPA ) : 300 mg daily , p.o . , until progression ( JMF-M regimen ) . None had received prior chemotherapy and /or hormonotherapy for metastatic disease . Ten patients had received radiotherapy .  Response to treatment was evaluated every two courses . Objective response was seen in 17 of the 23 patients ( 74 % , 95 % confidence interval = 52–90 % ) , with 2 long-lasting complete responses ( 9 % ) . The median response duration was 10 + months ( 3–45 + ) . The median survival was 16 + months ( 2–45 + ) . The 2 complete responders , the first in the lung and the second in groin nodes , are without evidence or recurrence after 32 and 45 months , respectively . The regimen was given on an outpatient basis and was well tolerated . The major toxic effects were myelosuppression ( less than 14 % leukopenia , anemia and thrombocytopenia ) . The MPA-related side effects were : weight gain ( 22 % ) , hypertension ( 17 % ) and thromboplebitis ( 17 % ) . In 2 patients , consolidation treatment with MPA was discontinued because of thromboplebitis . In conclusion , the JMF-M regimen is highly active with an acceptable toxicity in patients with recurrent or metastatic endometrial carcinoma
BACKGROUND Cytotoxic chemotherapy has a limited place in the management of advanced or recurrent endometrial cancer .
Commonly used agents include cisplatin and doxorubicin , but the side-effect profile may be unacceptable for many patients .
The feasibility of administration of combination chemotherapy is limited in many patients on account of significant co-morbidity .
While early-stage endometrial adenocarcinoma is a common gynaecological cancer with a favourable prognosis , advanced or recurrent disease presents a difficult management problem .
The platinum and anthracycline compounds have been widely used for many years , but their impact on progression-free survival ( PFS ) and overall survival ( OS ) is not clear .
This systematic review aim ed to evaluate both the benefits and adverse effects of cytotoxic chemotherapy in these women .