A daily diary for quality of life measurement in advanced breast cancer trials. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. Evaluation of VP-16 and the combination of adriamycin and vincristine in advanced breast cancer. Combination or mild single agent chemotherapy for advanced breast cancer? CMF vs epirubicin measuring quality of life. VP-16 + adriamycin vs. adriamycin alone in advanced adenocarcinoma of the breast, phase II, a randomized trial: a Southwest Oncology Group Study. The effect on survival of initial chemotherapy in advanced breast cancer: polychemotherapy versus single drug. Epirubicin or epirubicin and cisplatin as first-line therapy in advanced breast cancer. A phase III study Cisplatin plus oral etoposide (EoP) combination is more effective than paclitaxel in patients with advanced breast cancer pretreated with anthracyclines: a randomised phase III trial of Turkish Oncology Group A double blind comparative study of tegafur (FT) and UFT (a combination of Tegafur and uracil) in advanced breast cancer. Phase III study of intravenous vinorelbine in combination with epirubicin versus epirubicin alone in patients with advanced breast cancer: a Scandinavian Breast Group Trial (SBG9403). Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: a randomised phase III study with crossover on progression by the Scandinavian Breast Group. Combination chemotherapy and adriamycin in patients with advanced breast cancer. A Southwest Oncology Group study Randomized clinical trial of doxorubicin alone or combined with mitolactol in women with advanced breast cancer and prior chemotherapy exposure Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. Refractory breast cancer: a comparison of two different chemotherapy regimens. Weekly adriamycin versus VAC in advanced breast cancer. A randomized trial. Doxorubicin versus mitomycin versus doxorubicin plus mitomycin in advanced breast cancer: a randomized study. A comparative study of PALA, PALA plus 5‐FU, and 5‐FU in advanced breast cancer Adriamycin alone or combined with vincristine in the treatment of advanced breast cancer. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Epirubicin or epirubicin and vindesine in advanced breast cancer. A phase III study. A phase 2 evaluation of 1-(2-chloroethyl)-3-(4- methylcyclohexyl)-1-nitrosourea (NSC 95441) in patients with advanced breast cancer. Applications of dose intensity to problems in chemotherapy of breast and colorectal cancer. Single-drug vs combination cytotoxic chemotherapy in advanced breast cancer: a randomized study. Beta blockade during and after myocardial infarction: an overview of the randomized trials.
The Qualitator is a daily diary card to measure Quality of Life , developed for use in chemotherapy trials for patients with advanced breast cancer . In a trial at King 's College Hospital , 29 patients completed the Qualitator  and their scores were compared with scores in the Linear Analogue Self- Assessment and Nottingham Health Profile taken four-weekly . In a separate study at Guy 's Hospital , 31 patients completed the diary . The Qualitator offers accurate prognostic data regarding subsequent UICC response and survival and is simple to use PURPOSE To compare the efficacy of pegylated liposomal doxorubicin ( PLD ) with that of a common salvage regimen ( comparator ) in patients with taxane-refractory advanced breast cancer . PATIENTS AND METHODS Following failure of a first- or second-line  taxane-containing regimen for metastatic disease , 301 women were r and omly assigned to receive PLD ( 50 mg/m(2 ) every 28 days ) ; or comparator-vinorelbine ( 30 mg/m(2 ) weekly ) or mitomycin C ( 10 mg/m(2 ) day 1 and every 28 days ) plus vinblastine ( 5 mg/m(2 ) day 1 , day 14 , day 28 , and day 42 ) every 6 to 8 weeks . Patients were stratified before r and om assignment based on number of previous chemotherapy regimens for metastatic disease and presence of bone metastases only . RESULTS Progression-free survival ( PFS ) and overall survival ( OS ) were similar for PLD and comparator ( PFS : hazard ratio [ HR ] , 1.26 ; 95 % CI , 0.98 to 1.62 ; P = .11 ; median , 2.9 months [ PLD ] and 2.5 months [ comparator ] ; OS : HR , 1.05 ; 95 % CI , 0.82 to 1.33 ; P = .71 ; median , 11.0 months [ PLD ] and 9.0 months [ comparator ] ) . In anthracycline-naïve patients , PFS was somewhat longer with PLD , relative to the comparator ( n = 44 ; median PFS , 5.8 v 2.1 months ; HR , 2.40 ; 95 % CI , 1.16 to 4.95 ; P = .01 ) . Most frequently reported adverse events were nausea ( 23 % to 31 % ) , vomiting ( 17 % to 20 % ) , and fatigue ( 9 % to 20 % ) and were similar among treatment groups . PLD-treated patients experienced more palmar-plantar erythrodysesthesia ( 37 % ; 18 % grade 3 , 1 patient grade 4 ) and stomatitis ( 22 % ; 5 % grade s 3/4 ) . Neuropathy ( 11 % ) , constipation ( 16 % ) , and neutropenia ( 14 % ) were more common with vinorelbine . Alopecia was low in both the PLD and vinorelbine groups ( 3 % and 5 % ) . CONCLUSION PLD has efficacy comparable to that of common salvage regimens in patients with taxane-refractory metastatic breast cancer , thereby representing a useful therapeutic option 39 previously treated patients with metastatic breast cancer were treated in a partially r and omized study evaluating VP-16 and the combination of Vincristine ( VCR ) and Adriamycin ( ADR ) . Of the 19 patients treated with VP-16  initially , two had partial remissions . No responses were noted in eleven patients who corssed-over after failing VCR plus ADR . Of the 20 patients treated with VCR plus ADR initially , four patients had partial responses . An additional 2/15 patients responded on crossover after failing initially on VP-16 . No significant differences in time to last follow-up or death could be detected between the two treatment programs Forty patients with advanced breast cancer , r and omised to receive CMF or weekly low dose Epirubicin  , were evaluated by UICC criteria of response and WHO toxicity criteria , in addition to three QoL instruments : the ' Qualitator ' daily diary card , 4 weekly Nottingham Health Profile ( NHP ) and Linear Analogue Self- Assessment ( LASA ) . Response rates were 58 % for CMF and 29 % for epirubicin ( chi 2 = 3.51 , 1 d.f . , P > 0.05 ) . Median time to treatment failure was 24 weeks for CMF , 7 weeks for epirubicin ( P < 0.05 ) but survival was similar in both groups . Survival was better for responders than for non-responders ( medians 87 and 30 weeks , P = 0.02 ) . CMF caused more objective alopecia ( P < 0.001 ) , nausea and vomiting ( P < 0.001 ) and haematological toxicity ( P < 0.02 ) . However , QoL measures only recorded a significant difference in energy and pain , influenced primarily by the non-responders in each treatment group but with no difference in overall global scores . Scores for responders , irrespective of treatment , were better to start with ( LASA P = 0.001 ) ; at 12 weeks , scores had improved ( Qualitator P < 0.05 ; NHP P < 0.05 ) . Scores in non-responders showed no change . In this small study aggressive chemotherapy gave better response and similar survival without impairing Quality of life overall . Detailed QoL measurement should be integral to all cancer chemotherapy trials One hundred twenty-two patients with advanced adenocarcinoma of the breast were r and omized to receive adriamycin ( AD ) alone or a combination of VP-16 plus lower dose adriamycin ( VAD ) . The patients were stratified to good and poor risk . The starting dose ( day 1 ) of AD was 60 mg/m2 for good risk and 45 mg/m2 for poor risk . The starting dose of the VAD combination for the good-risk patient was VP-16 , 75 mg/m2 daily x 5 plus adriamycin 35 mg/m2 . The poor-risk dose for VAD was VP-16 , 50 mg/m2 daily x 5 plus adriamycin , 30 mg/m2 on day 1 . The total dose of AD was 450 mg/m2 on both arms . The patients who were on the VAD arm continued on VP-16 maintenance . Both arms were repeated every 21 days . There were 54 evaluable patients on the adriamycin arm and 52 evaluable patients on the VAD arm . Both arms were similar with regard to age , menopausal status , performance status , and prior hormonal therapy . More hematologic toxicity was seen in the adriamycin arm . Complete responses were observed on both arms , three ( 5 % ) with adriamycin and three ( 5 % ) with combination . Eleven ( 19 % ) and ten ( 18 % ) partial responses were observed with the adriamycin and VP-16 plus adriamycin , respectively . AD produced more stable disease than VAD ( 41 % vs. 29 % ) . Complete responses were seen only in the good-risk patients . Time to progression was delayed on the combination arm ( P = 0.02 ) . The survival in both arms was similar . The addition of VP-16 to adriamycin does not offer an important clinical advantage Since current clinical trials assessing new agents occur in patients with advanced breast cancer having failed one and sometimes many polychemotherapy programs , these new agents may not be given a fair trial . In an effort to assess the possibility of using an alternative study design , we analyzed older clinical trials that used a controlled study design , r and omizing between a single new drug and an established polychemotherapy program with a cross-over design upon failure . We were interested in noting that the pooled data did display a slight survival advantage ( median 3.7 months ) for the group receiving  polychemotherapy  as initial therapy . The survival distributions were clearly not significant using the log rank test , but did approach significance using the Smirnov . It is apparent that , while some slight advantage does occur for that group of patients receiving initial polychemotherapy , the magnitude of this effect is not great and is short in duration . Serious consideration should be given to the assessment of new agents as first-line therapy , particularly should they have a unique mode of action or lessened morbidities or toxicities Purpose : To compare the efficacy and toxicity of epirubicin to that of the combination of epirubicin and cisplatin in patients with advanced breast cancer . Patients and methods : A total of 155 patients were r and omized to receive either epirubicin ( 70 mg/m2 ) days 1 and 8 every 4 weeks or epirubicin ( 60 mg/m2 ) days 1 and 8 plus cisplatin ( 100 mg/m2 ) day 1 every 4 weeks . Epirubicin was continued until disease progression or to a cumulative dose of 1000 mg/m2 . Cisplatin was discontinued after six cycles . In 45 premenopausal women an oophorectomy was performed . None of the evaluable patients had received chemotherapy for metastatic disease . Results : Among evaluable patients ( 74 in the epirubicin group and 65 in the epirubicin plus cisplatin group ) there were 19 % vs 29 % complete responses , and 42 % vs 37 % partial responses , with no significant difference . In the epirubicin plus cisplatin group the response rate was significantly higher in previously untreated patients as compared with patients who had received adjuvant chemotherapy ( 74 % vs 55 % , P=0.002 ) . Median times to disease progression were 8.4 months in the epirubicin group and 15.3 months in the epirubicin plus cisplatin group ( P=0.045 ) . Median survival times were 15.1 and 21.5 months , respectively ( P=0.41 ) . In the epirubicin plus cisplatin group leukopenia and thrombocytopenia were significantly more frequent , 29 % of the patients developed mild to moderate peripheral neurotoxicity , 34 % reported tinnitus and hearing changes , 6 patients developed nephrotoxicity ( one died due to nephrotic syndrome ) , and 3 patients developed leukaemia ( two died of this cause ) . Congestive heart failure occurred in six patients in the epirubicin group and three patients in the epirubicin plus cisplatin group . Conclusion : Cisplatin plus epirubicin is an active , although highly toxic regimen when used as first-line therapy in advanced breast cancer . The time to disease progression was significantly longer in the cisplatin plus epirubicin group ( increased by 82 % ) . Due to toxicity , the combination regimen can not be recommended . However , the study indicated a very high activity of cisplatin in advanced breast cancer . Studies of first-line therapy in advanced breast cancer including cisplatin or other platin derivatives in combination with , for example , the taxanes are suggested Our objective was to determine whether oral etoposide and cisplatin combination ( EoP ) is superior to paclitaxel in the treatment of advanced breast cancer ( ABC ) patients pretreated with anthracyclines . From December 1997 to August 2003 , 201 patients were r and omised , 100 to EoP and 101 to paclitaxel arms . Four patients in each arm were ineligible . The doses of etoposide and cisplatin were 50 mg p.o . twice a day for 7 days and 70 mg m−2 intravenously ( i.v . ) on day 1 , respectively , and it was 175 mg m−2 on day 1 for paclitaxel . Both treatments were repeated every 3 weeks . A median of four cycles of study treatment was given in both arms . The response rate obtained in the EoP arm was significantly higher ( 36.3 vs 22.2 % ; P=0.038 ) . Median response duration was longer for the EoP arm ( 7 vs 4 months ) ( P=0.132 ) . Also , time to progression was significantly in favour of the EoP arm ( 5.5 vs 3.9 months ; P=0.003 ) . Median overall survival was again significantly longer in the EoP arm ( 14 vs 9.5 months ; P=0.039 ) . Toxicity profile of both groups was similar . Two patients in each arm were lost due to febrile neutropenia . The observed activity and acceptable toxicity of EoP endorses the employment of this combination in the treatment of ABC following anthracyclines A double blind study to compare the efficacy of oral UFT ( 400 mg Tegafur ( FT ) plus 896 mg uracil/day ) with that of oral FT ( 800 mg/day ) on advanced breast cancer was performed between November , 1986 , and November , 1989 . Sixty patients were registered for the trial and fifty-six cases were evaluated ( 28 for UFT and 28 for FT ) . The primary end points in the study were response rate and time to relapse . There were no significant differences in patients ' characteristics in either group . The objective response rates were 39 % ( 11/28 ; 95 % confidence interval ( C.I. ) , 22 - 59 % ) in UFT and 21 % ( 6/28 ; 95 % C.I. , 8 - 41 % ) in FT , without statistical significance ( P = 0.25 ) . For time to relapse , a trend was seen in favor of UFT , but this effect did not achieve statistical significance ( P = 0.09 ) . Both subjective and objective adverse effects were similar between the two treatments . The overall survivals were similar in both parts of the study . The size of the trial was too small for a definite conclusion to be drawn although , for both response rate and time to relapse , a trend was seen in favor of UFT . A large scale r and omized study will be necessary to compare the drugs in the management of patients with advanced breast cancer PURPOSE To determine whether the addition of intravenous ( IV ) vinorelbine to epirubicin increased the progression-free survival in first-line treatment of metastatic breast cancer . PATIENTS AND METHODS A total of 387 patients were r and omly assigned to receive IV epirubicin 90 mg/m(2 ) on day 1 and vinorelbine 25 mg/m(2 ) on days 1 and 8 , or epirubicin 90 mg/m(2 ) IV on day 1 . Both regimens were given every 3 weeks for a maximum of 1 year but discontinued prematurely in the event of progressive disease or severe toxicity . In addition , epirubicin was discontinued at a cumulative dose of 1000 mg/m(2 ) ( 950 mg/m(2 ) from June 1999 ) . Prior anthracycline-based adjuvant chemotherapy and prior chemotherapy for metastatic breast cancer was not allowed . Reported results were all based on intent-to-treat analyses . RESULTS Overall response rates to vinorelbine and epirubicin , and epirubicin alone , were 50 % and 42 % , respectively ( P = .15 ) . The complete response rate was significantly superior in the combination arm ( 17 % v 10 % ; P = .048 ) as was median duration of progression-free survival ( 10.1 months v 8.2 months ; P = .019 ) . Median survival was similar in the two arms ( 19.1 months v 18.0 months ; P = .50 ) . Leukopenia related complications , stomatitis , and peripheral neuropathy were more common in the combination arm . The incidences of cardiotoxicity and constipation were similar in both arms . CONCLUSION Addition of vinorelbine to epirubicin conferred a significant advantage in terms of complete response rate and progression-free survival , but not in terms of survival The aim of this study was to compare the efficacy and tolerability of docetaxel to methotrexate and 5-fluorouracil in advanced breast cancer after anthracycline failure . A r and omised multicentre trial was conducted in 283 patients with advanced breast cancer who had failed previous anthracycline treatment .  Docetaxel at a dose of 100 mg/m2 every 3 weeks ( n = 143 ) was compared with sequential methotrexate and 5-fluorouracil ( MF ; n = 139 ) given at day 1 and 8 every 3 weeks at dosages of 200 mg/ m2 and 600 mg/m2 , respectively . After progression , crossover to the alternative treatment group was recommended . There was a significantly higher overall response rate in the docetaxel 42 % ( CR 8 % + PR 34 % ) than in the MF arm 21 % ( CR 3 % + PR 18 % ) ( P < 0.001 ) . The median time to progression ( TTP ) was 6.3 months in the docetaxel arm and 3.0 months in the MF arm ( P < 0.001 ) . Docetaxel also had a significantly higher response rate of 27 % following crossover compared with MF ( 12 % ) . Significantly more side-effects ( leucopenia , infections , neuropathy , oedema , asthenia , skin , nail changes , alopecia ) were seen in the docetaxel than in the MF group . However , grade 3 and 4 side-effects were infrequent with both drugs , with the exception of fatigue , alopecia and infections . Median overall survival ( OS ) including crossover phase was 10.4 months in the docetaxel and 11.1 months in the MF arm ( P = 0.79 ) . Based on the response rate and the primary endpoint of TTP , docetaxel is superior to sequential methotrexate and 5-fluorouracil in advanced breast cancer after anthracycline failure In January , 1972 , the Southwest Oncology Group initiated two r and omized studies for patients with advanced breast cancer . The study for patients with prior chemotherapy showed a 33 % response rate with adriamycin . The study for patients without previous chemotherapy consisted of three treatment regimens : a weekly repeated combination of cyclophosphamide , methotrexate , 5‐flu‐orouracil , vincristine , and prednisone ; these same five drugs given in courses of 5 days repeated every 4 weeks ; and adriamycin as a single agent every 3 weeks . For the 283 evaluable patients , the response rates were : weekly combination 63/106 ( 59 % ) ; intermittent combination 39/98 ( 40 % ) ; and adriamycin 31/79 ( 39 % ) . The median duration of response was 8 months for weekly combination , 10 months for intermittent therapy and only 4 months for adriamycin  . Leukopenia was the dose‐limiting toxicity with all three regimens . The weekly combination is the most effective therapy for patients with advanced disease . Extensive trials of combinations that include adriamycin are underway ONE HUNDRED FIFTY-ONE WOMEN WITH ADVANCED BREAST CANCER who had failed prior chemotherapy were r and omized to monthly courses of doxorubicin ( 60 mg/m2 I.V. day 1 , observation after 500 mg/m2 ) or doxorubicin ( 40 mg/m2 I.V. day 1 ; maximum 500 mg/m2 ) and mitolactol ( 135 mg/m2 orally , days 1–10 ; 180 mg/m2 after maximum doxorubicin ) . Median survival times were 232 days for doxorubicin and 225 days for doxorubicin + mitolactol , and median times to progression were 112 days and 97 days , respectively . Results are inconsistent with a 25 % improvement in survival or time to progression for doxorubicin + mitolactol ( p = 0.04 and 0.02 , respectively , adjusted for stratification factors but not multiple testing ) . Regression rates for all patients , both measurable and evaluable , were 30 % for doxorubicin alone and 26 % for doxorubicin + mitolactol .  Regression rates were significantly higher in patients with measurable indicator lesions . Cardiac toxicity was seen in four patients , all of whom were receiving doxorubicin alone . It appears that the combination of doxorubicin + mitolactol is not substantially more effective than doxorubicin alone in women with advanced breast cancer and prior chemotherapy exposure PURPOSE Docetaxel and capecitabine , a tumor-activated oral fluoropyrimidine , show high single-agent efficacy in metastatic breast cancer ( MBC ) and synergy in pre clinical studies . This international phase III trial compared efficacy and tolerability of capecitabine/docetaxel therapy with single-agent docetaxel in anthracycline-pretreated patients with MBC . PATIENTS AND METHODS Patients were r and omized to 21-day cycles of oral capecitabine 1,250 mg/m(2 ) twice daily on days 1 to 14 plus docetaxel 75 mg/m(2 ) on day 1 ( n = 255 ) or to docetaxel 100 mg/m(2 ) on day 1 ( n = 256 ) . RESULTS Capecitabine/docetaxel result ed in significantly superior efficacy in time to disease progression ( TTP ) ( hazard ratio , 0.652 ; 95 % confidence interval [ CI ] , 0.545 to 0.780 ; P = .0001 ; median , 6.1 v 4.2 months ) , overall survival ( hazard ratio , 0.775 ; 95 % CI , 0.634 to 0.947 ; P = .0126 ; median , 14.5 v 11.5 months ) , and objective tumor response rate ( 42 % v 30 % , P = .006 ) compared with docetaxel .  Gastrointestinal side effects and h and -foot syndrome were more common with combination therapy , whereas myalgia , arthralgia , and neutropenic fever/sepsis were more common with single-agent docetaxel . More grade 3 adverse events occurred with combination therapy ( 71 % v 49 % , respectively ) , whereas grade 4 events were slightly more common with docetaxel ( 31 % v 25 % with combination ) . CONCLUSION The significantly superior TTP and survival achieved with the addition of capecitabine to docetaxel 75 mg/m(2 ) , with the manageable toxicity profile , indicate that this combination provides clear benefits over single-agent docetaxel 100 mg/m(2 ) . Docetaxel/capecitabine therapy is an important treatment option for women with anthracycline-pretreated MBC Sixty metastatic and recurrent breast cancer patients who had been given cyclophosphamide , methotrexate and fluorouracil ( CMF ) therapy previously and were treated at the Oncology Departments of Cukurova and Ege University Medical Schools between March 1992 - 94 , were r and omized into 2 groups for the chemotherapy program . The 30 patients in the 1st group were given etoposide : 200 mg x day x 5 days orally every 3 weeks . The 30 patients of the 2nd group were given fluorouracil : 500 mg x m2 , doxorubicin : 5O mg/m2 , cyclophosphamide : 500 mg/m2 intravenously every 3 weeks . The response rates were 21/30 in group 1 and 17/30 in group 2 . The median duration of responses was 11 months ( 8 - 21 ) in the 1st and 9 months ( 4 - 18 ) in the 2nd group . Severe myelotoxicity was observed in 2 of the patients in the 1st group and in 5 of the patients in the 2nd group In a prospect i ve r and omised study 128 patients with advanced breast cancer were treated either with Adriamycin ( 20 mg/week ) or vincristine , Adriamycin and cyclophosphamide ( VAC ) . An objective response was obtained in 31 and 35 % of patients in the two groups . There was no significant difference with regard to duration of response or survival . Weekly low dose Adriamycin was well tolerated . When subjective side effects occurred , they were usually slight and transient . In approx . 40 % of the patients no side-effects at all were observed . Eight per cent had alopecia requiring a wig . Only slight myelosuppression could be seen in a few patients and this had no practical implication s. Most or all of VAC patients experienced severe toxicity with regard to nausea , vomiting and alopecia . Also myelosuppression was more pronounced among VAC patients . It is concluded that weekly doses of Adriamycin as single agent therapy for advanced breast cancer is as effective as the VAC combination delivered every third week , with considerably less toxicity In a r and omized trial the antineoplastic and toxic effects of doxorubicin ( ADR ) , mitomycin ( MMC ) , and the combination of the two were evaluated in postmenopausal patients with advanced breast cancer using the following treatment regimens :  ADR ( 75 mg/m2 by iv bolus every 3 weeks ) ; MMC ( 20 mg/m2 by iv bolus every 6 weeks ) ; and ADR ( 45 mg/m2 by iv bolus every 3 weeks ) and MMC ( 10 mg/m2 by iv bolus every 6 weeks ) . One hundred one patients were entered in the study . Entrance to single-agent MMC therapy was stopped after allocation of 12 patients because of unacceptable side effects , especially nausea and vomiting , and the suggestion of minor efficacy . One of these patients had partial response , eight had no change , and three had progressive disease . The patients in the ADR and ADR plus MMC group were similar as to the following : age ( median , 60 years ) ; menopausal age ; disease-free interval ; performance status , extent of previous cytotoxic therapy ( approximately 90 % were pretreated ) and radiation therapy ; and dominant site of disease but with significantly more involved organ sites in the ADR plus MMC group . Among evaluable patients ( 42 in the ADR group and 39 in the ADR plus MMC group ) , response rates were as follows : complete response--21 versus five ; partial response--26 versus 44 ; no change--40 versus 38 ; and progressive disease--12 versus 13 ( P greater than 0.10 ) . Median times to disease progression were 5.2 and 7.8 months , respectively ( log-rank test , P = 0.03 ) , but survival times were similar , 9.3 and 10.2 months , respectively ( log-rank test , P greater than 0.40 ) . For the two treatment groups suppression of wbc count was similar , while anemia , thrombopenia , and nausea and vomiting were significantly more common among the ADR plus MMC-treated group . Five treatment-induced deaths were observed in the ADR plus MMC group ( one from sepsis ; two from diffuse hemorrhage ; and two from cardiomyopathy ) , compared to none in the ADR group . In conclusion , this study disclosed no major advantage of the combination of ADR plus MMC compared to ADR alone as second-line treatment of advanced breast cancer , but results from other studies may imply a possible role of MMC as part of second-line combination chemotherapy regimens Sixty‐three patients with Stage IV breast carcinoma refractory to st and ard combination chemotherapy agents such as 5‐fluorouracil ( 5‐FU )  were entered into a study to determine the efficacy of a multiple dose schedule of N‐(phosphonacetyl)‐L‐aspartic acid ( PALA ) and whether the addition of PALA improves the therapeutic efficacy of 5‐FU . Patients were r and omized to receive either PALA , 800 to 1000 mg/m2 per day for 5 days every 2 weeks ; or PALA + 5‐FU , 400 mg/m2 per day for 5 days , and 300 mg/m2 per day for 5 days every 28 days , respectively . The PALA alone arm of the study was closed after 20 patients had been treated and was replaced by 5‐FU , 300 to 400 mg/m2 per day for 5 days every 21 days . Overall response rates were 5 % for PALA alone , 28 % for PALA + 5‐FU , and 14 % for 5‐FU alone . All patients who responded to PALA + 5‐FU or 5‐FU alone had received prior therapy in which 5‐FU was part of the combination chemotherapy program and were considered refractory to this drug . Toxicity affected the gastrointestinal tract but was tolerable in all three arms of the study . Myelosuppression was negligible for PALA and PALA + 5‐FU and moderate for 5‐FU . The authors concluded that PALA + 5‐FU was superior to PALA alone in the therapy of these heavily pretreated patients . PALA alone had marginal efficacy . In view of its low hematologic toxicity , PALA + 5‐FU may be combined with more myelosuppressive drugs . Additional studies are necessary to ascertain whether PALA + 5‐FU is therapeutically superior to a full‐dose schedule of 5‐FU One hundred and nineteen women with advanced breast cancer treated previously by endocrine therapy but no prior chemotherapy were given adriamycin 70 mg/m2 i.v . on day 1 of a 3-weekly cycle for 8 courses , followed by a regimen of cyclophosphamide , methotrexate and 5-fluorouracil ( CMF ) until relapse . They were allocated r and omly to receive either no treatment ( group A ) or vincristine 1.4 mg/m2 i.v . on days 1 and 8 during treatment with adriamycin ( group AV ) . In 107 evaluable patients objective responses were seen in 30/53 patients ( 57 % ) in group A and in 28/54 patients ( 52 % ) in group AV . The projected dose of adriamycin received was 78 % in group A and 75 % in group AV ; and 60 % for vincristine in group AV . The subjective and haematological toxicity for adriamycin was similar in both groups , but 65 % of patients treated with vincristine developed neurotoxicity . The median duration of objective regressions was the same for both groups ( 7 months ) , and the median time to failure was 5 months for group A and 6 months for group AV respectively . The median survival of the responders tended to be longer in group AV ( 17.5 months ) than in group A ( 13 months ) , but this difference was not statistically significant ( P = 0.112 ) . It is concluded that there is no advantage therapeutically in combining vincristine and adriamycin in patients with advanced breast cancer In a large phase III trial of 511 patients with anthracycline-pretreated advanced/metastatic breast cancer , capecitabine/docetaxel combination therapy was shown to have significantly superior efficacy compared with single-agent docetaxel , including superior progression-free and overall survival and objective response rate . An up date d survival analysis with > /= 27 months follow-up shows that patients receiving combination therapy maintained significantly superior survival ( hazard ratio [ HR ] , 0.777 [ 95 % CI , 0.645 - 0.942 ] ; P < 0.01 ; median survival , 14.5 months vs. 11.5 months ) compared with those receiving single-agent docetaxel . Following the failure of docetaxel monotherapy , 35 % of patients did not receive additional cytotoxic chemotherapy  . Among patients r and omized to single-agent docetaxel , only those given post study single-agent capecitabine had significantly prolonged survival compared with those given any other post study chemotherapy ( HR , 0.500 ; P = 0.0046 ; median survival , 21.0 months vs. 12.3 months , respectively ) . By contrast , post study vinorelbine-containing chemotherapy did not affect survival following progression on single-agent docetaxel compared with other post study chemotherapy regimens ( HR , 1.014 ; P = 0.94 ; median survival , 13.5 months vs. 12.6 months , respectively ) . Among patients r and omized to combination therapy , discontinuing docetaxel of capecitabine has a similar effect on survival ( HR , 0.720 ; P = 0.20 ; median survival , 15.8 months vs. 18.3 months , respectively ) . Median survival was 18.3 months in patients who discontinued docetaxel and continued to receive capecitabine versus 15.8 months in patients who discontinued capecitabine and continued to receive docetaxel , with a trend toward improved survival in patients continuing to receive capecitabine . Although this is a retrospective analysis , these data suggest that the sequential administration of docetaxel followed by capecitabine is associated with prolonged survival in patients who are c and i date s for sequential single-agent therapy One hundred thirty-three evaluable patients with advanced breast cancer entered a r and omized trial comparing epirubicin 60 mg/m2 with a combination of epirubicin 45 mg/m2 and vindesine 3 mg/m2 day 1 and 8 every 4 weeks . In all 10 premenopausal women an oophorectomy was performed . Seventy-five patients had previously received cyclophosphamide , methotrexate , and 5-fluorouracil ( CMF ) for advanced disease and 68 had received adjuvant chemotherapy ( cyclophosphamide or CMF ) . Among evaluable patients ( 72 in the epirubicin group and 61 in the epirubicin + vindesine group ) response rates were as follows : complete response -- seven versus six ; partial response--31 versus 22 ; no change--16 versus 17 ( p greater than 0.40 ) . Median time to disease progression was 6 months in both groups and median survival times were identical ( 12 months ) . Thrombocytopenia was less frequent in the epirubicin + vindesine group ( p less than 0.01 ) . In the epirubicin + vindesine group , mild to moderate peripheral neuropathy was observed in 40 % of the patients . Congestive heart failure developed in one patient with a cumulative dose of epirubicin less than 1000 mg/m2 and in 7 of 15 patients who had greater than 1000 mg/m2 . Four died of this cause . In conclusion , epirubicin is effective as a single agent for advanced breast cancer . The combination with vindesine does not increase its efficacy Summary A program utilizing 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea ( methyl-CCNU ) ( NSC 95441 ) at a dosage of 225 mg/sq m p.o . on Day 1 was contrasted with a combination program utilizing 5-fluorouracil , cyclophosphamide , and prednisone with or without vincristine in 43 patients with disseminated breast cancer . Prior to r and omization patients were stratified according to dominant disease , free interval , and menstrual category . If the initial treatment failed , a cross-over assignment to the alternate treatment program was made . One of 22 patients responded to methyl-CCNU as primary therapy , contrasting with 7 of 11 responding to the combination program without vincristine and 5 of 10 to the combination program with vincristine . On cross-over , thus far , none have responded to methyl-CCNU but one-third have responded to the combination program . Toxic effects included gastrointestinal upset in 10 of 30 patients who took methyl-CCNU and in 28 of 38 who received the combination programs . Myelosuppression ( leukocyte count less than 3000/cu mm of blood ) occurred in 13 of 30 patients given methyl-CCNU and in 29 of 38 patients given the combination programs . Platelets were suppressed in 8 of 30 patients by methyl-CCNU and in 10 of 38 patients by the multiple-drug programs . Neurological complications were limited to the group treated with vincristine , in which 17 of 20 patients had peripheral neuropathies . Alopecia was confined to the multiple-treatment group of patients Studies were analyzed to show the correlation of response with dose intensity of single-agent 5-fluorouracil ( 5-FU ) against colorectal cancer , multiagent CMF ( cyclophosphamide , methotrexate , 5-FU ) regimens against advanced breast cancer , and  adjuvant  therapy in stage II breast cancer . In colorectal cancer studies , subgroups in which  5-FU was given by intravenous ( IV ) bolus , infusion , and orally were analyzed . One study reported delivered dose levels after reductions for toxicity . This allowed calculations of received dose intensity for the three dose levels , and comparison with projected dose intensities . The data suggest that the dose-intensity response line is steep , once a threshold dose intensity has been surpassed . An increase of only 100 mg/m2/wk of received dose intensity of 5-FU increased the response rate from 20 % to 29 % , which in relative terms was an increase of almost 50 % . Received dose intensity may correlate with response , not only in groups of patients , but also in individual patients , and this may , in fact , be the most important application of the concept of dose intensity Abstract One hundred and thirty-five patients with advanced breast cancer were r and omized to receive either a five-drug combination consisting of cyclophosphamide , methotrexate , 5 -fluorouracil , vincristine and prednisone ( study group ) or a single agent , 5 -fluorouracil alone ( control group ) . Objective responses were seen in 69 % of the patients in the study group ( 4768 ) and 18 % of patients in the control group ( 1267 ) . The median duration of response ( 12.5 vs 6 months ) and the median survival were significantly greater in the study group . The toxicity was somewhat greater with the multiple drug regimen compared with the single-drug Long-term beta blockade for perhaps a year or so following discharge after an MI is now of proven value , and for many such patients mortality reductions of about 25 % can be achieved . No important differences are clearly apparent among the benefits of different beta blockers , although some are more convenient than others ( or have slightly fewer side effects ) , and it appears that those with appreciable intrinsic sympathomimetic activity may confer less benefit . If monitored , the side effects of long-term therapy are not a major problem , as when they occur they are easily reversible by changing the beta blocker or by discontinuation of treatment . By contrast , although very early IV short-term beta blockade can definitely limit infa rct size , more reliable information about the effects of such treatment on mortality will not be available until a large trial ( ISIS ) reports later this year , with data on some thous and s of patients entered within less than 4 hours of the onset of pain . Our aim has been not only to review the 65-odd r and omized beta blocker trials but also to demonstrate that when many r and omized trials have all applied one general approach to treatment , it is often not appropriate to base inference on individual trial results . Although there will usually be important differences from one trial to another ( in eligibility , treatment , end-point assessment , and so on ) , physicians who wish to decide whether to adopt a particular treatment policy should try to make their decision in the light of an overview of all these related r and omized trials and not just a few particular trial results . Although most trials are too small to be individually reliable , this defect of size may be rectified by an overview of many trials , as long as appropriate statistical methods are used . Fortunately , robust statistical methods exist -- based on direct , unweighted summation of one O-E value from each trial -- that are simple for physicians to use and underst and yet provide full statistical sensitivity . These methods allow combination of information from different trials while avoiding the unjustified direct comparison of patients in one trial with patients in another . ( Moreover , they can be extended of such data that there is no real need for the introduction of any more complex statistical methods that might be more difficult for physicians to trust . ) Their robustness , sensitivity , and avoidance of unnecessary complexity make these particular methods an important tool in trial overviews
BACKGROUND Combination chemotherapy regimens are frequently favoured over single agents for the treatment of metastatic breast cancer , in an attempt to achieve superior tumour response rates .
It is not known however whether giving more intensive chemotherapy regimens results in better health outcomes , when both survival and toxicity are considered , and whether better response rates and rates of progression free survival actually translate to better overall survival .
OBJECTIVES To compare single agent with combination chemotherapy for the treatment of metastatic breast cancer .