A daily diary for quality of life measurement in advanced breast cancer trials. High‐dose cyclophosphamide and 5‐fluorouracil versus vincristine, doxorubicin, and cyclophosphamide in advanced carcinoma of the breast: A phase III study of the piedmont oncology association (POA) A prospective evaluation of chemohormonal therapy remission maintenance in advanced breast cancer Combination or mild single agent chemotherapy for advanced breast cancer? CMF vs epirubicin measuring quality of life. The effect on survival of initial chemotherapy in advanced breast cancer: polychemotherapy versus single drug. Response and survival in advanced breast cancer after two non-cross-resistant combinations. Cyclophosphamide, Adriamycin and Platinum (CAP) Combination Chemotherapy, A New Effective Approach in the Treatment of Disseminated Breast Cancer. Preliminary Report Randomized trial to compare the efficacy and toxicity of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with methotrexate mitoxantrone (MM) in advanced carcinoma of the breast Prognostic factors in the initial response to therapy by patients with advanced breast cancer. Paclitaxel and epirubicin versus paclitaxel and carboplatin as first-line chemotherapy in patients with advanced breast cancer: a phase III study conducted by the Hellenic Cooperative Oncology Group. Doxorubicin versus methotrexate both combined with cyclophosphamide, 5-fluorouracil and tamoxifen in postmenopausal patients with advanced breast cancer--a randomised study with more than 10 years follow-up from the Danish Breast Cancer Cooperative Group. Danish Breast Cancer Cooperative Group (DBCG Randomized trial of 3 different regimens of combination chemotherapy in patients receiving simultaneously a hormonal treatment for advanced breast cancer. Improving the quality of life during chemotherapy for advanced breast cancer. A comparison of intermittent and continuous treatment strategies. Vincristine, doxorubicin, and cyclophosphamide versus low‐dose intravenous cyclophosphamide, methotrexate, and 5‐fluorouracil in advanced breast cancer. A randomized trial of the piedmont oncology association Combination chemotherapy and adriamycin in patients with advanced breast cancer. A Southwest Oncology Group study Evaluation of a fixed alternating treatment in patients with advanced breast cancer. Refractory breast cancer: a comparison of two different chemotherapy regimens. Paclitaxel (Taxol)/doxorubicin combinations in advanced breast cancer: the Eastern Cooperative Oncology Group experience. A comparison of cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone (CMFVP) in patients with advanced breast cancer Combination chemotherapy with cmf (cyclophosphamide, methotrexate, 5-Fluorouracil) versus cnf (mitoxantrone, 5-Fluorouracil, cyclophosphamide) in advanced breast-cancer - a multicenter randomized study. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy Chemotherapy of advanced breast cancer. Results of a controlled trial comparing two three-drug regimens. Chemotherapy of advanced breast cancer: A randomized trial of vincristine, adriamycin, and cyclophosphamide (VAC) versus cyclophosphamide, methotrexate, 5‐fluorouracil, and prednisone (CMFP) A comparison of continuation versus late intensification followed by discontinuation of chemotherapy in advanced breast cancer. A prospective randomized trial of the Italian Oncology Group for Clinical Research (G.O.I.R.C.). A comparison of intermittent vs. continuous and of adriamycin vs. methotrexate 5‐drug chemotherapy for advanced breast cancer A Cancer and Leukemia Group B study Superiority of adriamycin over oral nitrosoureas in patients with advanced breast carcinoma. A southwest cancer chemotherapy study group study High-intensity therapy versus low-intensity therapy in advanced breast cancer patients. A phase III clinical trial comparing the combination cyclophosphamide, adriamycin, cisplatin with cyclophosphamide, 5-fluorouracil, prednisone in patients with advanced breast cancer. High‐Dose Medroxyprogesterone Acetate plus Mitomycin‐C or Vindesine in the Treatment of Advanced Breast Cancer Adriamycin versus methotrexate in five‐drug combination chemotherapy for advanced breast cancer. A randomized trial Beta blockade during and after myocardial infarction: an overview of the randomized trials. An ongoing European organization for research and treatment of cancer crossover trial comparing single-agent paclitaxel and doxorubicin as first- and second-line treatment of advanced breast cancer.
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 Forty‐nine patients with advanced carcinoma of the breast who had received no prior chemotherapy were r and omized to receive either high‐dose cyclophosphamide ( C ) 1250 mg/M2 intravenously on day 1 and 5‐fluorouracil ( F ) 600 mg/M2 intravenously on days 1 through 5 ( CF ) , or vincristine ( V ) 1.5 mg/M2 , doxorubicin ( A ) 50 mg/M2 and cyclophosphamide ( C ) 500 mg/M2 ( VAC ) , all intravenously on day 1 . Both regimens were repeated at 3‐week intervals . Nine of 25 patients ( 36 % ) treated with CF and ten of 21 patients ( 48 % ) treated with VAC showed a complete or partial response as defined by the ( UICC ) guidelines . The estimated median time to progression for all patients was 3.5 months for CF and 6.0 months for VAC , with the median time to progression for responding patients being 8.5 months on CF and 6.3 months on VAC . Estimated survival is also similar for the two regimens . Ten of the patients treated with high‐dose CF experienced septic episodes and four died . Toxicity on the CF arm necessitated premature closure of the study , and thus full statistical comparison of the efficacy of the two regimens can not be made Summary From October 1973 to October 1977 the ECOG prospect ively evaluated cyclophosphamide , methotrexate , and fluorouracil ( CMF ) versus CMF plus fluoxymesterone ( CMFH ) maintenance therapies in responders to 6 months of induction therapy which consisted of either CMF , CMF plus prednisone ( CMFP ) , or adriamycin plus vincristine ( AV ) . Following the maintenance r and omization 12 % of the patients converted from a PR to a CR status . The median time from r and omization to treatment failure was 9.5 months for CMFH and 6.7 months for CMF ( p = 0.03 ) . This difference was observed only for partial responders ( p = 0.01 ) and not for complete responders . Patients receiving CMFH  tended to maintain higher hemoglobin , leukocyte , and platelet levels , and receive a higher dosage of each of the cytotoxic drugs . The results are taken as evidence that the addition of fluoxymesterone to a maintenance CMF regimen provides a therapeutic advantage . It is hypothesized that this effect is due at least in part to fluoxymesterone associated maintenance of improved marrow function result ing in greater myelosuppressive drug delivery 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 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 A prospect i ve study with two cytotoxic combinations ( cyclophosphamide , methotrexate , and fluorouracil ( CMF ) , and adriamycin plus vincristine ( AV ) ) was carried out in 110 patients with advanced breast cancer . There was no significant difference between the treatment groups in the response rate after primary treatment , the median duration of response , and the median survival . In both groups responders survived for longer than non-responders . Secondary treatment after crossover for progression or relapse result ed in response rates of 35 % for AV and 20 % for CMF .  Toxicity was mainly represented by reversible haemosuppression . These results are comparable with those obtained with other multiple-drug regimens , and combination chemotherapy alone seems to have reached a plateau in its capacity to control disseminated breast cancer The prospect i ve controlled Phase III clinical trial tested the therapeutic value of the cis-platinum-adriamycin-cyclophosphamide combination ( CAP ) , compared with the combination including cyclophosphamide , methotrexate , 5-fluorouracil , vincristine and prednisolone ( CMFVP ) , in untreated metastatic breast cancer . One hundred and twenty-three patients ( > 2 cycles ) were evaluated : 61 on the CAP , and 62 on the CMFVP schedule .  An objective response ( CR+PR ) to CAP combination chemotherapy was achieved in 72 % of patients ( 43/61 ) , with a high rate ( 36 % ) of complete remissions . In terms of metastatic site , the response rate appeared to be particularly high in soft tissue and visceral organ ( lung , liver ) metastases . In the CMFVP group , an objective response was noted in 26 of 62 patients ( 42 % ) , with 16 % complete remissions . The difference in overall therapeutic response - and in the complete remission rate as well - was statistically significant to the advantage of the CAP regimen ( P < 0.01 ) . The duration of remissions was 6 - 28 + months ( mean = 14 ) for the CAP , and 4 - 15 + months ( mean = 9 ) for the CMFVP schedule . Toxic side effects were more pronounced in the CAP group , particularly myelosuppression , with anemia prevailing . Side effects to CMFVP treatment were moderate . In 39 CMFVP previously treated cases , CAP was administered as second-line treatment , and an objective response was observed in 51 % of cases ( 20/39 ) . Results of this controlled trial showed the advantage of the CAP combination chemotherapy in the treatment of metastatic breast cancer Summary One hundred and sixteen patients with locally advanced or metastatic breast cancer were r and omized to receive CMF ( cyclophosphamide 600 mg m–2 day 1 and 8 i.v . , 5-fluorouracil 600 mg m–2 day 1 and 8 i.v . , , methotrexate 40 mg m–2 day 1 and 8 i.v . , monthly for 6 cycles ) or MM ( methotrexate 30 mg m–2 , mitoxantrone 6.5 mg m–2 , both i.v . day 1 3-weekly for 8 cycles ) as first line treatment with chemotherapy .  Objective responses occurred in 17 patients out of 58 ( 29 % ) who received CMF and nine out of 58 ( 15 % ) who received MM ; 95 % confidence interval for difference in response rates ( –1%–29 % ) , P = 0.07 . No statistically significant differences were seen in overall survival or time to progression between the two regimes although a tendency towards a shorter progression time on the MM regime must be acknowledged . There was , however , significantly reduced haematological toxicity ( P < 0.001 ) and alopecia ( P < 0.001 ) and fewer dose reductions and delays in patients r and omized to MM . No statistically significant differences were seen between the two regimes in terms of quality of life ( QOL ) . However , some association between QOL and toxicity was apparent overall with pooled QOL estimates tending to indicate a worsening in psychological state with increasing maximum toxicity over treatment . Despite the fact that results surrounding response rates and time to progression did not reach statistical significance , their possible compatibility with an improved outcome on CMF treatment must be borne in mind . However , MM is a well-tolerated regimen with fewer side-effects than CMF , which with careful patient management and follow-up , therefore , may merit consideration as a first-line treatment to palliate patients with metastatic breast cancer who are infirm or elderly Identification of important prognostic factors with respect to the patient 's initial response to therapy was made from a set of 25 covariates available on 281 patients with advanced breast cancer . Since the patients studied were all participants in a r and omized clinical trial that involved three different treatment regimens ( repeated weekly treatment of a combination of cyclophosphamide , methotrexate , 5-fluorouracil , vincristine , and prednisone ; intermittent treatment of the same preceding five drugs given in 5-day courses every 4 weeks ; or treatment every 3 weeks with adriamycin as a single agent ) , the effect of these treatments on the selection of important covariates was assessed . Although some evidence indicated that the set of important covariates differed by treatment , the differences were not strong enough to be of practical importance . Non-Caucasian patients did poorly on all regimens with a response rate of only 31 % compared to 62 % for Caucasian patients . The covariates of major prognostic importance for Caucasians were : disease-free interval , liver involvement , and performance status . Ambulatory patients with long disease-free intervals and no liver involvement had the best prognosis . After adjustments were made for these three covariates , the remaining covariates ( such as menopausal status , bone involvement , number of metastatic sites , and duration of metastatic disease ) were not significantly related to response . As reported earlier , the treatment effect was significant , even after adjustments were made for the important covariates BACKGROUND To compare survival between patients with advanced breast cancer ( ABC ) treated with epirubicin/paclitaxel ( Taxol ) or paclitaxel/carboplatin ( Cp ) chemotherapy . PATIENTS AND METHODS From January 1999 to April 2002 , 327 eligible patients with ABC were r and omized to receive either paclitaxel 175 mg/m(2 ) in a 3-h infusion followed by epirubicin ( EPI ) 80 mg/m(2 ) ( group A ) or paclitaxel , as in group A , followed by Cp at an AUC of 6 mg x min/ml ( group B ) every 3 weeks for six cycles . RESULTS After a median follow-up of 23.5 months , median survival was not significantly different between the two groups ( 22.4 months versus 27.8 months , P=0.25 ) , whereas median time to treatment failure was significantly longer in patients treated with paclitaxel/Cp ( 8.1 months in group A versus 10.8 months in group B , P=0.04 ) . Both regimens were well tolerated . In total , 39 patients ( 24 % ) in group A and 46 ( 29 % ) in group B suffered at least one severe side-effect . Quality -of-life assessment and cost analysis did not reveal any significant differences between the two groups . CONCLUSION Our study suggests that the paclitaxel/Cp combination is an effective therapeutic alternative for patients with ABC in which anthracycline administration has the potential of being harmful To evaluate the substitution of methotrexate with doxorubicin ( Dox ) in CMF-(cyclophosphamide , methotrexate , 5-fluorouracil ) containing regimen for advanced breast cancer , 415 postmenopausal patients below the age of 66 years , naïve to chemotherapy , were accrued from 1980 to 1984 and followed-up until 1995 . They received tamoxifen 30 mg daily orally and by r and omisation either 400 mg/m2 , cyclophosphamide , 25 mg/m2 doxorubicin and 500 mg/m2 5-fluorouracil ( CAF ) or 40 mg/m2 methotrexate instead of Dox ( CMF ) intravenously ( i.v . ) days 1 + 8 repeated every 4 weeks . Dox was substituted by methotrexate at a cumulative dose of 550 mg/m2 . Among 341 eligible patients the response rate and median time to progression was significantly in favour of CAF : 53 % CAF versus 36 % CMF ( P = 0.002 ) and 11.8 months CAF versus 6.5 months CMF ( P = 0.001 ) . Median duration of response was 19.5 CAF versus 18.0 CMF months , and survival 20.8 CAF versus 17.4 CMF months ( non-significant ) . The two regimens were equimyelotoxic . There were no treatment-related fatalities but 1 patient with congestive heart failure on CAF was reported . Nausea/vomiting , stomatitis and infections were modest in both groups , whilst alopecia was more common with CAF . Regression analysis showed that long recurrence free interval , good performance status , and no visceral involvement was significantly related to long-term survival , whilst the treatment regimen was not . It is concluded that in chemotherapy-naïve patients with advanced breast cancer  Dox-containing regimens are superior and remain the first choice of chemotherapy , especially in patients with visceral metastases , until newer drugs and combinations have been proven to be superior We report the results of a r and omized trial carried out by the Swiss Group for Clinical Cancer Research ( SAKK ) and in which 230 patients with advanced breast cancer receiving concurrently a hormonal treatment ( oophorectomy for pre- and tamoxifen for postmenopausal women )  were r and omly allocated to three different regimens of combination chemotherapy . The therapeutic results registered with the two more intensive combinations ( LMP/FVP and LMFP/ADM ) were similar with regard to response rates , time to progression and survival . The patients receiving the low-dose chemotherapy lmfp showed a statistically significant lower response rate ( 32 % , P less than 0.001 ) and a shorter survival ( P = 0.03 ) than the results observed in patients treated with the two other regimens . This difference was particularly pronounced , at least regarding survival , in the following subgroups : postmenopausal women , patients with a poor performance status , dominant visceral lesions , two sites of disease and a disease-free interval longer than 12 months . Patients with bony metastases as dominant lesion fared similarly with all three regimens of chemotherapy . This latter subset of advanced breast cancer patients should probably be spared too intensive cytotoxic treatment . This is , to our knowledge , the first report of a r and omized trial showing an evident correlation between response rate and survival in various subgroups of patients with advanced breast cancer treated with different chemotherapeutic regimens Since  chemotherapy  for metastatic breast cancer is not curative , consideration of the quality of life is important in selecting a treatment regimen . We conducted a r and omized trial comparing continuous chemotherapy , administered until disease progression was evident , with intermittent therapy , whereby treatment was stopped after three cycles and then repeated for three more cycles only when there was evidence of disease progression . Each approach was tested with doxorubicin combined with cyclophosphamide or with cyclophosphamide combined with methotrexate , fluorouracil , and prednisone . Intermittent therapy result ed in a significantly worse response ( P = 0.02 by Mann-Whitney test ) , a significantly shorter time to disease progression ( relative risk based on proportional-hazards model , 1.8 ; 95 percent confidence interval , 1.4 to 2.4 ) , and a trend toward shorter survival ( relative risk , 1.3 ; confidence interval , 0.99 to 1.6 ) . The quality of life was expressed as linear-analogue self- assessment scores for physical well-being , mood , pain , and appetite and as a quality -of-life index . It improved significantly during the first three cycles , when all patients received treatment . Thereafter , intermittent therapy was associated with worse scores for physical well-being ( by 23 percent of scale ; 95 percent confidence interval , 11 to 35 percent ) , mood ( 25 percent ; 13 to 37 percent ) , and appetite ( 12 percent ; 0 to 24 percent ) and for the quality -of-life index as indicated by the patient ( 14 percent ; 5 to 23 percent ) and the physician ( 16 percent ; 7 to 26 percent ) . Changes in the quality of life were independent prognostic factors in proportional-hazards models of subsequent survival . We conclude that , as tested , continuous chemotherapy is better than intermittent chemotherapy for advanced breast cancer Eighty‐one evaluable patients with recurrent or metastatic breast cancer were r and omized to receive either vincristine 1 mg/m2 , doxorubicin 40 mg/m2 on day one and cyclophosphamide 200 mg/m2 orally days 3–6 ( VAC ) ; or cyclophosphamide 350 mg/m2 , methotrexate 20 mg/m2 , and 5‐fluorouracil 350 mg/m2 ( CMF ) intravenously , all on day 1 . Courses of each of the above regimens were repeated every three weeks . Twenty‐one of 45 patients ( 47 % ) on VAC and seven of 44 patients ( 16 % ) on CMF had complete or partial response ( P < 0.05 ) . The duration of response was six months for CMF and nine months for VAC . Hematologic toxicity was minimal for both groups but three patients receiving VAC developed cardiac toxicity . Overall survival projections at this time indicate no differences between the VAC or CMF treated patients 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 A total of 128 patients were r and omly assigned to two induction treatment programs : Adriamycin and L-PAM versus Cytoxan , 5-Fluorouracil , and Prednisone in an effort to assess their primary capacity for objective response . The two regimens appeared quite comparable in this respect . The 100 patients who had achieved clinical benefit following initial treatment were subsequently r and omly allocated to reveive either a fixed alternate treatment program involving the two drug regimens or were continued on the treatment program responsible for their initial improvement . Although those patients who received the fixed alternate treatment shcedule had a somewhat longer progression-free interval compared to the two single-treatment programs ( median duration of 16 months versus 12 months , respectively ) , the three treatment programs including the fixed alternate treatment schedules had comparable median survivals of 21 - 24 months with little difference noted in survival curves at any point thus far in the analysis . There were no differences noted in survival for the fixed alternating treatment group of patients , with respect to which induction regimen had been utilized to achieve initial response . The toxicity for these treatment programs was tolerable and compatible with outpatient administration . Myelosuppression occurred in the vast majority of patients on either regimen but in both regimens was relatively platelet sparing 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 Paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) , the first taxane to enter routine clinical practice , has aroused considerable interest due to its novel mechanism of action and its significant activity in metastatic breast cancer . Given this activity , it seemed logical to attempt to combine paclitaxel with doxorubicin , the other most active single agent in metastatic breast cancer . The Eastern Cooperative Oncology Group performed two trials investigating paclitaxel/doxorubicin combinations in patients with advanced breast cancer in an attempt to identify a tolerable dose and schedule of the combination . In the first trial , paclitaxel and doxorubicin were alternated every 3 weeks in doses of 200 mg/m2 and 75 mg/m2 , respectively , for patients who had received no more than one prior chemotherapeutic regimen .  Therapy was well tolerated in this setting . At these doses , paclitaxel induced more granulocytopenia and less thrombocytopenia than did doxorubicin .  Objective responses ( complete and partial responses ) were seen in seven of 12 patients ; two other patients had improved disease ( relief of pain in bony metastases ) . A second limited-institution Eastern Cooperative Oncology Group trial evaluated paclitaxel and doxorubicin given in combination . In this phase I trial , doxorubicin was given as an intravenous push and paclitaxel as a 24-hour continuous infusion . The sequence of drug administration ( D-->P or P-->D ) was alternated both between and within patients , so that we might evaluate the effect of administration schedule on toxicity . Therapy was begun at an initial paclitaxel dose of 150 mg/m2 and an initial doxorubicin dose of 50 mg/m2 in six patients , with a subsequent six patients receiving 175 and 60 mg/m2 , respectively , of paclitaxel and doxorubicin . In addition , patients received granulocyte colony-stimulating factor 5 micrograms/kg/d . While therapy at the initial dose level was well tolerated , dose-limiting mucositis was seen at the second dose level , although only when paclitaxel preceded doxorubicin . This suggests that sequence of drug administration in paclitaxel-based regimens may play an important role as a determinant of toxicity and ( perhaps ) efficacy , a finding similar to that seen when paclitaxel and cisplatin were combined in patients with ovarian cancer . Based on this study , we identified the sequence of doxorubicin ( 50 mg/m2 ) followed by paclitaxel ( 150 mg/m2 ) to be the maximum tolerated dose . This combination is currently being compared with paclitaxel alone and doxorubicin alone in patients with advanced breast cancer in an intergroup trial led by the Eastern Cooperative Oncology Group Summary The Southeastern Cancer Study Group , in a prospect ively r and omized study involving patients with advanced breast cancer , has compared a low dose intermittently administered five-drug regimen including cyclophosphamide , methotrexate , 5-fluorouracil , vincristine , and prednisone ( CMFVP ) with an aggressively administered three-drug regimen including cyclophosphamide , doxorubicin , and 5-fluorouracil ( CAF ) . CAF induced more responses and more complete responses and a longer duration of disease control . However , only a marginal difference was demonstrated in overall survival between the two regimens ( p = < 0.10 ) . Patients with a good risk pattern of metastases , i.e. those with nodular local chest wall recurrence , nodular pulmonary metastases , or bone-only metastases were more likely to achieve a response and survive longer than those with a poor risk pattern , i.e. lymphangitic pulmonary metastases , pleural effusion with chest wall ulceration , or widespread metastases , including hepatic . All of the differences between the two regimens were noted in the good risk pattern groups . CAF provided no additional benefit to patients presenting with poor risk patterns of metastases . Adriamycin-containing combinations may achieve a greater degree of tumor cell kill in certain subsets of patients with advanced breast cancer , but this provides only a marginal increase in survival A multicentric r and omized study was conducted to compare the CNF regimen ( cyclophosphamide at 600 mg/m2/iv , mitoxantrone at 10 mg/m2/iv , 5-fluorouracil at 600 mg/m2/iv ) with the CMF regimen ( methotrexate at 40 mg/m2/iv instead of mitoxantrone ) administered every 3 weeks to previously untreated locally advanced or metastatic breast cancer patients . In 119 patients evaluable for therapeutic response , complete plus partial response rate was 44 % for CNF and 29 % for CMF ( p>0.05 ; 95 % C.I. : CNF=32%-56 % , CMF=18%-40 % ) . No statistically significant difference regarding time to progression , over survival or response to second-line chemotherapy with Epidoxorubicin was observed between the two regimens . Both regimens were well tolerated , but the percent of alopecia and leucopenia was significantly higher in the CNF patient group ( 31 % versus 5 % and 18 % versus 0 % , respectively ; p<0.01 ) . In conclusion , CNF was demonstrated to be slightly more toxic but more effective as compared to CMF ( global response : 44 % versus 29 % , respectively ) . These findings should be taken into consideration when planning future studies of adjuvant chemotherapy A prospect i ve r and omized trial was conducted comparing the clinical response of 78 previously untreated patients with advanced metastatic breast cancer to a combination of cyclophosphamide , methotrexate , and 5‐fluorouracil ( CMF ) or to a combination of cyclophosphamide , adriamycin , and 5‐fluorouracil ( CAF ) . Sixty‐two percent of the patients receiving CMF responded to treatment compared to an 82 % response rate for the patients receiving CAF . Although within acceptable limits , hematologic and GI toxicity was greater with CAF . There was no significant difference in the duration of response to the two regimens . Therefore , the therapeutic difference between the two therapies is a higher initial response rate to the adriamycin containing regimen Abstract Seventy patients with breast cancer in an advanced stage were treated , at r and om , according to one of the two regimens of cyclic administration , associating , on one h and , doxorubicin + vincristine + methotrexate and on the other h and , vincristine + cyclophosphamide + 5 fluorouracil . Only the immediate results are studied in this controlled trial in 61 evaluable patients . They are significantly better with the first association : 63 % measurable objective responses vs 47.5 % ( 0.025 and 30 % of tumoral regressions superior to 50 % vs 3.2 % ( 0.001 . The toxicity is hardly more marked ( mainly cardiovascular and hematological ) in the second regimen than in the first one , but remains altogether acceptable for an induction chemotherapy Fifty‐one patients with metastatic breast cancer were r and omly allocated to receive either a four drug combination consisting of cyclophosphamide , methotrexate , 5‐fluorouracil , and prednisone ( CMFP ) , or a combination of vincristine , Adriamycin , and cyclophosphamide ( VAC ) with cross‐over on relapse . Objective responses were seen in 17 of 26 patients ( 65 % ) in the CMFP group and in 14 of 25 patients ( 56 % ) in the VAC group , but this difference was not statistically significant . The median duration of response for each group was one year . The estimated median survival was greater for the CMFP group , but this was not significant . Toxicity was more severe with the VAC regimen . It is concluded that there is no therapeutic advantage of the VAC over the CMFP regimen One hundred ninety-eight postmenopausal women with metastatic breast carcinoma were entered in this study . After six induction cycles with cyclophosphamide , methotrexate and 5-fluorouracil ( CMF ) , patients with at least stable disease were r and omized to the " continuation arm " ( continuation of CMF until progression ) ( A , 49 evaluable patients ) or to the " intensification-discontinuation arm " ( addition of adriamycin and vincristine to two of the three drugs of CMF for six more cycles ; i.e. , CMAV , CFAV , MFAV , twice ; discontinuation of chemotherapy ; radiotherapy to pre- study sites of disease in patients prospect ively considered as c and i date s to receive this treatment ) ( B , 46 evaluable patients ) . After r and omization , escalation of response category occurred in five patients on A ( 10 % ) and in five on B ( 11 % ) . Time to progression was transiently delayed in arm B within 6 months after r and omization . There were no significant differences in the overall time to progression , duration of response or survival . On arm B , after discontinuation of chemotherapy , median time to relapse was 22 weeks . This time was significantly longer in patients who were c and i date s for radiation therapy ( 36 weeks , P = 0.005 ) , or with a disease-free interval greater than 1 year ( 32 weeks , P = 0.004 ) or who achieved complete remission ( 60 weeks , P = 0.0001 ) . On arm B , three patients ( 7 % ) are still alive in complete remission in excess of three , five and six years following discontinuation of therapy . This study indicates that late intensification of chemotherapy followed by discontinuation of treatment may maintain palliation , and allow a long treatment-free period in responding patients with advanced breast carcinoma . ( ABSTRACT TRUNCATED AT 250 WORDS THE THERAPEUTIC EFFECTIVENESS OF INTERMITTENT vs. continuous combination chemotherapy and of the substitution of adriamycin for methotrexate in a 5-drug regimen was evaluated in women with metastatic breast carcinoma . Patients were r and omly allocated to receive continuous therapy with cyclophosphamide , methotrexate , 5-fluo-rouracil , vincristine , prednisone ( CMFVP-C , 86 patients ) , intermittent CMFVP ( CMFVP-I , 109 patients ) , or intermittent CAFVP ( 107 patients ) . The CR + PR rate with CAFVP ( 71 % ) was superior to CMFVP-C ( 50 % , p = 0.003 ) and to CMFVP-I ( 50 % , p = 0.002 ) . The remission duration with CAFVP ( 14 months , median ) was superior to CMFVP-I ( 7 months ) ( p < 0.01 ) , and tended to be superior to CMFVP-C ( 9 months ) ( p = 0.07 ) . There was a survival advantage of CAFVP ( 19 months , median ) over CMFVP-I ( 13 months ) ( p = 0.01 ) , but not over CMFVP-C ( 16 months ) ( p = 0.24 ) . Among CR + PR patients , the survival with CAFVP ( 29 months , median ) was superior ( p = 0.02 ) to both CMFVP-I ( 18 months ) and CMFVP-C ( 21 months ) . The CMFVP-C regimen was associated with the highest incidence of leukopenia and neurologic toxicity , but the lowest incidence of GI toxicity . The results indicate that the CAFVP regimen is well tolerated and is superior to the CMFVP regimens In a continuing search for agents effective in advanced breast cancer , nonr and omized studies by the Southwest Cancer Chemotherapy Study Group have shown a 29 % response rate with BCNU , a 19 % response rate with CCNU , and a 36 % response rate with adriamycin . Following these leads , a r and omized Phase III study has compared adriamycin ( 60–75 mg/m2 intravenously every 3 weeks ) with the oral nitrosoureas , CCNU ( 100–130 mg/m2 orally every 6 weeks ) and methyl CCNU ( 125–150 mg/m2 orally every 6 weeks ) in patients with advanced breast cancer , all of whom had already failed in at least one trial with conventional chemotherapeutic agents . The patients ' age , menopausal status , sites of metastatic involvement , and extent of prior therapy were nearly identical in the three treatment groups . Ten inevaluable patients  died within the first 2 weeks from tumor . For the remaining 100 patients , the response rate was : adriamycin 15/40 ( 38 % ) ; CCNU 4/20 ( 14 % ) ; and methyl CCNU 1/31 ( 3 % ) . The median duration s of response  for adriamycin , CCNU , and methyl CCNU were 7 , 3 , and 1 1/2 months respectively . Patients receiving adriamycin had significantly superior survival from die start of chemotherapy , and the duration of survival  of adriamycin responders ( 12 + months ) was significantly superior ( P < .001 ) to adriamycin non‐responders ( 5 months ) . Metastatic lesions  responding to adriamycin  included skin and soft tissue ( 46 % response rate ) , lungs ( 36 % ) , liver ( 20 % ) , and bones ( 19 % ) compared with only soft tissue and skin responses ( 12 % ) with the nitrosoureas . Myelosuppression was the dose‐limiting toxicity with all three regimens , but was less prominent with methyl CCNU , suggesting that the dose of this agent could have been higher . An exploration of adriamycin in patients without prior chemotherapy is presently ongoing , with a response rate that is currently in excess of 50 % and equal to the response rate of a control population receiving a commonly used five‐drug combination regimen . Adriamycin is an effective new agent in the therapy of breast cancer , and combination trials seem indicated The aim of this study was to evaluate the significance of response to the first two cycles of FEC ( 5-fluorouracil , 4-epirubicin , cyclophosphamide ) in patients with advanced breast cancer . A total of 99 patients entered the study . They showed either high risk criteria and were previously untreated or showed low risk criteria and were pretreated by hormonal therapies . Eighty-two patients were evaluable . In 22 ( 27 % ) who had disease progression despite two cycles of FEC , further therapeutic attempts proved ineffective , the median survival being 2.8 months . The remaining patients responded either by stable disease ( SD , n = 29 ; 35 % ) , by partial or by complete remission ( PR , CR , n = 31 ; 38 % ) . These 60 patients were r and omized to two regimes of maintenance therapy : FEC every 3 weeks or LMF ( leukeran , methotrexate , 5-fluorouracil ) every 6 weeks . The subsequent course of the disease was not different in both arms . It was neither influenced by the quality of early response , i.e. SD , PR , CR , nor by the intensity of chemotherapy . The prognostic impact of early response to two cycles of FEC proved to be higher than other prognostic parameters in the patients examined . Thus , early response may serve as a valid guide to adapt maintenance chemotherapy in individual patients with advanced breast cancer We assessed the efficacy of a regimen consisting of four cycles of cyclophosphamide , Adriamycin ( Adria Laboratories , Inc , Columbus , Ohio ) , cisplatin ( CAP ) followed by maintenance with cyclophosphamide , 5-fluorouracil , prednisone ( CFP ) compared with CFP alone in a r and omized trial of 86 patients with advanced breast cancer . The objective regression rates were 46 % ( CFP ) and 49 % ( CAP with CFP ) which included complete regression rates of 7 % ( CFP ) and 4 % ( CAP with CFP ) . The median time to progression was nine months for CFP and six months for CAP with CFP . Median survival in the CFP group was 18 months v 11 months in the CAP recipients . Due to the therapeutic trend in favor of patients receiving CFP , we terminated the study before achieving our initially projected accrual . We observed over a twofold excess of substantial nausea and vomiting among patients receiving the platinum-based regimen . In our view , the CAP followed by the CFP regimen is a more toxic program that offers no clinical ly meaningful improvement over CFP to patients with advanced breast cancer Forty women with metastatic breast cancer were r and omized to receive either mitomycin-C ( MMC ) ( 21 patients ) or vindesine ( 19 patients ) with high dose medroxyprogesterone acetate ( MPA ) .  Response rates were not significantly different ( 33 % for MPA and MMC and 28 % for MPA and vindesine ) ; the duration of response was better for patients receiving the MMC combination ( median of 10.5 months versus 6 months for those on the vindesine combination ) Adriamycin is of noteworthy efficacy in the treatment of metastatic breast cancer . Its role in combination regimens is under investigation . One hundred seventy‐five women with advanced breast cancer were entered into a prospect ively r and omized trial comparing two five‐drug regimens . Regimen CMFVP consisted of cyclophosphamide ( C ) , methotrexate ( M ) , 5‐fluorouracil ( F ) , vincristine ( V ) , and prednisone ( P ) . Regimen CAFVP was identical but substituted Adriamycin ( A ) for methotrexate .  Twenty‐seven patients were disqualified ; 148 were evaluable . With CMFVP the complete response rate ( CR ) was 11 % , and the partial response rate ( PR ) was 46 % ; with CAFVP , CR was 13 % and PR was 45 % . Duration of response tended to be slightly longer for patients on the Adriamycin arm . The median survival for CR and PR patients with CMFVP was 20.2 months , which was shorter ( p = .07 ) than the 33 month median survival with CAFVP . Although statistical significance was not reached at the 5 % level , the increased survival of responders on the Adriamycin regimen supports the data of other studies which suggest that first line combination chemotherapy in advanced breast cancer should include Adriamycin . Cancer 42:2141–2148 , 1978 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 The activity of paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) in advanced breast cancer patients who have failed doxorubicin treatment is well established , but the optimal sequence between these two important agents remains to be determined . The European Organization for Research and Treatment of Cancer therefore design ed a prospect i ve r and omized clinical trial in which patients not exposed to anthracyclines in the adjuvant setting received either first-line paclitaxel , given as a 3-hour infusion at a dose of 200 mg/m2 followed at the time of disease progression by second-line doxorubicin , given as a bolus injection at a dose of 75 mg/m2 or the reverse sequence . The target accrual is 330 patients . Interim results on 207 evaluable patients of 289 r and omized are presented
BACKGROUND Antitumour antibiotics are used in the management of metastatic breast cancer .
Some of these agents have demonstrated higher tumour response rates than non-antitumour antibiotic regimens , however a survival benefit has not been established in this setting .
OBJECTIVES To identify and review the r and omised evidence comparing anti-tumour antibiotic containing chemotherapy regimens with regimens not containing an anti-tumour antibiotic in the management of women with metastatic breast cancer .