***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 A prospect i ve , multicenter , r and omized , Phase III trial comparing the efficacy of combination chemotherapy with 5‐fluorouracil , doxorubicin , and cyclophosphamide ( FAC ) with a combination of vinorelbine and doxorubicin ( NA ) in the treatment of patients with advanced breast carcinoma was undertaken 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 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 Italian Oncology Group for Clinical Research tested two experimental chemotherapy strategies in an attempt to improve the results achievable with conventional chemotherapy in metastatic breast cancer . One hundred sixty-two patients were r and omly allocated as follows : ( a ) to the conventional cyclophosphamide , methotrexate , 5-fluorouracil chemotherapy regimen ( CMF ) ; ( b ) to a rotational crossing program ( ROT-CROSS ) ; or ( c ) to a sequential intensification program ( SEQ-INT ) . The same single agents ( C , M , F , cisplatin , etoposide , and doxorubicin ) were administered in both experimental arms , but following a different policy . The SEQ-INT program induced a significantly higher complete response ( 32 % vs. 6 % , p = 0.0006 ) and objective response rate ( 72 % vs. 42 % , p = 0.0047 ) than CMF did . There were no differences in survival between CMF and either experimental arm . A number of side effects were significantly more with both experimental chemotherapies than with CMF , but the treatments were generally tolerable . Although some caution is required when interpreting a significant advantage found between an entire chemotherapeutic strategy and a single conventional combination , this study documents the potential therapeutic advantage of administering different sequential chemotherapies , and changing each at the time of maximum result without waiting for a progression . The impressive cytoreductive effects achievable with this policy ( SEQ-INT ) in metastatic disease merit further investigation in the adjuvant setting 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 Four hundred eleven women with metastatic breast cancer were r and omly assigned to receive either 60 mg/m2 doxorubicin ( 130 patients ) , 320 mg/m2 bisantrene ( 146 patients ) , or 14 mg/m2 mitoxantrone ( 135 patients ) . The doses were given intravenously every 3 weeks with a cross-over design to determine their relative efficacy and toxicity . To be eligible , patients must have had one previous chemotherapy regimen , and patients who were estrogen receptor positive must have failed endocrine therapy . There were 365 patients assessable for response and 399 assessable for toxic effects . The median age was 57 years ; 18 % were premenopausal or perimenopausal . Visceral dominant disease was present in 66 % of the patients . Ninety-seven percent of the patients had a disease-free interval from diagnosis to first recurrence of less than 1 year . The response rate was 28 % with doxorubicin , 13 % with bisantrene , and 14 % with mitoxantrone ( P = .004 ) . Median time to treatment failure was 133 days with doxorubicin , 66 days with bisantrene , and 68 days with mitoxantrone ( logrank P = .06 ) . The median survival was 315 days for doxorubicin , 290 days for bisantrene , and 177 days for mitoxantrone ( logrank P = .04 ) , although survival at 2 years was similar for all three agents . There were five responses in the 66 patients crossed over to doxorubicin and one response each for patients crossed over to bisantrene ( 39 patients ) or mitoxantrone ( 63 patients ) . Toxicity leading to discontinuance of therapy was more common with doxorubicin , and discontinuance of therapy was due primarily to patient 's request or cardiotoxicity . The major dose-limiting toxic effect for all three agents was leukopenia . Nausea and vomiting , mucositis , and alopecia were more severe with doxorubicin .  Congestive heart failure developed in nine patients treated with doxorubicin , zero patients treated with bisantrene , and two patients treated with mitoxantrone . A decrease in the left ventricular ejection fraction , as defined by moderate to severe Alex and er grade changes , was more common in patients treated with doxorubicin ( doxorubicin-treated patients = 20 % , bisantrene-treated patients = 5 % , and mitoxantrone-treated patients = 10 % ) . This study demonstrates that bisantrene and mitoxantrone have only modest activity in metastatic breast carcinoma . The activity of doxorubicin is greater than that of the other two agents , but at a cost of increased toxicity 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 
    Output:
    
Most regimens had very similar efficacy profiles ( < 5 % difference in HR ) as first- and subsequent-line therapies .
Stepwise improvements in efficacy of chemotherapy and targeted treatments cumulatively have achieved major improvements in the survival of patients with advanced breast cancer .
Many options that can be used in first and subsequent lines of therapy have comparable efficacy profiles