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Surrogate markers and survival in women receiving first-line combination anthracycline chemotherapy for advanced breast cancer.

Hackshaw A, Knight A, Barrett-Lee P, Leonard R - Br. J. Cancer (2005)

Bottom Line: The treatment effect on survival was quantified by the hazard ratio.The relationship between survival and each surrogate marker was assessed by a weighted linear regression of the hazard ratio against the odds ratio.There was a significant linear association between survival and complete or partial tumour response (P<0.001, R(2)=34%), complete tumour response (P=0.02, R(2)=12%), progressive disease (P<0.001, R(2)=38%) and time to progression (P<0.0001, R(2)=56%); R(2) is the proportion of the variability in the treatment effect on survival that is explained by the treatment effect on the surrogate marker.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK & UCL Cancer Trials Centre, London, UK. a.hackshaw@ctc.ucl.ac.uk

ABSTRACT
Surrogate markers may help predict the effects of first-line treatment on survival. This metaregression analysis examines the relationship between several surrogate markers and survival in women with advanced breast cancer after receiving first-line combination anthracycline chemotherapy 5-fluorouracil, adriamycin and cyclophosphamide (FAC) or 5-fluorouracil, epirubicin and cyclophosphamide (FEC). From a systematic literature review, we identified 42 randomised trials. The surrogate markers were complete or partial tumour response, progressive disease and time to progression. The treatment effect on survival was quantified by the hazard ratio. The treatment effect on each surrogate marker was quantified by the odds ratio (or ratio of median time to progression). The relationship between survival and each surrogate marker was assessed by a weighted linear regression of the hazard ratio against the odds ratio. There was a significant linear association between survival and complete or partial tumour response (P<0.001, R(2)=34%), complete tumour response (P=0.02, R(2)=12%), progressive disease (P<0.001, R(2)=38%) and time to progression (P<0.0001, R(2)=56%); R(2) is the proportion of the variability in the treatment effect on survival that is explained by the treatment effect on the surrogate marker. Time to progression may be a useful surrogate marker for predicting survival in women receiving first-line anthracycline chemotherapy and could be used to estimate the survival benefit in future trials of first-line chemotherapy compared to FAC or FEC. The other markers, tumour response and progressive disease, were less good.

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The relationship between the treatment effect on median survival time and each of the four surrogate markers. The regression lines are as follows, with the corresponding P-value, coefficient of determination (R2) and standard error of the regression coefficient (s.e.) in brackets: (A) Log10 hazard ratio=−0.0081+0.2796 × log10 odds ratio for complete/partial response (P<0.0001, R2=34%, s.e.=0.0590), (B) Log10 hazard ratio=−0.0097+0.1266 × log10 odds ratio for complete response (P=0.02, R2=12%, s.e.=0.0521), (C) Log10 hazard ratio=0.0015–0.1781 × log10 odds ratio for progressive disease (P<0.0001, R2=38%, s.e.=0.0380), (D) Log10 hazard ratio=0.0135+0.5082 × log10 ratio of median time to progression (P<0.001, R2=56%, s.e.=0.0928). The size of the symbols is proportional to the inverse of the variance (the weight). For time to progression the size is proportional to the number of patients in the trial.
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fig1: The relationship between the treatment effect on median survival time and each of the four surrogate markers. The regression lines are as follows, with the corresponding P-value, coefficient of determination (R2) and standard error of the regression coefficient (s.e.) in brackets: (A) Log10 hazard ratio=−0.0081+0.2796 × log10 odds ratio for complete/partial response (P<0.0001, R2=34%, s.e.=0.0590), (B) Log10 hazard ratio=−0.0097+0.1266 × log10 odds ratio for complete response (P=0.02, R2=12%, s.e.=0.0521), (C) Log10 hazard ratio=0.0015–0.1781 × log10 odds ratio for progressive disease (P<0.0001, R2=38%, s.e.=0.0380), (D) Log10 hazard ratio=0.0135+0.5082 × log10 ratio of median time to progression (P<0.001, R2=56%, s.e.=0.0928). The size of the symbols is proportional to the inverse of the variance (the weight). For time to progression the size is proportional to the number of patients in the trial.

Mentions: Figure 1 shows the relationship between the treatment effect on the median survival time (survival ratio) and the treatment effect on tumour response and disease progression (odds ratio). There was a statistically significant linear association between survival and complete or partial tumour response (P-value <0.0001); 34% of the variability in the treatment effect on survival can be explained by the treatment effect on tumour response. When the data are restricted to only those patients with a complete response, there was still evidence of a linear association with survival (P-value 0.02), though only a small proportion of the variability could be explained (R2=12%). There was also a relationship with progressive disease (P-value<0.0001, R2=38%) and time to progression (P-value <0.0001, R2=56%); the latter suggesting that a moderately high proportion of the variability in the treatment effect on survival can be explained by the treatment effect on time to progression. The results on time to progression were similar in the 9 trials that included death as an event (regression coefficient 0.4817, P-value=0.017, R2=58%).


Surrogate markers and survival in women receiving first-line combination anthracycline chemotherapy for advanced breast cancer.

Hackshaw A, Knight A, Barrett-Lee P, Leonard R - Br. J. Cancer (2005)

The relationship between the treatment effect on median survival time and each of the four surrogate markers. The regression lines are as follows, with the corresponding P-value, coefficient of determination (R2) and standard error of the regression coefficient (s.e.) in brackets: (A) Log10 hazard ratio=−0.0081+0.2796 × log10 odds ratio for complete/partial response (P<0.0001, R2=34%, s.e.=0.0590), (B) Log10 hazard ratio=−0.0097+0.1266 × log10 odds ratio for complete response (P=0.02, R2=12%, s.e.=0.0521), (C) Log10 hazard ratio=0.0015–0.1781 × log10 odds ratio for progressive disease (P<0.0001, R2=38%, s.e.=0.0380), (D) Log10 hazard ratio=0.0135+0.5082 × log10 ratio of median time to progression (P<0.001, R2=56%, s.e.=0.0928). The size of the symbols is proportional to the inverse of the variance (the weight). For time to progression the size is proportional to the number of patients in the trial.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2361525&req=5

fig1: The relationship between the treatment effect on median survival time and each of the four surrogate markers. The regression lines are as follows, with the corresponding P-value, coefficient of determination (R2) and standard error of the regression coefficient (s.e.) in brackets: (A) Log10 hazard ratio=−0.0081+0.2796 × log10 odds ratio for complete/partial response (P<0.0001, R2=34%, s.e.=0.0590), (B) Log10 hazard ratio=−0.0097+0.1266 × log10 odds ratio for complete response (P=0.02, R2=12%, s.e.=0.0521), (C) Log10 hazard ratio=0.0015–0.1781 × log10 odds ratio for progressive disease (P<0.0001, R2=38%, s.e.=0.0380), (D) Log10 hazard ratio=0.0135+0.5082 × log10 ratio of median time to progression (P<0.001, R2=56%, s.e.=0.0928). The size of the symbols is proportional to the inverse of the variance (the weight). For time to progression the size is proportional to the number of patients in the trial.
Mentions: Figure 1 shows the relationship between the treatment effect on the median survival time (survival ratio) and the treatment effect on tumour response and disease progression (odds ratio). There was a statistically significant linear association between survival and complete or partial tumour response (P-value <0.0001); 34% of the variability in the treatment effect on survival can be explained by the treatment effect on tumour response. When the data are restricted to only those patients with a complete response, there was still evidence of a linear association with survival (P-value 0.02), though only a small proportion of the variability could be explained (R2=12%). There was also a relationship with progressive disease (P-value<0.0001, R2=38%) and time to progression (P-value <0.0001, R2=56%); the latter suggesting that a moderately high proportion of the variability in the treatment effect on survival can be explained by the treatment effect on time to progression. The results on time to progression were similar in the 9 trials that included death as an event (regression coefficient 0.4817, P-value=0.017, R2=58%).

Bottom Line: The treatment effect on survival was quantified by the hazard ratio.The relationship between survival and each surrogate marker was assessed by a weighted linear regression of the hazard ratio against the odds ratio.There was a significant linear association between survival and complete or partial tumour response (P<0.001, R(2)=34%), complete tumour response (P=0.02, R(2)=12%), progressive disease (P<0.001, R(2)=38%) and time to progression (P<0.0001, R(2)=56%); R(2) is the proportion of the variability in the treatment effect on survival that is explained by the treatment effect on the surrogate marker.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK & UCL Cancer Trials Centre, London, UK. a.hackshaw@ctc.ucl.ac.uk

ABSTRACT
Surrogate markers may help predict the effects of first-line treatment on survival. This metaregression analysis examines the relationship between several surrogate markers and survival in women with advanced breast cancer after receiving first-line combination anthracycline chemotherapy 5-fluorouracil, adriamycin and cyclophosphamide (FAC) or 5-fluorouracil, epirubicin and cyclophosphamide (FEC). From a systematic literature review, we identified 42 randomised trials. The surrogate markers were complete or partial tumour response, progressive disease and time to progression. The treatment effect on survival was quantified by the hazard ratio. The treatment effect on each surrogate marker was quantified by the odds ratio (or ratio of median time to progression). The relationship between survival and each surrogate marker was assessed by a weighted linear regression of the hazard ratio against the odds ratio. There was a significant linear association between survival and complete or partial tumour response (P<0.001, R(2)=34%), complete tumour response (P=0.02, R(2)=12%), progressive disease (P<0.001, R(2)=38%) and time to progression (P<0.0001, R(2)=56%); R(2) is the proportion of the variability in the treatment effect on survival that is explained by the treatment effect on the surrogate marker. Time to progression may be a useful surrogate marker for predicting survival in women receiving first-line anthracycline chemotherapy and could be used to estimate the survival benefit in future trials of first-line chemotherapy compared to FAC or FEC. The other markers, tumour response and progressive disease, were less good.

Show MeSH
Related in: MedlinePlus