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Clinical outcomes: to be a surrogate or not to be ...?

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Clinical trials remain the bedrock of the introduction of new therapies for patients with cancer... Widespread use of screening mammography, breast conservation, adjuvant hormonal therapy, adjuvant chemotherapy and, most recently, adjuvant trastuzumab have all been based on the results of well designed clinical trials... In advanced disease, although an improvement in survival remains the over-arching wish of most patients, when this is not likely there nevertheless remain important improvements that are highly clinically relevant... There are good data that improvements in quality of life and/or reduction in symptoms correlate with tumour response, so that where patients are very symptomatic, demonstration of an increased response rate is a worthwhile gain, provided that this does not come at the cost of major toxicity... In contrast, for many women with more indolent, relatively asymptomatic disease, absence of progression may be the primary goal... It is interesting to note, therefore, that patients with stable disease for at least 6 months on hormonal therapy often have similar OS to those whose disease actually shrinks on therapy, justifying the use of TTP and/or clinical benefit as the primary end-point for many such studies... For example, if only half of the patients have sensitive disease, then in a cohort of three patients (the classic phase I design) there is a one in eight (0.125) chance that no biological effect will be seen at one level simply because all three tumours were totally resistant; across three active dose levels the chance that we will have one cohort with no responses becomes 0.29, or almost one in three! If one then considers the risk that a biologically maximally effective dose is identified because no responses are seen at a higher dose level, it becomes apparent that this can happen not infrequently... It became clear over many years that when patients are treated with 3 to 6 months of chemotherapy, those patients who have no residual invasive disease in the primary tumour and/or ipsilateral axillary lymph nodes have the best long-term outcome... However, it remains true that on the one hand the addition of taxanes and/or trastuzumab to neoadjuvant chemotherapy does increase the proportion of patients achieving pCR, and on the other that the addition of those same agents to postoperative adjuvant therapy does lead to improved OS... Therefore, pCR would appear to be a surrogate predictor of a more effective adjuvant therapy; what it does not yet appear to do is to identify the precise patients who will benefit from the therapy! Two obvious candidates in the field of preoperative or neoadjuvant therapy are falls in proliferation in patients treated with primary (short-term or long-term) endocrine therapy, or the proportion of patients achieving pCRs to neoadjuvant chemotherapy... Both appear to be reliable, at least most of the time, but neither has yet been shown to have an ideal level of discrimination between agents that can and cannot lead to changes in ultimate outcomes... For new biological agents this is even less certain, although the success of trastuzumab suggests that we can have confidence that a model developed for untargeted cytotoxics, and loosely targeted hormonal therapies, may work out for many newer agents.

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Biological drug development – defining biologically effective dose (BED) using advanced disease as a model.
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Figure 2: Biological drug development – defining biologically effective dose (BED) using advanced disease as a model.

Mentions: For cytotoxics, the phase I-II-III development sequence (as shown in Figure 1) was in fact based on the experience that the maximum tolerated dose (MTD) in phase I often turned out to be an effective and tolerated dose in early stage disease. However, for cytotoxics the identification of a dose on the basis that it caused an acceptable level of cytotoxicity in normal tissues, which could then cause a desirable level of cytotoxicity in malignant tissues, is perhaps not a great surprise! All patients contribute toward the toxicity end-point in a conventionally designed phase I study, and so it is a relatively efficient way to reach the dose level likely to deliver efficacy if it exists. In contrast (Figure 2), the way in which we might determine a maximum biologically effective dose could be more difficult.


Clinical outcomes: to be a surrogate or not to be ...?
Biological drug development – defining biologically effective dose (BED) using advanced disease as a model.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2230534&req=5

Figure 2: Biological drug development – defining biologically effective dose (BED) using advanced disease as a model.
Mentions: For cytotoxics, the phase I-II-III development sequence (as shown in Figure 1) was in fact based on the experience that the maximum tolerated dose (MTD) in phase I often turned out to be an effective and tolerated dose in early stage disease. However, for cytotoxics the identification of a dose on the basis that it caused an acceptable level of cytotoxicity in normal tissues, which could then cause a desirable level of cytotoxicity in malignant tissues, is perhaps not a great surprise! All patients contribute toward the toxicity end-point in a conventionally designed phase I study, and so it is a relatively efficient way to reach the dose level likely to deliver efficacy if it exists. In contrast (Figure 2), the way in which we might determine a maximum biologically effective dose could be more difficult.

View Article: PubMed Central - HTML

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Clinical trials remain the bedrock of the introduction of new therapies for patients with cancer... Widespread use of screening mammography, breast conservation, adjuvant hormonal therapy, adjuvant chemotherapy and, most recently, adjuvant trastuzumab have all been based on the results of well designed clinical trials... In advanced disease, although an improvement in survival remains the over-arching wish of most patients, when this is not likely there nevertheless remain important improvements that are highly clinically relevant... There are good data that improvements in quality of life and/or reduction in symptoms correlate with tumour response, so that where patients are very symptomatic, demonstration of an increased response rate is a worthwhile gain, provided that this does not come at the cost of major toxicity... In contrast, for many women with more indolent, relatively asymptomatic disease, absence of progression may be the primary goal... It is interesting to note, therefore, that patients with stable disease for at least 6 months on hormonal therapy often have similar OS to those whose disease actually shrinks on therapy, justifying the use of TTP and/or clinical benefit as the primary end-point for many such studies... For example, if only half of the patients have sensitive disease, then in a cohort of three patients (the classic phase I design) there is a one in eight (0.125) chance that no biological effect will be seen at one level simply because all three tumours were totally resistant; across three active dose levels the chance that we will have one cohort with no responses becomes 0.29, or almost one in three! If one then considers the risk that a biologically maximally effective dose is identified because no responses are seen at a higher dose level, it becomes apparent that this can happen not infrequently... It became clear over many years that when patients are treated with 3 to 6 months of chemotherapy, those patients who have no residual invasive disease in the primary tumour and/or ipsilateral axillary lymph nodes have the best long-term outcome... However, it remains true that on the one hand the addition of taxanes and/or trastuzumab to neoadjuvant chemotherapy does increase the proportion of patients achieving pCR, and on the other that the addition of those same agents to postoperative adjuvant therapy does lead to improved OS... Therefore, pCR would appear to be a surrogate predictor of a more effective adjuvant therapy; what it does not yet appear to do is to identify the precise patients who will benefit from the therapy! Two obvious candidates in the field of preoperative or neoadjuvant therapy are falls in proliferation in patients treated with primary (short-term or long-term) endocrine therapy, or the proportion of patients achieving pCRs to neoadjuvant chemotherapy... Both appear to be reliable, at least most of the time, but neither has yet been shown to have an ideal level of discrimination between agents that can and cannot lead to changes in ultimate outcomes... For new biological agents this is even less certain, although the success of trastuzumab suggests that we can have confidence that a model developed for untargeted cytotoxics, and loosely targeted hormonal therapies, may work out for many newer agents.

No MeSH data available.