Diffusion of Docetaxel in Metastatic Prostate Cancer
Diffusion of Docetaxel in Metastatic Prostate Cancer
In this study, we found that docetaxel diffusion largely preceded definitive phase III evidence of efficacy in CRPC. Importantly, docetaxel diffusion was slower for certain subgroups of disadvantaged patients, including blacks and those with lower income. Also, docetaxel diffusion occurred simultaneously across multiple cancers, suggesting that its uptake was independent of clinical evidence for particular cancers.
Studies of cancer treatment use by patient SES, demographic levels, and health status have frequently shown lower usage for disadvantaged patients. Differences by geographic region have also been found. Diffusion, which tracks patterns of usage over time, has been explicitly studied in some instances. Slower diffusion for older patients, minorities, and patients with lower SES were identified. In this study, docetaxel diffusion was slower for socioeconomically and demographically disadvantaged patients. The absence of differences in cumulative incidence by comorbidity status is surprising, but may be because of sicker patients becoming castration resistant more quickly, hastening receipt of chemotherapy.
The observation that disadvantaged patients have slower diffusion presents opportunities to improve uptake of proven new therapies in subpopulations. For instance, direct-to-consumer advertising (DTCA) has recently been shown to improve the appropriate use of aromatase inhibitors. Since oncology patients are frequently aware of DTCA, DTCA could be a useful tool to promote the use of proven new therapies in certain target populations. Even if patient out-of-pocket costs for newer treatments are similar, anxiety about how to pay may exist, in which case improved communication between physicians and patients is crucial for clarifying treatment costs.
Evidence of a sigmoid shape for use of docetaxel over time is consistent with prior observations that social dynamics, especially among physicians, accelerate new innovation diffusion. Thus, enhancing communication channels among physicians, especially between key opinion leaders and their colleagues, may encourage more rapid adoption of treatments. One factor that has been repeatedly identified to increase adoption rates is attendance at scientific symposia, which serve as forums for disseminating information about new treatments. Unfortunately, the nature of the relationships among physicians was not analyzable in this study because of lack of data on their social links.
The rapid uptake of docetaxel in CRPC prior to definitive evidence from a phase III trial is a concern. Considerations that may have led to early adoption of docetaxel include prior FDA indications in other solid tumors and the fact that conventional treatment, mitoxantrone, provided only palliative relief, whereas early pilot trials for docetaxel showed the additional promise of a survival benefit. However, despite the early evidence, the positive result for docetaxel in randomized trials was not a foregone conclusion. Indeed, multiple phase III trials for drugs already in wide use have returned negative results. In some instances, phase III evidence led to an appropriate diminution in the use of the new drug, though not in all.
The evidence in Figure 5 indicates that docetaxel diffusion occurred across different cancers approximately simultaneously, in most cases prior to FDA approval. This suggests that once oncologists begin to use a drug for a given cancer, they may be more likely to do so for other cancers; the mechanism that allows this is off-label drug use. Off-label use is considered appropriate in many instances, with 25% to 50% of cancer drug prescriptions delivered off label. Reimbursement for off-label drug use is facilitated by inclusion in medical compendia. For instance, Medicare contractors are required by Congress to pay for cancer drug prescriptions if their use is supported by selected standard medical compendia. Importantly, taxane-based therapy, including docetaxel, was itself included in standard medical compendia for treatment of CRPC prior to publication of phase III evidence. Reliance on compendia to facilitate treatment reimbursement represents an attempt to balance tradeoffs. On the one hand, the requirement that every variation in target population for a drug require a separate FDA indication would overwhelm available resources. On the other hand, reliance on compendia of potentially questionable quality may lead to inappropriate use. And, in fact, questions about the quality of the medical compendia have been raised. A recent review found that compendia "lack transparency, cite little current evidence, and lack systematic methods to review or update evidence". The evaluation of evidence for docetaxel in particular was found to be problematic. The questionable quality of medical compendia is astonishing in light of the role compendia play in determining reimbursement. The American Society of Clinical Oncology has stated that the "system for identifying medically appropriate cancer therapies, including those that involve off-label uses… requires attention".
One limitation in this study is the inability to identify the true denominator of patients who become castration resistant, a key eligibility criterion for receiving docetaxel. Identifying CRPC cases based on receipt of chemotherapy does not capture patients with CRPC who received no chemotherapy. Such patients may be too sick to receive chemotherapy. Thus, diffusion estimates for CRPC are likely biased high. In this context, performance status would be an informative descriptive factor, but it was not available. The necessity of using Medicare claims to identify relapse or recurrence is often problematic, but especially when treatment is itself the endpoint, because it raises the question of whether patients not identified as relapse/recurrent by Medicare claims (ie, HMO patients) may be different, limiting generalizability of the findings. Also, the use of Medicare data limits the analysis to patients age 65 years or older. However, prostate cancer occurs primarily in patients age 65 years or older (~70% of cases), and older patients may receive suboptimal care, representing a critical target population. Physician-level data were not available; therefore, the extent to which physicians were exposed to marketing efforts (which may have reinforced docetaxel uptake) was not identifiable in the data, nor were differences in diffusion according to facility type or degree of provider specialization. Finally, these results may not be generalizable to agents with different trial evidence profiles.
Currently, the FDA is reviewing whether to loosen constraints on the marketing of drugs prescribed off label. In contrast, our findings point to the potential risks of off-label use. By enabling the widespread diffusion of a new therapy prior to definitive phase III evidence, the off-label mechanism undermines the assumption that phase III comparative clinical trials necessarily determine which treatments become standard care. In this setting, inappropriate use is inevitable, with potential costs in increased morbidity and mortality if a different drug may have been more appropriate. Inappropriate use also places an unnecessary financial burden on health care payers. As declared by ASCO, medical compendia, which facilitate off-label reimbursement, require greater oversight, especially if they serve as the arbiters of reimbursement for Medicare, a federal program. Ultimately, greater levels of investment in clinical research are required to produce the highest levels of evidence—especially phase III trial evidence—for a given indication, in order to reduce the tendency for off-label use.
Discussion
In this study, we found that docetaxel diffusion largely preceded definitive phase III evidence of efficacy in CRPC. Importantly, docetaxel diffusion was slower for certain subgroups of disadvantaged patients, including blacks and those with lower income. Also, docetaxel diffusion occurred simultaneously across multiple cancers, suggesting that its uptake was independent of clinical evidence for particular cancers.
Studies of cancer treatment use by patient SES, demographic levels, and health status have frequently shown lower usage for disadvantaged patients. Differences by geographic region have also been found. Diffusion, which tracks patterns of usage over time, has been explicitly studied in some instances. Slower diffusion for older patients, minorities, and patients with lower SES were identified. In this study, docetaxel diffusion was slower for socioeconomically and demographically disadvantaged patients. The absence of differences in cumulative incidence by comorbidity status is surprising, but may be because of sicker patients becoming castration resistant more quickly, hastening receipt of chemotherapy.
The observation that disadvantaged patients have slower diffusion presents opportunities to improve uptake of proven new therapies in subpopulations. For instance, direct-to-consumer advertising (DTCA) has recently been shown to improve the appropriate use of aromatase inhibitors. Since oncology patients are frequently aware of DTCA, DTCA could be a useful tool to promote the use of proven new therapies in certain target populations. Even if patient out-of-pocket costs for newer treatments are similar, anxiety about how to pay may exist, in which case improved communication between physicians and patients is crucial for clarifying treatment costs.
Evidence of a sigmoid shape for use of docetaxel over time is consistent with prior observations that social dynamics, especially among physicians, accelerate new innovation diffusion. Thus, enhancing communication channels among physicians, especially between key opinion leaders and their colleagues, may encourage more rapid adoption of treatments. One factor that has been repeatedly identified to increase adoption rates is attendance at scientific symposia, which serve as forums for disseminating information about new treatments. Unfortunately, the nature of the relationships among physicians was not analyzable in this study because of lack of data on their social links.
The rapid uptake of docetaxel in CRPC prior to definitive evidence from a phase III trial is a concern. Considerations that may have led to early adoption of docetaxel include prior FDA indications in other solid tumors and the fact that conventional treatment, mitoxantrone, provided only palliative relief, whereas early pilot trials for docetaxel showed the additional promise of a survival benefit. However, despite the early evidence, the positive result for docetaxel in randomized trials was not a foregone conclusion. Indeed, multiple phase III trials for drugs already in wide use have returned negative results. In some instances, phase III evidence led to an appropriate diminution in the use of the new drug, though not in all.
The evidence in Figure 5 indicates that docetaxel diffusion occurred across different cancers approximately simultaneously, in most cases prior to FDA approval. This suggests that once oncologists begin to use a drug for a given cancer, they may be more likely to do so for other cancers; the mechanism that allows this is off-label drug use. Off-label use is considered appropriate in many instances, with 25% to 50% of cancer drug prescriptions delivered off label. Reimbursement for off-label drug use is facilitated by inclusion in medical compendia. For instance, Medicare contractors are required by Congress to pay for cancer drug prescriptions if their use is supported by selected standard medical compendia. Importantly, taxane-based therapy, including docetaxel, was itself included in standard medical compendia for treatment of CRPC prior to publication of phase III evidence. Reliance on compendia to facilitate treatment reimbursement represents an attempt to balance tradeoffs. On the one hand, the requirement that every variation in target population for a drug require a separate FDA indication would overwhelm available resources. On the other hand, reliance on compendia of potentially questionable quality may lead to inappropriate use. And, in fact, questions about the quality of the medical compendia have been raised. A recent review found that compendia "lack transparency, cite little current evidence, and lack systematic methods to review or update evidence". The evaluation of evidence for docetaxel in particular was found to be problematic. The questionable quality of medical compendia is astonishing in light of the role compendia play in determining reimbursement. The American Society of Clinical Oncology has stated that the "system for identifying medically appropriate cancer therapies, including those that involve off-label uses… requires attention".
One limitation in this study is the inability to identify the true denominator of patients who become castration resistant, a key eligibility criterion for receiving docetaxel. Identifying CRPC cases based on receipt of chemotherapy does not capture patients with CRPC who received no chemotherapy. Such patients may be too sick to receive chemotherapy. Thus, diffusion estimates for CRPC are likely biased high. In this context, performance status would be an informative descriptive factor, but it was not available. The necessity of using Medicare claims to identify relapse or recurrence is often problematic, but especially when treatment is itself the endpoint, because it raises the question of whether patients not identified as relapse/recurrent by Medicare claims (ie, HMO patients) may be different, limiting generalizability of the findings. Also, the use of Medicare data limits the analysis to patients age 65 years or older. However, prostate cancer occurs primarily in patients age 65 years or older (~70% of cases), and older patients may receive suboptimal care, representing a critical target population. Physician-level data were not available; therefore, the extent to which physicians were exposed to marketing efforts (which may have reinforced docetaxel uptake) was not identifiable in the data, nor were differences in diffusion according to facility type or degree of provider specialization. Finally, these results may not be generalizable to agents with different trial evidence profiles.
Currently, the FDA is reviewing whether to loosen constraints on the marketing of drugs prescribed off label. In contrast, our findings point to the potential risks of off-label use. By enabling the widespread diffusion of a new therapy prior to definitive phase III evidence, the off-label mechanism undermines the assumption that phase III comparative clinical trials necessarily determine which treatments become standard care. In this setting, inappropriate use is inevitable, with potential costs in increased morbidity and mortality if a different drug may have been more appropriate. Inappropriate use also places an unnecessary financial burden on health care payers. As declared by ASCO, medical compendia, which facilitate off-label reimbursement, require greater oversight, especially if they serve as the arbiters of reimbursement for Medicare, a federal program. Ultimately, greater levels of investment in clinical research are required to produce the highest levels of evidence—especially phase III trial evidence—for a given indication, in order to reduce the tendency for off-label use.
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